Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclosporin A (CSA) is an immunosuppressive agent that in experimental models has antiproliferative activity against colon cancer and other human neoplasms. A phase II trial was conducted to evaluate CSA in refractory colorectal malignancies. CSA was administered at a starting dose of 7.0 mg/kg twice daily (total dose, 14 mg/kg/day) and escalated to tolerance. Of 18 patients with measurable disease, 17 were evaluable. All had been treated with one fluorouracil-containing regimen. The European Cooperative Oncology Group (ECOG) performance status was 0 or 1 in 17 of the 18 patients. No objective responses were seen. Four patients maintained stable disease lasting from 10 to 75+ weeks. Significant toxicity occurred in 9 of 17 (53%) patients. Dose reduction was necessary in 10 of 17 (59%). Sustained escalation beyond the initial dose was possible in only two cases. Toxicities included nausea and vomiting (71%), nephrotoxicity (41%), fatigue (35%), flu-like symptoms (29%), and neurotoxicity (18%). In the dose and schedule employed in this trial, CSA is ineffective in refractory colorectal cancer and produces significant toxicity.
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PMID:A phase II trial of cyclosporin A in the treatment of refractory metastatic colorectal cancer. 203 7

The therapeutic activity of 5-FU in large bowel cancer is enhanced by increasing the intracellular pool of reduced folates. We treated 45 patients with advanced colon cancer with HDFA and 5-FU for 5 consecutive days. None had been given previous radio- or chemotherapy. All had measurable disease. Not one complete response was observed. Thirteen of the 39 evaluable patients showed partial response. Median duration of response was 9+ months. The probability of 50% survival was 15 months for all evaluable patients. There was no case of severe toxicity and the principal toxic effects were oral mucositis and diarrhea. To date, HDFA + 5-FU is one of the most effective treatments for large bowel cancer.
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PMID:High-dose folinic acid (HDFA) combined with 5-fluorouracil (5-FU) in first line chemotherapy of advanced large bowel cancer. 350 48

Both DFMO and methyl-GAG inhibit sequential enzymatic reactions in the pathway of polyamine biosynthesis. Since polyamines may be important factors in proliferation of cancer cells, we initiated a phase-I study of these agents in patients with advanced cancer. DFMO was given by mouth at a constant daily dose of 4 g/m2 starting on day 1 of the treatment protocol. The dose of methyl-GAG ranged from 200 to 700 mg/m2 administered IV every 2 weeks beginning on day 4. Twenty-two patients were entered into the protocol. Toxic reactions to this therapy were dose-related and included nausea, fatigue, diarrhea, and myelosuppression. One patient with colon cancer experienced a greater than 50% decrease in measurable disease but developed severe myelotoxicity. While DFMO was well tolerated, the combination of drugs appeared to cause substantially more hematologic and gastrointestinal toxicity than encountered during our recent experience with methyl-GAG used alone. We suggest that future studies of this drug combination carefully evaluate levels of polyamines and inhibition of enzymatic activity to minimize toxicity.
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PMID:Sequential inhibition of polyamine synthesis. A phase I trial of DFMO (alpha-difluoromethylornithine) and methyl-GAG [methylglyoxal-bis(guanylhydrazone)]. 641 31

5-Fluorouracil (5-Fu) was administered by a constant venous infusion schedule at a dose of 300 mg/m2/d for 30-180 days. The dose schedule was associated with minimal toxicity in 32 patients with gastrointestinal cancer treated by employing a portable infusion pump for ambulatory drug delivery. Cumulative dose of 5-Fu was extended to three to four times that achieved by intermittent bolus therapy or short-term 5-day infusion therapy. Objective tumor regression was observed in six of 22 patients with measurable disease; 10 patients had stable disease, five of whom had a decrease in CEA levels. The responses according to tumor type were as follows: 1/1 gastric cancer; 1/2 hepatoma; and 4/18 colon cancer. The superiority of this new treatment schedule for 5-Fu will need to be established by prospective randomized clinical trials.
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PMID:Protracted ambulatory venous infusion of 5-fluorouracil. 683 1

The aspartate transcarbamoylase inhibitor, N-(phosphonacetyl)-L-aspartate (PALA), synergistically enhanced the cytotoxicity of a combination of 5-fluorouracil (5-FU) and interferon-alpha (IFN) against human colon cancer cell lines in vitro. To test the efficacy of this combination in the clinical setting, patients with locally advanced or advanced gastric carcinoma were treated with the combination of PALA, 5-FU and IFN (PFI). Patients were required to have biopsy-proven disease beyond the scope of surgical resection, measurable disease, no prior chemotherapy, adequate bone marrow, renal and hepatic function, to be fully ambulatory and to have given informed consent. Drug was administered as follows: PALA, 250 mg/m2, 15 min i.v. infusion, days 1, 15, 22, 29, and then weekly; 5-FU, 750 mg/m2 daily x 5 as a continuous i.v. infusion beginning day 2, then at 750 mg/m2 days 16, 23 and 30, then weekly; IFN, 9 MU subcutaneously three times per week beginning day 2. There were 22 patients enrolled. The major toxicities were fatigue and associated neurotoxicity, with acceptable gastrointestinal and haematological toxicities. There was one complete responder (5%) and 3 partial responders (14%); two of these responses were durable (> 3 years). Despite this modest clinical activity, other regimens for advanced gastric cancer such as FAMTX and ELF appear to have greater activity with comparable toxicity.
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PMID:Phase II trial of N-(phosphonacetyl)-L-aspartate (PALA), 5-fluorouracil and recombinant interferon-alpha-2b in patients with advanced gastric carcinoma. 875 62

Biochemical modulation is one of the most interesting fields in cancer chemotherapy. Interferon-alpha (IFNalpha) is a cytokine that is able to influence the pharmacodynamics of 5-fluorouracil (5FU) through a number of mechanisms. With the aim of confirming some data emerging from the literature, we initiated a multicentric randomized study comparing the combination of 5FU and IFNalpha-2a with 5FU alone in the treatment of advanced or metastatic colon cancer. A group of 205 colon cancer patients (104 in the 5FU arm and 101 in the 5FU + IFNapha-2a arm) were included in the final intention-to-treat analysis. Rectal cancers were not considered eligible. All patients had measurable disease, were aged 75 years or less, had a Karnofsky index of at least 60 and had good bone marrow, renal, liver and cardiac functions. No previous chemo-immunotherapy was allowed. The treatment was 750 mg/m2 5FU (4 h i.v. infusion) on days 1 5 and then i.v. bolus weekly, starting from day 12, with or without IFNalpha-2a given s.c. three times weekly (starting dose 3 x 10(6) IU rising to 9 x 10(6) IU, if tolerated). Patients were treated until progression or, if responsive, for a maximum of 48 weeks and then observed for a period of 2 years. The primary end-point of the study was objective clinical response (OR); secondary parameters were time to progression, overall survival, and time to death after progression. WHO criteria were used for both clinical response and toxicity measurements. Dose reduction was planned a priori in the event of significant toxicity due to 5FU, IFNalpha-2a or both. Association between primary and secondary end-points and treatment was studied by univariate and multivariate analysis. Altogether, 47 patients achieved a documented response. A 25% OR was observed in the combination arm while a 21% OR was seen in the 5FU arm; this difference is not statistically significant (P = 0.6). Patients with a small tumour burden (below 5 cm2) showed a higher probability of response in both arms. Patients in the experimental arm had a higher but not statistically significant cumulative progression-free probability. Median survival was 47.1 weeks overall, while it was 43.7 and 48.5 weeks in the control and experimental arms, respectively. The combination was clearly more toxic than 5FU alone, leukopenia being the most frequent side-effect in the experimental arm and nausea and vomiting in the control arm. In conclusion these results are quite disappointing and 5FU + IFNalpha-2a can not be considered a standard treatment for advanced colon cancer.
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PMID:5-Fluorouracil plus interferon alpha-2a compared to 5-fluorouracil alone in the treatment of advanced colon carcinoma: a multicentric randomized study. 961 46

Epidemiological studies indicate that nonsteroidal anti-inflammatory agents may reduce colorectal cancer incidence and mortality. Moreover, sulindac has been shown to attenuate the growth and progression of colonic neoplasms in an experimental model of colon carcinoma and in patients with familial adenomatous polyposis. To determine whether sulindac (300 mg/day) would increase toxicity associated with 5-fluorouracil (5-FU) and levamisole, 15 patients with advanced colorectal cancer were treated. Median treatment duration was 3 (range, 0.6-6.0) months, and median age was 56 years (33% >/= 60 years). All patients had failed prior 5-FU-based therapy, had measurable disease, and were evaluable for toxicity. Grade III/IV granulocytopenia occurred in four patients; three patients had received prior pelvic irradiation resulting in a predisposition to myelosuppression. Two patients developed grade III anemia, and occult gastrointestinal bleeding was suspected in one. No other grade II or greater gastrointestinal or other nonhematological toxicity occurred. One patient had a partial response, 3 patients had disease stabilization, and 10 patients progressed on study. Our results indicate that sulindac does not significantly increase short-term toxicity associated with 5-FU and levamisole. To determine whether sulindac increases the efficacy of adjuvant chemotherapy, we propose a phase III randomized trial in patients with lymph node-positive colon cancer.
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PMID:Phase I trial of sulindac plus 5-fluorouracil and levamisole: potential adjuvant therapy for colon carcinoma. 981 87