Chemotherapy--Antimetabolites -  

Antimetabolites comprise a broad and well-known group of drugs that inhibit key steps in the lifecycle of cells. They are used in the treatment of cancer in part because they appear to affect cancer cells more strongly than normal cells. When used correctly, they have the ability to kill cancer cells, which have a high rate of metabolism, while preserving normal cells.

Some of the most widely used antimetabolites in the treatment of colon cancer are the fluoropyrimidines. The most commonly used fluoropyrimidine in the treatment of colon cancer is 5-fluorouracil (5FU), which has been a mainstay of colon cancer treatment for many years. After intravenous administration, 5-fluorouracil is converted to several active metabolites. One of these, FdUMP, binds to the enzyme thymidylate synthetase, which is required for DNA synthesis, and inactivates it thereby halting cell growth. The investigational agent raltitrexed (Tomudex) also prevents cancer cells from growing by inhibiting  the enzyme thymidylate synthetase, and it is currently being evaluated in clinical trials.

A variety of compounds have been used together with 5-fluorouracil to enhance its therapeutic effect. One of these, leucovorin (folinic acid) is often used together with 5-fluorouracil in the treatment of colon cancer; in fact, the combination of 5-fluorouracil and leucovorin is now a standard therapy for this disease. Trimetrexate is another modulator of 5FU and is currently being investigated in clinical trials.

There has been additional interest in developing ways of administering 5-fluorouracil in an oral form. The challenge in developing these new compounds is that 5-fluorouracil is rapidly degraded into inactive metabolites when administered orally. A variety of approaches have therefore been taken to develop oral versions of 5-fluorouracil. These include administering 5-fluorouracil together with inhibitors of the enzyme dihydropyrimidine dehydrogenase, the main enzyme responsible for breaking down 5-FU. Another approach has been to develop compounds that can be easily absorbed and then broken down inside the body to 5FU and its active metabolites. A variety of oral 5FU analogs are now either commercially available or in clinical trials. These include Xeloda, Orzel, eniluracil, and others. These agents appear to differ somewhat from intravenous 5FU with regard to side effects. Their efficacy, however, is not expected to be significantly different from intravenously administered 5FU.

Drug Name:   FUDR

Synonyms:    floxuridine

Drug Class:

Chemotherapy--Antimetabolites 

Drug Approval Status:    Approved for some cancers

Description:

FUDR is an analog of 5-fluorouracil, one of the most commonly used drugs in the treatment of colorectal cancer. In clinical trials, FUDR has been used primarily in the directed treatment of liver metastases using hepatic arterial infusion. With this technique, chemotherapy can be directly infused into the liver.

Several clinical trials have evaluated the benefit of hepatic arterial infusion in patients with liver metastases from colorectal cancer. Several large clinical trials have demonstrated improved response rates when hepatic arterial infusion is compared to systemic chemotherapy with 5FU. None of these trials, however, demonstrated a survival benefit for hepatic arterial infusion. The use of FUDR as a component of hepatic arterial infusion therefore remains investigational in this setting.

Hepatic arterial infusion with FUDR has also been investigated as an adjuvant therapy following curative resection of liver metastases in patients with metastatic colorectal cancer. In a randomized trial performed by Kemeny et al (NEJM), patients undergoing surgery for liver metastases were randomized to receive either postoperative systemic chemotherapy alone or postoperative systemic chemotherapy with hepatic arterial infusion of FUDR. In this trial, hepatic disease free survival was prolonged in the patients receiving hepatic arterial infusion. However, overall survival was no different in the two groups. Hepatic arterial infusion with FUDR following resection of liver metastases therefore also remains an investigational approach.

Side Effects:

Side effects for FUDR include diarrhea, nausea/vomiting, mucositis, fever, and fatigue.

How Taken:

Intravenous infusion.

Pharmaceutical Companies:

Roche Pharmaceuticals, Boehringer Ingelheim, Bedford Labs

Drug Name:   Declopramide

Synonyms:    Oxi-104

Drug Class:

Chemotherapy--Antimetabolites  

Drug Approval Status:    Phase II

Description:

Declopramide is a DNA repair inhibitor that is thought to sensitize cancer cells to chemotherapy and radiotherapy treatment. It appears to exert its effect, at least in part, by inhibiting the nuclear transcription factor, NF-kappa-B.

According to the company that manufactures the drug, two phase I trials with declopramide have been completed. Both trials used declopramide in combination with standard chemotherapy. The trials demonstrated that declopramide could be administered safely with standard chemotherapeutic agents-either 5-FU or cisplatin. One response was noted in a patient with colon cancer; however, because declopramide was given in combination with a standard chemotherapy agent it is difficult to assess how much declopramide contributed to this effect. Phase II trials with declopramide are underway.

Side Effects:

Information is currently unavailable.  

How Taken:

Orally.

Pharmaceutical Companies:

OxiGene

Drug Name:   LY231514

Synonyms:    multitargeted antifolate, MTA

Drug Class:

Chemotherapy--Antimetabolites 

Drug Approval Status:    Phase I/II

Description:

LY231514, a multitargeted antifolate, is in clinical trials as a treatment for colon cancer.  Studies on colon cancer cells in the laboratory showed that LY231514 can increase the potency of another anticancer agent, gemcitabine. For this reason, LY231514 is in trials both alone, and in combination with gemcitabine.

In phase I clinical trials, the toxicity and maximum tolerated dose was assessed in patients with advanced cancer. Thirty-seven patients received one of nine different doses of LY231514. The maximum tolerated dose was determined to be 600 mg/m². Partial responses were noted in two patients with advanced colon cancer as well as two patients with advanced pancreatic cancer. A number of adverse effects were reported, including decreased white cell counts, and reversible kidney damage. From this study, the authors concluded that the dose for phase II trials should be 600 mg/m².

In a phase II clinical trial conducted in Canada, twenty-nine patients with advanced colon cancer received either 600 mg/m²  or 500 mg/m² infusions of LY231514 every 21 days. The overall response rate was 17.2%. The authors note a number of side effects including fever, nausea, diarrhea and skin rash. From this data, the authors concluded that LY231514 has modest activity against metastatic colon cancer.

Another phase II clinical trial examined the efficacy of LY231514 against colon cancer and rectal cancer. Thirty-nine patients were given 600 mg/m² infusions of LY231514 once every 21 days. The response rate was 15.2% and the mean time of survival was 16.2 months. Toxicities noted include decreased white cell count, anemia, and skin reactions. From this study the authors conclude that LY231514 has activity in patients with colorectal cancer.

Recently, the results of a phase I trial of LY231514 in combination with gemcitabine were reported. Patients with advanced solid tumors were given varying doses of gemcitabine in combination with LY231514. The first group of patients was treated with one to 14 courses of treatment consisting of gemcitabine on days one and eight, and LY231514 on day one. The maximum tolerated dose for this course of treatment was determined to be 1,000 mg/m² of gemcitabine and 500 mg/m² of LY231514. The second group was given one to ten courses of treatment consisting of gemcitabine on day one and eight, then LY231514 on day eight. The maximum tolerated dose for this course was determined to be 1,250 mg/m² of gemcitabine and 500 mg/m² of LY231514. The authors noted thirteen objective responses. Toxicities noted include low white cell count, nausea, fatigue, rash, and increased liver enzyme. From this data the authors conclude that the combination of gemcitabine and LY231514 is active against a number of tumors, and that the second dosing schedule is better tolerated.

Side Effects:

Side effects include decreased white cell count, increased susceptibility to infection, nausea, fatigue rash, elevated liver enzymes, reduced platelet count, anemia, fever, lethargy, decreased appetite, vomiting, mouth sores, abdominal pain, and reversible impairment of kidney function.

How Taken:

Intravenous infusion.

Pharmaceutical Companies:

Eli Lilly

Drug Name:   Raltitrexed

Synonyms:    Tomudex

Drug Class:

Chemotherapy--Antimetabolites  

Drug Approval Status:    Phase I

Description:

Based on encouraging results from laboratory studies showing synergism between raltitrexed (Tomudex) and 5-FU, studies are underway to test its clinical efficacy in colorectal cancer.  Raltitrexed specifically inhibits thymidylate synthase, an important enzyme involved in cellular replication, thereby killing cancer cells which have a high rate of cell division.   

In a phase I study of raltitrexed to treat advanced head and neck cancer and colorectal cancer, a dose escalation protocol helped determine tolerable levels of raltitrexed.  In this study, raltitrexed was administered in combination with levofolinic acid and fluoouracil (5-FU).  Fifty eight patients were enrolled in this study.  The authors report that the combination therapy was well tolerated and active in colorectal and head and neck cancers. 

Two other phase I studies have been conducted and the results were recently reported jointly.  In one of those studies, raltitrexed was combined with bolus 5-FU.  In the second study, 5-FU was intravenously infused in combination with raltitrexed.  Although these data are preliminary, they are encouraging.  In the first study (bolus 5-FU), the authors report significant disease stabilization in patients who had previously failed 5-FU therapy.  In the second study (infused 5-FU), the authors report that 53% of participants responded to treatment.       

Additionally phase I studies are being conducted to test the combination of raltitrexed with platinum based agents such as oxaliplatin and/or anthracyclines.  In a study of raltitrexed and oxaliplatin, 48 patients with advanced solid tumors were enrolled including 17 with mesothioloma and 11 with colorectal cancer.  Of the 45 patients evaluable for efficacy, 10 (22%) showed a partial response and 18 (40%) had stable disease.  In the colorectal cancer group, six out of ten evalubale patients with heavily treated colorectal cancer had stable disease which was associated with an improvement in disease-related symptoms in some cases. 

More studies are being conducted to corroborate these study results.   

Side Effects:

Raltitrexed was well tolerated in preliminary studies.  Some patients did experience lowered blood cell counts, nausea, and diarrhea.  

How Taken:

This drug is given via intravenous (IV) injection.

Pharmaceutical Companies:

BTG, AstraZeneca

Drug Name:   TS-1

Synonyms:

Drug Class:

Chemotherapy--Antimetabolites  

Drug Approval Status:    Phase II

Description:

S-1 is a novel oral antitumor drug combination based on the fluorouracil thymidylate synthetase inhibitor. S-1 contains  three main components: a precursor of the active ingredient fluorouracil (5-FU), a substance to prevent fluorouracil degradation, and potassium oxonate (Oxo) to reduce gastrointestinal toxicity. Recent results suggest that oral S-1 administration is comparable in efficacy to infusions of 5-fluorouracil (5-FU), without the disadvantages of continuous intravenous administration.

Phase I and early phase II clinical trials with oral administration of S-1 have been completed. A dose of 80 mg/m2/day, given twice a day, after breakfast and supper in a 28-day consecutive oral regimen was found to be most effective. In a recent study, twelve patients (5 with gastric cancer, 4 with colorectal cancer, and 3 with breast cancer) were treated for 28-days consecutively with two divided doses per day. No fluctuations in pharmacokinetics or any drug accumulation were observed. Because the profile of orally administered S-1 was almost similar to that of continuous intravenous infusion of 5-FU, the authors suggest that oral S-1 may improve patients' quality of life.

Side Effects:

Information is not currently available. 

How Taken:

This drug is taken orally twice a day.

Pharmaceutical Companies:

Taiho, Bristol-Myers Squibb

Drug Name:   Tegafur + Uracil + Leucovorin

Synonyms:    Orzel

Drug Class:

Chemotherapy--Antimetabolites 

Drug Approval Status:    Phase III

Description:

The oral anticancer agent Orzel, which contains uracil and tegafur (UFT) plus calcium folinate, was recently reported to have an activity comparable to intravenously administered 5-fluorouracil (5-FU) in the treatment of colorectal cancer. UFT contains both a precursor of the active fluorouracil and an inhibitor of its degradation which results in sustained higher blood and tumor levels of fluorouracil. Oral administration of fluorouracil preparations is preferable to the inconveniences and complications of intravenous infusions.

Several phase I and II trials have evaluated the maximum tolerated dose, pharmacokinetics, efficacy, and safety of Orzel in the treatment of colorectal cancer. Results have shown that tegafur/uracil at 300 mg/m2/day in divided doses given every 8 hours for 28 days provides prolonged exposure to fluorouracil. Compared with intravenous fluorouracil plus folinic acid (leucovorin) regimens, tegafur/uracil + calcium folinate has similar efficacy with less toxicity and fewer complications. 

The National Surgical Adjuvant Breast and Bowel Project Protocol C-06 performed a randomized comparison of the relative efficacies of 5-FU/calcium folinate vs UFT plus oral calcium folinate. Preliminary analysis of toxicity findings among 473 evaluable patients indicates that both regimens are well tolerated and have similar toxicity profiles. 

Another study showed that the efficacy in the adjuvant therapy of rectal cancer of protracted infusions of 5-fluorouracil (5-FU) combined with pelvic radiotherapy can be matched by a completely oral program combining Orzel with pelvic radiation therapy.An open-label, disease-oriented, phase I randomized controlled trial of Orzel in combination with simultaneous pelvic radiation for recurrent rectal cancer was conducted to determine the maximum tolerated dose and dose-limiting toxicity of this regimen. 

A multicenter phase I trial combining Orzel with irinotecan (CPT-11, Camptosar) for the treatment of patients with advanced or metastatic colorectal cancer will open shortly to determine the side-effect profile, dose-limiting toxicities, and the maximum tolerated dose of this combination. This study will involve a cohort of six patients who will receive irinotecan 200 mg/m2 by intravenous infusion over 90 minutes on day 1 while on days 1 to 14, patients will receive UFT 250 mg/m2/d and calcium folinate 90 mg/d, both divided into three equal doses. This will be followed by a 1-week rest period with treatment for the next cycle resumed on day 22. In subsequent cohorts of six patients, UFT and irinotecan will in turn be escalated provided toxicity is acceptable. 

Another trial is being set up to evaluate whether the combination of Orzel with oxaliplatin is as effective in colorectal cancer as the combination of 5-fluorouracil and oxaliplatin.

Side Effects:

Preliminary reports indicate that this drug is well tolerated.

How Taken:

This drug is taken orally, three times a day.

Pharmaceutical Companies:

Taiho, Bristol-Myers Squibb

Drug Name:   Trimetrexate

Synonyms:    Neutrexin

Drug Class:

Chemotherapy--Antimetabolites 

Drug Approval Status:    Phase III

Description:

Trimetrexate (TMTX) is a folate analogue being tested in combination with 5-fluourouracil (5-FU) and leucovorin (LV) for treatment of colorectal cancer. TMTX was originally investigated as an antimalarial agent and is FDA approved to treat Pneumocystis carinii pneumonia. A number of preclinical and clinical studies suggest that TMTX may be a potent modulator of 5-FU. TMTX exerts its therapeutic efficacy by enhancing the ability of 5-FU to inhibit the enzyme thymidylate synthase. Since thymidylate synthase is an important regulator of cellular replication, the overall effect of TMTX is to enhance 5-FU based therapy. One of the advantages of TMTX over other antifolates is that TMTX does not interfere with the uptake of LV, thus allowing the substances to be used together effectively.

Early preclinical data suggested that TMTX had activity against colon cancer cell lines. These studies suggested that TMTX had a synergistic effect with 5-FU when TMTX was administered with or before 5-FU. This observation has been corroborated in several other laboratory studies and has been subsequently shown to have clinical relevance in determining dose schedules. Other preclinical studies have shown that TMTX does not compete with LV for cellular uptake and that the addition of TMTX to current treatment regimens might complement the effect of 5-FU/LV. These latter studies led directly to clinical trials testing the efficacy of TMTX in combination with 5-FU/LV to treat colorectal cancer. 

TMTX has been administered 24 hours prior to administration of 5-FU/LV in 41 patients with advanced gastrointestinal malignancies (mostly colorectal) in an open-label phase II trial. The partial response rate in this study was 20% in evaluable patients (7 of 35), with six of seven responders having received previous 5-FU-based therapy. Median time to progression was 6.3 months and median survival was 14months. A follow-up study of TMTX with 5-FU/LV was conducted in thirty-six patients with unresectable or metastatic colorectal cancer who had not been treated for advanced disease. Two patients (7%) achieved a complete response and 13 (43%) a partial response, for an overall response (OR) rate of 50% (95% confidence interval [CI]). Median survival time for the entire cohort from this study was 53.4 weeks. 

Early results from a European randomized phase III trial were recently reported at the Chemotherapy Foundation Symposium XVII (January, 2000). In 222 patients (mean follow-up of 17 months), the overall response rate of patients treated with 5FU/LV/TMTX was 29% vs. 26% in the control arm (5-FU/LV). Overall survival time was 13 months in TMTX-treated group vs. 10 months in control. Neither of these differences was statistically significant at the time of data analysis. Final results from this study are expected next year.

Side Effects:

Side effects include nausea, diarrhea, and in some instances, severe allergic reactions. Of note, toxicity to blood cells was a relatively minor occurrence in most patients. 

How Taken:

This drug is given via intravenous (IV) infusion.

Pharmaceutical Companies:

Pfizer

Drug Name:   ZD-9331

Synonyms:

Drug Class:

Chemotherapy--Antimetabolites 

Drug Approval Status:    Phase III

Description:

ZD-9331 is a thymidylate synthase inhibitor that blocks the growth and replication of cancer cells by interfering with DNA synthesis. ZD-9331 has been shown to be active against cancer cells that are resistant to a closely related investigational drug, ZD-1694.

In a study designed to assess the safety of ZD-9331, 43 cancer patients (24 with colorectal cancer and 5 with ovarian cancer) took ZD-9331 over a 4-week period. Most patients tolerated ZD-9331 well, although nausea and diarrhea were commonly observed side effects. Higher doses of ZD-9331 were associated with bone marrow suppression. At the doses studied, disease stabilization was noted in 10 patients with colorectal or ovarian cancer.

Side Effects:

Common side effects include nausea, diarrhea, and liver dysfunction. 

How Taken:

ZD-9331 can be taken orally or by intravenous infusion.

Pharmaceutical Companies:

BTG, AstraZeneca

Chemotherapy--Farnesyl Transferase Inhibitors

Farnesyl transferase inhibitors comprise a group of novel anticancer agents that share the ability to inhibit the product of a gene called “ras,” that can contribute to the development of cancer.  Mutations in the ras gene occur in many different types of cancer, including a majority of colon cancers. These mutations often result in increased synthesis of the ras protein. High levels of the ras protein lead to uncontrolled cell growth and cancer. Farnesyl transferase inhibitors are designed to block one of the key biochemical steps required for the ras protein to function. It is thought that by blocking this step and inhibiting the function of the ras protein, cancer cells may lose the ability to grow. Farnesyl transferase inhibitors thus appear to be a promising new class of anticancer compounds. Most farnesyl transferase inhibitors are in early clinical development, and their efficacy and safety is still being determined.

Drug Name:   CP-609754

Synonyms:

Drug Class:

Chemotherapy--Farnesyl Transferase Inhibitors

Drug Approval Status:    Phase I Clinical Trial

Description:

One of several new agents that inhibit farnesyl transferase, CP-609754 has shown promise in animal models and is currently being tested for safety in humans. It is too early to tell if it will be active against colon cancer.

Side Effects:

Information is currently unavailable.

How Taken:

Orally.

Pharmaceutical Companies:

OSI Pharmaceuticals, Pfizer

Drug Name:   L-778123

Synonyms:    ras inhibitors

Drug Class:

Chemotherapy--Farnesyl Transferase Inhibitors

Drug Approval Status:    Phase I Clinical Trial

Description:

L778123 is one of several new drugs that inhibit farnesyl transferase and thus inhibit the product of the ras oncogene. L778123 has been tested in phase I trials, and phase II trials in colon cancer have been completed. Data regarding the efficacy of L778123 in colon cancer are awaited.

Side Effects:

Information is currently unavailable.  

How Taken:

Intravenous infusion

Pharmaceutical Companies:

Merck & Co

Drug Name:   R115777

Synonyms:

Drug Class:

Chemotherapy--Farnesyl Transferase Inhibitors

Drug Approval Status:    Phase I

Description:

R115777 is an investigational drug currently being studied as a treatment for advanced colon cancer.  R115777 is an inhibitor of the enzyme farnesyl transferase, which is believed to be involved in cancer development.

A phase I clinical trial was performed to assess the safety of R115777.  Twenty-seven patients were treated with R115777 for 5 days followed by 9 days of rest.  Side effects were associated with the highest dose of R115777 studied.  One patient with metastatic colon cancer exhibited improved cough and clinical signs of disease improvement, which remained stable for 5 months.  Further studies of R115777 taken alone, or in combination with chemotherapy, are required to assess the drug’s efficacy.

Side Effects:

The most severe side effects include nausea, vomiting, headache, fatigue, anemia, and low blood pressure.

How Taken:

R115777 is taken orally as a liquid or as a capsule. 

Pharmaceutical Companies:

Janssen Pharmaceuticals

Drug Name:   SCH 6636

Synonyms:

Drug Class:

Chemotherapy--Farnesyl Transferase Inhibitors

Drug Approval Status:    Phase II

Description:

SCH 66336 is an investigational drug currently being studied as a treatment for advanced colon cancer.  SCH 66336 is an inhibitor of the enzyme farnesyl transferase, which is believed to be involved in cancer development.

Preclinical studies of SCH 66336 performed in laboratory mice indicate that the drug is effective against a variety of human tumors.  SCH 66336 was effective against human tumors from colon, lung, pancreas, prostate, and urinary bladder that were transplanted into genetically engineered mice.  SCH 66336 was even more effective when animals were simultaneously treated with standard chemotherapy agents (cyclophosphamide, 5-fluorouracil, or vincristine).  In another strain of laboratory mice, prophylactic treatment with SCH 66336 delayed the onset of tumor formation, reduced the average number of tumors per animal, and reduced the average tumor weight.  

Another preclinical study was performed to determine the efficacy of SCH 66336 on laboratory-grown tumor cell lines.  Simultaneous treatment of tumor cell lines with SCH 66336 and the antitumor agent paclitaxel (Taxol) was more effective than treatment with either drug alone.

A phase I clinical trial of SCH 66336 was performed in 20 patients with solid tumors to assess the maximum tolerable dosage of the drug.  Patients were treated twice daily for 7 days out of every 3 weeks.  Side effects (gastrointestinal toxicity and fatigue) were associated with the highest levels of SCH 66336 studied.  Laboratory tests from this trial indicate that SCH 66336 is biologically active in the human body and is able to inhibit farnesyl transferase.  Further studies are required to determine if SCH 66336 is biologically active against human tumors.

Side Effects:

Side effects include nausea, vomiting, diarrhea, and fatigue.  

How Taken:

Orally.  

Pharmaceutical Companies:

Schering Plough

Chemotherapy--Platinum Analogs

Platinum analogs knot up a cancer cell’s DNA strands, which results in two different anti-cancer effects. First, knotting prevents the DNA from being properly copied.  Cells that attempt to reproduce themselves but fail to copy their DNA will eventually die.  Second, written along the DNA strands are the instructions to make molecules that a cell needs to survive. When the strands are knotted up, the instructions cannot be read, the molecules cannot be made, and the cell dies.  Oxaliplatin is a platinum analog with demonstrated effectiveness in treating colorecral cancers. 

Oxaliplatin fights cancer when administered alone. 20- 25% of previously untreated patients respond to oxaliplatin.  In addition, 10% of patients who have already failed to respond to 5-FU respond to oxaliplatin.

Oxaliplatin also fights cancer in combination with other drugs. Several small studies have evaluated oxaliplatin combined with 5-FU /leucovorin. Each study involved >50 patients with colorectal cancers that had spread to other parts of their bodies.  The patients had already undergone treatment with other anti-cancer drugs, making them less likely to respond to additional drug treatments, but they still enjoyed response rates of 20-58%. One study, involving 200 patients who had not previously been treated with drugs, tested oxaliplatin plus 5-FU/leucovorin versus 5-FU/leucovorin alone. 53% of patients responded to oxaliplatin plus 5-FU/leucovorin while only 12% responded to 5-FU/leucovorin without oxaliplatin. However, there was no difference in overall survival between these two groups.

While some platinum-based drugs cause kidney damage, nausea, and vomiting, these are not major side effects of oxaliplatin. 5-10% of patients taking oxaliplatin experience vomiting but this can usually be treated with the proper medications. Reduced blood cell production occurs in about 5% of patients.  The most common side effect of oxaliplatin, and the one that limits the amount of the drug that can be taken, is malfunctioning of the nervous system. This may be experienced as abnormal sensations and/or muscular weakness and occurs in up to 15% of patients. Rarely, unusual sensations in the throat can occur that are often triggered by exposure to cold food and beverages.  These symptoms are easily remedied by avoiding the causative agents.   

Drug Name:   Oxaliplatin

Synonyms:    Eloxatin, Eloxatine

Drug Class:

Chemotherapy--Platinum Analogs

Drug Approval Status:    Phase III

Description:

Numerous studies have been conducted to evaluate the efficacy of oxaliplatin in combination with other drugs in the treatment of colorectal cancer.  

Several early studies evaluated the effect of oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin.  Using various dosing regimens these studies concluded that patients resistant to leucovorin and 5-FU alone who underwent oxaliplatin treatment in combination with bimonthly leucovorin and 5-FU showed signs of improvement.    

In a Europe-wide study of several hundred patients with advanced colorectal cancer, trial participants were administered either oxaliplatin alone but at varying doses or oxaliplatin in combination with 5-FU and folinic acid.  Results from this trial suggest that oxaliplatin is effective in treating advanced colorectal cancer patients who were unresponsive to 5-FU. 

A phase II trial of oxaliplatin was conducted on 32 patients with metastatic colorectal cancer who had relapsed after or during chemotherapy with 5-FU and folinic acid and/ or irinotecan.  In this study, treatment consisted of oxaliplatin 50 mg/m2 by two-hour intravenous (i.v.) infusion followed by folinic acid 500 mg/m2 (two-hour i.v. infusion) and 5-FU 2,500 mg/m2 (24-hour continuous i.v. infusion) on days 1, 8, 15, 22, 29, 36. The regimen was repeated every 50 days.  The authors report that the objective response rate was 13% and all responses were partial.  Administration of oxaliplatin according to this treatment schedule was less toxic than other reported treatment regimens, although the incidence of severe diarrhea was high (>50%). 

Recently oxaliplatin was assessed for its ability as a first line treatment for metastatic colorectal cancer.  Two hundred patients were randomly assigned to receive a 5 day course of 5-FU and leucovorin with or without oxaliplatin on the first day of each course.  Each course was repeated every 21 days.  The authors report that 53% of patients treated with oxaliplatin had objective responses compared to 16% of partiens without.  They conclude that oxaliplatin significantly improved treatment success in their protocol.      

Side Effects:

Side effects include severe diarrhea and nerve problems.

How Taken:

This drug is given via intravenous (IV) injection.

Pharmaceutical Companies:

Debiopharm, Sanofi-Synthelabo, Dr Reddy's, Eli Lilly

Chemotherapy--Topoisomerase Inhibitors

One trait that distinguishes a cancer cell from a normal cell is the cancer cell’s tendency to reproduce itself rapidly. Before cancer cells can reproduce, however, each cell must make an exact copy of its DNA. One of the enzymes critical for this process is called topoisomerase I. When a cell tries to copy its DNA without topoisomerase I, the long strands of DNA are broken. A cell with such damaged DNA eventually dies.  Colorectal cancer cells have higher than normal amounts of topoisomerase I indicating that this enzyme is particularly important for their survival.  A class of drugs called topoisomerase inhibitors has been developed that kills cancer cells by blocking the action of topoisomerase I. 

Irinotecan (CPT-11, Camptosar) is a topoisomerase inhibitor.  Early studies have shown overall response rates of 20-32% when irinotecan is used as the initial treatment for colorectal cancer, and of 15-20% when irinotecan is used to treat patients who have already failed to respond to 5-FU. In a larger, more advanced study of 5-FU non-responsive patients, treatments aimed at eliminating or reducing symptoms and complications were more effective at increasing survival when combined with irinotecan than when given without it. Thus, irinotecan has an accepted role in treating patients who show no response to 5-FU.

Two large recent studies compared patients treated with irinotecan plus 5-FU/leucovorin to those treated with 5-FU/leucovorin or irinotecan alone.  Both studies showed response rates of 39-41% to the combined drugs and lower response rates, 20-23%, to either of the drugs used singly. Recent updates of these studies report that treatment with the combined drugs leads to an improvement in overall survival. Because of these results, it has been suggested that irinotecan plus 5-FU/leucovorin should be the initial treatment for patients with colorectal cancer that has spread to other sites in their bodies. In addition, physicians are studying the possible usefulness of these drugs after the surgical treatment of earlier stages of colorectal cancer.

The most common side effects of irinotecan are diarrhea and reduced production of a particular type of white blood cell involved in the immune system.  Depending on the drug dose and schedule of administration, 15-50% of patients experience each of these effects. The diarrhea can be severe. In some cases diarrhea occurs during or shortly after administration of the drug and is associated with cramping, vomiting, and flushing. Alternatively, the diarrhea may occur 12 or more hours after treatment. This delayed form of diarrhea becomes more common after several doses of the drug have been taken.  In both cases, the diarrhea can be relieved with the appropriate anti-diarrhea drugs. Antibiotics are given if symptoms persist or a fever develops. Other, much less frequent, side effects include irritation of the lining of the mouth and other body cavities, fatigue, abnormal liver function, nausea, and vomiting.

Drug Name:   9-aminocamptothecin

Synonyms:    9-AC

Drug Class:

Chemotherapy--Topoisomerase Inhibitors

Drug Approval Status:    Phase I

Description:

9-aminocamptothecin is a water-insoluble derivative of the antitumor drug camptothecin.  Camptothecin is a strong inhibitor of topoisomerase I, an enzyme required for the replication of DNA in actively dividing cells.  Preclinical studies indicated that 9-aminocamptothecin is highly toxic to a variety of different tumor cell types.  9-aminocamptothecin has been evaluated in several small clinical studies involving patients with metastatic colorectal cancer.

In one study, seventeen patients with previously untreated metastatic colorectal cancer were treated with 9-aminocamptothecin given as a 72-hour continuous intravenous infusion (35 mcg/m2/h) followed by 11 days of rest (28 days total). Treatment with 9-aminocamptothecin was well tolerated by most patients, but did not result in any objective responses.

In a second trial, seventeen patients with previously untreated metastatic colorectal cancer were given a continuous intravenous infusion of 9-aminocamptothecin (480 mcg/m2/d) for 5 days.  Treatments were given weekly for 3 weeks.  No objective responses were observed in any of the 17 patients.

In a third clinical trial involving patients with colorectal carcinoma, 9-aminocamptothecin was administered to patients whose tumors were resistant to previous treatment with the antitumor drug 5-fluorouracil. In this study, 14 patients were treated with a continuous intravenous infusion of 9-aminocamptothecin (59 mcg/m2/h) for 72 hours, with treatments repeated every 14 days.  Patients were given granulocyte-colony stimulating factor on days 5-12 following each 9-aminocamptothecin treatment to prevent bone marrow suppression.  Although 8 patients experienced stable disease for a median of 4.1 months during treatment, no objective responses were observed in any of the patients.  

These trials, although small, suggest that 9-aminocamptothecin has minimal activity in colorectal cancer when given as a single agent. Trials of 9-aminocamptothecin in combination with other agents have not yet been completed in patients with colorectal cancer.

Side Effects:

Side effects include bone marrow toxicity, nausea, vomiting, diarrhea, and fatigue.  

How Taken:

Intravenous infusion.  

Pharmaceutical Companies:

Pharmacia & Upjohn, IDEC

Drug Name:   Intoplicine

Synonyms:    RP 60475

Drug Class:

Chemotherapy--Topoisomerase Inhibitors

Drug Approval Status:    Phase I

Description:

Intoplicine is an antitumor drug that interacts with both topoisomerase I and II and has demonstrated a broad spectrum of activity in preclinical studies with an acceptable toxicity profile.  Topoisomerase I and II are enzymes critical to the unwinding of DNA during cell division.  Blocking these enzymes can prevent cells from dividing. 

In a phase I dose-escalation study of intoplicine, twenty-eight patients with refractory advanced malignancies received doses ranging from 7 to 420 mg/m2/day administered as a continuous 72 hour i.v. infusion. Fifty-three courses were given. No objective antitumor responses were observed. Intoplicine in whole blood exceeded that found in plasma by 3- to 7-fold, indicating that red blood cells may be a drug reservoir. Preclinical cytotoxic concentrations were not achieved at the dose levels studied. 

In a phase I study to determine the maximum tolerated dose, thirty-two patients with solid malignant tumors received intoplicine by a 24 hour continuous infusion of 12-640 mg/m2 every 21 days. The recommended dose for phase II studies with intoplicine administered as a 24 hour infusion is 384 mg/m2. 

In a phase I study to evaluate pharmacodynamics of intoplicine involving thirty-three patients, sixty-nine courses of intoplicine were administered as a 1 hour i.v. infusion at dose levels ranging from 12 to 360 mg/m2. The phase II recommended dose is 270 mg/m2 every 3 weeks with close monitoring of hepatic and cardiac functions. Blood pharmacokinetics was evaluated in eighteen patients since it was found that red blood cells represented a significant drug reservoir for intoplicine. Plasma and blood pharmacokinetics were linear within the dose range studied. Potentially cytotoxic concentrations were reached at clinically achievable doses.

Side Effects:

Side effects include liver toxicity and suppression of the bone marrow's production of blood cells and platelets.

How Taken:

This drug is given via intravenous (IV) injection.

Pharmaceutical Companies:

ILEX Oncology

Gene Therapy

Gene therapy is a broad term that refers to the manipulation of DNA for the treatment of diseases. Gene therapy remains highly experimental in the treatment of colon cancer. One approach that has been tried in colon cancer is to genetically modify blood cells to make them better able to attack colon cancer cells in the body. Other investigators have attempted to genetically modify viruses so that they attack only colon cancer cells and not normal, healthy cells. The concept of gene therapy is attractive in that it holds the promise of specifically targeting only cancer cells without great toxicity to the rest of the body. However, these approaches remain in very early stages of development.

Drug Name:   CC49-zeta gene therapy

Synonyms:

Drug Class:

Gene Therapy

Drug Approval Status:    Phase II

Description:

CC49-zeta is a recombinant gene therapy agent that combines a humanized antibody with a fragment of the human T-cell receptor. This synthetic receptor specifically recognizes an antigen found on the surface of most human adenocarcinomas, making it a potential cancer therapy that utilizes the patient's own immune system to kill cancer cells.

Preliminary studies indicate that human T-cells that have been treated with CC49-zeta can kill laboratory-grown tumor cell lines and primary adenocarcinoma tumors isolated from cancer patients. CC49-zeta-treated T-cells did not kill neighboring cells that did not have the adenocarcinoma surface antigen, indicating that cell killing was specific for the tumor cells. Animal studies indicate that mice transplanted with human tumor cells were protected if they were injected with CC49-zeta-treated human T-cells, suggesting that the CC49-zeta treated human T-cells specifically killed the human tumor cells. These preliminary results suggest that CC49-zeta gene therapy may be effective cancer treatment in humans.

Side Effects:

Information is not currently available.

How Taken:

CC49-zeta is a gene therapy approach to cancer treatment.

Pharmaceutical Companies:

Cell Genesys

Drug Name:   IL-2 gene therapy

Synonyms:

Drug Class:

Gene Therapy 

Drug Approval Status:    Phase I

Description:

Interleukin-2 (IL-2) is a chemical messenger normally produced by T cells and natural killer cells that activates the immune system by inducing proliferation of T cells, B cells, and monocytes. Treatment with IL-2 has been shown to have a moderate anti-cancer effect in several mouse models of cancer, as well as in Phase I clinical trials.

Expression of IL-2 through retroviral transduction either in injected tumor cells or fibroblasts leads to reduced tumor growth and an enhanced anti-tumor immune reaction in mice. Gene therapy treatment of colorectal cancer patients with a fixed dose of tumor cells (10^7 cells) and fibroblasts secreting IL-2 at escalating doses demonstrated a 5-fold increase in tumor-specific cytotoxic T-cell precursors in two of six evaluable patients. 

In a study of ten cancer patients treated with natural killer-like T cells expressing IL-2 in the range of 330-1800 pg per 10^6 cells per day, six patients remained in progressive disease, three patients showed no change by treatment, and one patient had a complete response.

Side Effects:

IL-2 treatment is well tolerated with no serious side-effects, although fatigue and/or flu-like symptoms were experienced by the majority of patients. 

How Taken:

This therapy is accomplished via intravenous infusions with IL-2 secreting cells.

Pharmaceutical Companies:

Immune Response

Monoclonal Antibodies

The use of monoclonal antibodies to treat cancer has been a relatively recent and exciting development. Monoclonal antibodies are specifically designed biological molecules that can be tailored to recognize and bind to different targets in the body. In recent years, new biotechnology techniques have allowed for the development of antibodies that can be specifically targeted against cancer cells. One of the first effective monoclonal antibodies to be developed and to become widely used was Rituximab, which specifically targets lymphoma cells. A second monoclonal antibody, Herceptin, is able to target breast cancer cells that express the Her-2 receptor, and has been demonstrated to improve response rates and overall survival in breast cancer patients. Monoclonal antibodies in the treatment of colon cancer remain investigational. While the technology to develop effective monoclonal antibodies now exists, it is less clear how to specifically target colon cancer cells with these antibodies. Several monoclonal antibodies are now being investigated in colon cancer. These include a variety of antibodies that  inhibit molecules thought to play a key role in colon cancer growth (i.e. Vascular Endothelial Growth Factor, Epidermal Growth Factor Receptor, etc). The efficacy and safety of these antibodies is currently being determined in clinical trials.

Drug Name:   Anti-VEGF Monoclonal Antibody

Synonyms:    Bevacizumab

Drug Class:

Monoclonal Antibodies

Drug Approval Status:    Phase II

Description:

Vascular endothelial growth factor (VEGF) is a potent stimulator of new blood vessel growth. Since rapid growth of new blood vessels fuels the uncontrolled expansion of cancerous tissue, blocking new blood vessel growth using antibodies to VEGF has potential to be a potent cancer therapy. Furthermore, inhibiting blood vessel growth also holds promise for controlling metastasis.

In a preclinical study, cells from human malignancies were transplanted into immunodeficient mice. Mice bearing vascularized tumors were treated with either anti-VEGF antibody or plain saline. Anti-VEGF antibody treatment reduced permeability to macromolecules in tumors and additionally reduced tumor blood vessel diameters. This mechanism may lead ultimately to tumor regression. 

Other preclinical studies confirm these results in mice. Four different human carcinomas (gastric and colonic) were transplanted into immunodeficient mice and anti-VEGF was administered. Treatment with anti-VEGF significantly inhibited primary tumor growth and also prevented liver metastasis. 

Another study using nude mice transplanted with a human cancer cell line also showed that anti-VEGF treatment was an effective anti-tumor agent. In this study, anti-VEGF was able to prevent metastasis of cancer cells from the portal vein into the liver and pancreas of test subjects. 

Recently, a clinical study of recombinant human monoclonal antibody-VEGF (rhuMAb-VEGF) was conducted in patients with metastatic colorectal cancer. 104 patients were randomized to receive either 5-FU/leucovorin (n=36), 5-FU/leucorvin/low dose rhuMAb-VEGF (n=35), or 5-FU/leucovorin/high dose rhuMAb-VEGF (n=33). The efficacy criteria were response rate and time to disease progression  as reported by investigators and confirmed by a blinded independent review. Preliminary data suggest that patients treated with both low and high dose rhuMAb-VEGF in combination with 5-FU/leucovorin fared better than patients receiving 5-FU/leucovorin alone.

Side Effects:

A preliminary trial reports that rhu-Mab VEGF was well tolerated.  There is little other information available at this time concerning adverse events associated with rhu-Mab VEGF. 

How Taken:

This drug is given via intravenous (IV) infusion.

Pharmaceutical Companies:

Genentech

Drug Name:   CEA-Cide

Synonyms:    anti-CEA antibody

Drug Class:

Monoclonal Antibodies

Drug Approval Status:    Phase II

Description:

hMN-14 is a humanized version of a high affinity mouse antibody directed against carcinoembryonic antigen (CEA), an antigen produced by a subset of human tumors. In a phase I clinical study, twelve colorectal cancer patients with small volume disease metastatic to the liver were injected with 131I-labeled hMN-14. At the maximum tolerated dose of 60 mCi/m2, 18% of patients had partial remissions, and 45% had minor/mixed responses or experienced stabilization of previously rapidly progressing disease.

While 131I is most easily conjugated to hMN-14, other potential radioisotopes with longer blood circulation half-lives, such as 32P, are also being investigated for their therapeutic potential. 

Side Effects:

Reports indicate that treatment is well tolerated with no serious side-effects.

How Taken:

This drug is given via intravenous (IV) injection.

Pharmaceutical Companies:

Immunomedics

Drug Name:   CeaVac

Synonyms:    MAb 3H1

Drug Class:

Monoclonal Antibodies

Drug Approval Status:    Phase II

Description:

Patients with colorectal cancer have specific antibody responses to the carcinoembryonic antigen (CEA). CeaVac is a vaccine therapy under development that stimulates the immune system of cancer patients to attack and destroy cancerous cells.

In a clinical trial, the effectiveness of CeaVac was compared to conventional 5-FU therapy and to surgical resection of cancerous colon. Thirty-two patients at various stages of colon cancer (Dukes B, C, and D) who had undergone surgical resection of their cancer were enrolled in this study. All patients received CeaVac and 14 patients were treated additionally with 5-FU. At the conclusion of the trial, all patients were found to have immune responses (both humoral and cellular) against CEA. Furthermore, the authors found that 5-FU treatment did not interfere with CeaVac's ability to elicit an immune response.

Side Effects:

Information is not currently available. 

How Taken:

This agent is given via intravenous (IV) injection.

Pharmaceutical Companies:

Titan Pharmaceuticals

Drug Name:   F19

Synonyms:

Drug Class:

Monoclonal Antibodies

Drug Approval Status:    Phase I

Description:

F19, a monoclonal antibody labeled with radioactive iodine, is currently under investigation as a therapy for colon cancer. F19 is used in radioimmunotherapy, which treats cancer by delivering radiation directly to the tumor. The radioactivity is linked to an antibody that specifically seeks out and binds to the tumor cell. In the case of F19, the antibody binds to a component of colorectal tumors called fibroblast activation protein (FAP). Normal cells contain much lower levels of FAP, so the F19 antibody and the radiation it carries affect healthy tissue less than the tumor cells. Over 95% of colorectal tumors, do contain FAP, and thus the therapy specifically targets these cells.

In a phase I clinical trial, 17 patients with colorectal cancer that had metastasized to the liver were given F19, and its safety and ability to target tumor cells was assessed. Patients were given F19 seven to eight days prior to either the surgical removal of the liver metastases, or surgery to implant a catheter for regional chemotherapy.  Tumors were removed from 15 of the 17 patients, and then examined to locate where F19 had accumulated.  As expected, the radioactively labeled F19 was found only in the tumor cells, and not in the normal liver cells. In addition, no toxicities were observed in patients who received F19. From this study the authors concluded that radioactively labeled F19 can be used to image colorectal tumors, and that F19 may be used as either a diagnostic agent or a therapy for tumors that express FAP.

Side Effects:

Information is currently unavailable.

How Taken:

Intravenous injection.

Drug Name:   Herceptin

Synonyms:    Trastuzumab

Drug Class:

Monoclonal Antibodies

Drug Approval Status:    Approved for breast cancer, in trials for colon cancer

Description:

Herceptin is a monoclonal antibody to the HER-2 receptor. HER-2 is a human epidermal growth factor receptor that is overexpressed in a variety of human malignancies. Herceptin has been best studied in the treatment of  patients with breast cancer. In a randomized trial of patients with HER-2 positive breast cancer, patients treated with Herceptin after completing chemotherapy had a longer time to tumor progression than did patients who received no other therapy. Based on the results of this and other encouraging trials, Herceptin is now commonly used in patients with HER-2 positive breast cancer. Herceptin is generally well tolerated, with only mild side effects.

It is estimated that 15-30% of colorectal cancers overexpress the HER-2 receptor. Whether Herceptin has activity against colon cancer, however, remains unknown. Given the demonstrated activity of Herceptin in patients with HER-2 overexpressing breast cancer, trials with Herceptin in patients with HER-2 overexpressing colon cancer are currently underway.

Side Effects:

Herceptin is generally well tolerated, with mild side effects.

How Taken:

Intravenous infusion.

Pharmaceutical Companies:

Genentech, Hoffman LaRoche

Drug Name:   MN-14

Synonyms:    anti-CEA immunoradiotherapy

Drug Class:

Monoclonal Antibodies

Drug Approval Status:    Phase I

Description:

MN-14 is a monoclonal antibody that is being investigated as a possible therapy for colon cancer. MN-14 is used as a radioimmunotherapy, in which an antibody is used to deliver radiation specifically to a tumor cell. The monoclonal antibody MN-14 recognizes and binds to the carcinoembryonic antigen (CEA), a protein found in cancer cells but not in normal cells. Therapies using MN-14 labeled with either radioactive isotopes of either iodine (I), or rhenium (Re) have been investigated.

A recent report from Germany detailed pre-clinical study of MN-14. In this study, tumors were induced in mice by injecting human colon cancer cells. At either 10 or 20 days post-injection the mice were given one of four treatments: a ¹³¹I-labeled MN-14, an ¹³¹I-labeled low affinity antibody to CEA, chemotherapy with 5-flurouracil and leucovorin, or chemotherapy with irinotecan. In mice with ten-day-old tumors, those that were treated with MN-14 had an 80% rate of regression, compared to 20% for mice who received the low affinity antibody. ¹³¹I-labeled MN-14 also caused tumor regression in 20% of mice with twenty-day-old tumors. This report also described a phase I clinical trial of ¹³¹I-labeled MN-14. Twelve patients with metastatic colon cancer were given ¹³¹I-labeled MN-14 in escalating doses. The maximum tolerated dose was determined to be 60 mCi/m². Eighteen percent of patients had partial remissions, and 45% had either a minor or mixed response, or stabilization of progressing disease. The authors conclude that the clinical response rates are encouraging, and that they are comparable to response rates with conventional chemotherapies.

In a recent trial, the pharmacokinetics and toxicity of ¹⁸⁸Re-labeled MN-14 were determined, and compared with previous data where M-14 labeled with radioactive iodine was administered.  Eleven patients with advanced gastrointestinal cancer were given varying doses of MN-14 labeled with radioactive rhenium. The ¹⁸⁸Re-labeled MN-14 showed increased uptake in the liver, spleen, and kidneys when compared to ¹³¹I-labeled MN-14. The maximum tolerated dose was estimated to be 60 mCi/m². Bone marrow suppression was noted. From this study, the authors conclude that ¹⁸⁸Re-labeled MN-14 can be administered at a high dose on an outpatient basis, making it a preferred candidate for radioimmunotherapy.

Side Effects:

Side effects include bone marrow suppression, decreased white cell counts, and increased susceptibility to infection.  

How Taken:

This drug is given via intravenous (IV) infusion.

Pharmaceutical Companies:

Immunomedics

Drug Name:   huC242-DM1

Synonyms:    C242-DM1

Drug Class:

Monoclonal Antibodies

Drug Approval Status:    Phase I

Description:

C242-DM1 is a monoclonal antibody joined to a toxic compound. C242-DM1 specifically recognizes a protein found in human colorectal cancers, thereby targeting the toxic compound to the tumor. Preclinical studies indicate that C242-DM1 may be an effective treatment for colorectal cancers. In addition to killing laboratory-grown colon cancer cells, C242-DM1 was able to cure laboratory mice transplanted with human colon tumors

Side Effects:

No human side effects have yet been reported.

How Taken:

No information is currently available on how C242-DM1 is taken.

Pharmaceutical Companies:

ImmunoGen, SmithKline Beecham

Tyrosine Kinase Inhibitors

Tyrosine kinase inhibitors are a relatively new class of small molecules that are targeted against growth factor receptors. Growth factor receptors are molecules located on the cell surface. The binding of growth factors to these receptors results in activation of the receptor, which in turn results in a cascade of signals inside the cell that cause cell growth. Many growth factor receptors, including both vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) belong to a family of proteins called tyrosine kinases. Inhibition of the tyrosine kinase function prevents the activation of the growth factor receptor and therefore prevents cell growth.

It is thought that the growth of cancer cells may in part be due to inappropriate activation of growth factor receptors on the cell surface. Preventing this activation, through the use of tyrosine kinase inhibitors, therefore appears to be a promising way to prevent the growth of cancer cells.

Drug Name:   C225

Synonyms:    IMC-225

Drug Class:

Tyrosine Kinase Inhibitors

Drug Approval Status:    Phase I

Description:

Of the many new drugs in development for colon cancer, perhaps none has received more attention than C225. C225 is one of a new class of drugs that inhibit the epidermal growth factor receptor (EGFR). Epidermal growth factor appears to play a role in the development of several types of cancer. Inhibiting the growth factor receptor is therefore an attractive approach to inhibiting cancer growth.

A report of a single patient with colon cancer who was treated with C225 last year and had dramatic tumor shrinkage received much media attention. Fortunately, this appears to be more than simply an isolated case, and subsequent studies appear to be confirming that C225 has activity in colon cancer. The company has recently reported results from a trial in which patients who have developed tumor growth on a standard chemotherapeutic drug, irinotecan, are then continued on therapy with irinotecan given together with the new drug, C225. Some of these patients have in fact experienced tumor shrinkage after the C225 was added to their regimen.

It will be interesting to see what proportion of patients end up responding to this new treatment. If these are more than simply isolated responses, C225 and other inhibitors of EGFR may well play an important role in the future treatment of colon cancer and in other malignancies.

Side Effects:

Information is currently unavailable.  

How Taken:

Intravenous infusion.

Pharmaceutical Companies:

ImClone Systems, Inc

Drug Name:   SU5416

Synonyms:

Drug Class:

Tyrosine Kinase Inhibitors

Drug Approval Status:    Phase I

Description:

SU5416 is an experimental drug currently being investigated as a treatment for advanced colon cancer.  SU5416 is an inhibitor of vascular endothelial growth factor (VEGF).

Preclinical studies indicate that laboratory mice treated with daily injections of SU5416 exhibited decreased levels of metastatic cancer and a lower level of micro-blood vessel formation, which is required for tumors to grow.  Furthermore, SU5416 inhibits the growth of tumor cells, possibly by causing them to undergo programmed cell death.

Phase I clinical trials of SU5416 indicate that the drug is effective against both colorectal and non-small-cell lung cancers.  The efficacy of SU5416 is currently being investigated in combination with standard chemotherapy.

Side Effects:

Information is currently unavailable.

How Taken:

Information is currently unavailable.  

Pharmaceutical Companies:

Sugen Inc.

Vaccines

Cancer vaccines remain in the early stages of clinical development. Cancer vaccines work using the same principle as other vaccines: they immunize people against cancer. It is thought that cancer develops in part by being able to elude the body’s own immune system. By using a cancer vaccine, it may be possible to allow the body’s immune system to recognize cancer cells and eliminate them. The use of vaccines to treat cancer has been best examined in the treatment of malignant melanoma. Whether vaccines will be useful in the treatment of colon cancer remains uncertain. One group of patients in whom vaccines may be particularly useful is those who have had colon cancer removed surgically, but are at risk of developing a recurrence. Several vaccine trials are being performed in such patients, to see if immunization will reduce the chance of recurrence.

Drug Name:   CTP-37

Synonyms:    Avicine

Drug Class:

Vaccines

Drug Approval Status:    Phase II

Description:

It is believed that human chorionic gonadotropin (hCG) expression is upregulated in cancer cells. It is hypothsized that hCG in the membrane of cancer cells might help those cells evade immune surveillance. CTP-37 is a vaccine that stimulates the recipient's immune system to block the effect of excess hCG in cancer cells, thereby rendering those cells susceptible to destruction.

Side Effects:

Information is not currently available. 

How Taken:

This agent is given via intravenous injection.

Pharmaceutical Companies:

AVI BioPharma

Drug Name:   OncoVAX-CL

Synonyms:

Drug Class:

Vaccines

Drug Approval Status:    Phase III

Description:

Oncovax is a tumor vaccine under development by Intracel Corporation.  In a recent press release by the company, they report that a meta analysis of three clinical trials suggests that Oncovax significantly improves the recurrence-free interval and recurrence-free survival in Stage II colon cancer patients. 

More specific results from these trials will be presented in September, 2000 at the Millennium World Congress on Vaccines and Immunization in Liege, Belgium. 

Side Effects:

Information is currently unavailable.  

How Taken:

This agent is given via intravenous injection.

Pharmaceutical Companies:

Intracel

Drug Name:   OncoVax-CL, Jenner

Synonyms:

Drug Class:

Vaccines

Drug Approval Status:    Phase II Clinical Trial

Description:

GA-733-2 is a cell surface protein highly expressed in some cancer cells, including colorectal cancers. Owing to its relatively high and specific expression on colon cancers, GA-733-2 has been the target of immunotherapies designed to induce cell death in malignant cells. OncoVax-CL is a vaccine that induces tumor specific destruction by targetting GA-733-2. Jenner Biotherapies is developing OncoVax-CL.

In one preclinical study, the authors immunized mice with an adenovirus expressing the full length GA-733-2 protein. In cases where mice had been pre-transplanted with human colorectal cancer expressing human GA-733-2, the immunization induced significant and specific tumor regression. Of significance, cured mice were resistant to re-challenge with human colorectal cancer cells that did not express GA-733-2, suggesting immunogenicity of other antigens present on the parental cancer cells. 

A study was conducted on sera of colon cancer patients to determine if patients produce autoantibodies to GA-733-2. Sera was collected from 1068 patients with varying stages of colorectal cancer and examined for the presence of GA-733-2 reactivity against a recombinant form of the protein. A total of 14.5% of patients tested had IgG specific for the antigen. Furthermore, there was a tendency to a higher frequency of patients with antibodies among those in the advanced stages of colon cancer: 11% in stage A and 32% in stage D respectively (P = 0.06). The authors conclude that there is no correlation between the high incidence of autoantibodies and survival in their study. 

24 patients with colorectal cancer were given immunotherapy with anti-GA-733-2 antibodies and were analyzed for subsequent induction of adaptive immune responses. In 5 patients, the authors report that tumors regressed after therapy. Furthermore, tumor regression was associated with a T-cell response specific for GA-733-2. The relationship between specific T-cell response and tumor regression was reported to be significant (P=0.0005). Thus the induction of a T-cell response might be an important effector function with anti-tumor antibody therapy . 

In a clinical study, 6 patients who had undergone surgical resection of their Dukes B or C colon cancer were immunized with human monoclonal anti-idiotypic antibodies to the nominal antigenic epitope of the GA-733-2 protein. All patients developed a cellular immune response against the GA-733-2 antigen as shown by in vitro cell proliferation assays and cytokine profiles. In vitro data was supported in vivo by the delayed-type hypersensitivity reaction. Furthermore, treatment induced specific antibody responses in 5 out of 6 patients. These results, although preliminary, suggest that therapy with anti-idiotype monoclonal antibodies might be a safe and effective way to immunize against colorectal malignancies.

Side Effects:

Information is currently unavailable. 

How Taken:

This agent is given via intravenous injection .

Pharmaceutical Companies:

Jenner Biotherapies