Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The discovery of interferon in 1957 by Drs. Isaacs and Lindenmann led to major revisions in the concepts of man's defenses against viral infections. There are at least two types of interferon. Along with their antiviral properties, they have recently been shown to exert a suppressive effect on the humoral and cellular immune response; they affect both B and T lymphocytes. A variety of substances, including virus, polyribonucleotides, and mitogens for T lymphocytes, are good interferon inducers. T lymphocytes seem to be necessary for these inducers to exert their immunosuppressive effects. The immunosuppressive effects of interferon inducers suggests that interferons may be mediators of suppressor T lymphocyte effects. In the virus system, interferon does not exert its antiviral effects by direct action on the virus, but rather derepresses a cell gene that results in the production of an antiviral protein. This antiviral protein is probably the mediator of inhibition of virus replication. This is a complex sequence of events that results in the interaction of interferon with the cell membrane and the resulting production of the antiviral state in the cell. This review will examine the various steps of this involved process.
CRC Crit Rev Biochem 1976 Nov
PMID:Interferon: effects on the immune response and the mechanism of activation of the cellular response. 1 14

5-Fluorouracil (5-FU) is still the mainstay of chemotherapy in patients with metastatic colorectal cancer. A prolonged infusion of 5-FU is more active than any other schedule of 5-FU used to date. Cisplatin does not improve treatment results compared with 5-FU alone and is not recommended outside clinical trials. Biomodulation of 5-FU is a major step forward in the treatment of colorectal cancer patients and as the standard chemotherapy for advanced colorectal cancer. Two schedules of folinic acid daily for 5-day (low and high doses) and weekly high dose in combination with daily or weekly 5-FU are the most widely used schedules. Although the response rates to either schedule are comparable, the profile of toxicity is different, being stomatitis for the daily schedule and diarrhea for the weekly schedule as the dose-limiting toxicity. Modulation of 5-FU by methotrexate is time dependent. An interval of 24 hours between methotrexate and 5-FU is necessary for effective modulation. Other modulators, like interferon and N-phosphonoactyl-L-aspartate (PALA), are promising treatment options currently under investigation in randomized trials. The data from phase II and III trials using modulation of 5-FU by folinic acid, PALA, or methotrexate, or using continuous infusion 5-FU indicate that all of these strategies are active. Randomized trials are currently underway to further investigate these therapeutic approaches and whether a specific modulation offers more therapeutic advantages.
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PMID:Chemotherapeutic strategies in metastatic colorectal cancer: an overview of current clinical trials. 137 4

Because of the different sites and mechanisms of biochemical interaction among 5-fluorouracil (5-FU), leucovorin (LV) and interferon (IFN), we hypothesized that the concomitant use of IFN could increase the activity of the 5-FU/LV combination in colorectal cancer patients. Forty-five patients were included in the study and all were evaluable for response and toxicity. They were treated with 5-FU 370 mg/sqm i.v. d 2-6; LV 200 mg/sqm i.v. d 2-6; IFN alpha 2b 3 million U im d 1-7 every 21 days. Six patients achieved complete responses, 17 partial responses, 14 had stable disease and 8 progressed on therapy for an overall response rate of 51%. Median survival has not been reached. At a median follow-up of 14 months 33 of 45 patients remain alive. Nine patients experienced toxicity grade 3 (6 diarrhea and 3 stomatitis). Our results seem to suggest that IFN could increase 5-FU/LV activity and that this combination is well tolerated.
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PMID:Double biochemical modulation of 5-fluorouracil by leucovorin and cyclic low dose interferon alpha 2b in advanced colorectal cancer patients. 149 68

The systemic management of patients with colorectal cancer continues to focus on the use of 5-fluorouracil (5-FU). In the setting of metastatic disease, parenteral 5-FU has been shown to be superior to oral 5-FU; however, survival duration seems similar whether such parenteral 5-FU is administered in a "loading," weekly, or continuous infusion manner. The addition of other cytotoxic agents such as semustine, mitomycin C, or cisplatin to 5-FU does not appear to increase the response rate or prolong survival. The results of five randomized trials assessing the value of intraarterial hepatic infusions of 5-FU or floxuridine show that such regional chemotherapy increases the likelihood of hepatic response compared with systemic treatment but has little effect on survival and is associated with significant toxicity. Recent efforts in the management of patients with advanced disease have been directed at optimizing the activity of 5-FU by (1) enhancing the inhibition of DNA synthesis through the concomitant administration of folinic acid; (2) increasing drug incorporation into RNA through pretreatment with methotrexate or phosphonacetyl-L-aspartate; and (3) improving the drug's activity through the synergistic action of alpha-2a-interferon. Although the results of some of these investigations have been promising, only the 5-FU and folinic acid combination consistently has appeared to be superior to single-agent 5-FU. These different approaches to biochemical modulation are being compared in ongoing cooperative group trials.
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PMID:Chemotherapy for metastatic colorectal cancer. 151 93

A high rate of response to 5-fluorouracil (5FU) and alpha-interferon (alpha IFN) combination therapy has been reported in metastatic colorectal cancer patients. Therefore, designed a trial of high-dose continuous-infusion 5FU, oral leucovorin (LV), and alpha IFN in this group of patients. Because this combination has not previously been tested and severe toxicity has been reported for 5FU and alpha IFN combination therapy, we conducted a phase I trial in which 11 patients presenting with previously untreated metastatic colorectal cancer were treated with escalating doses of alpha IFN together with fixed doses of 5FU and LV. WHO grade III toxicity consisting mainly of oral mucositis was noted in four patients. No grade IV toxicity occurred. Although alpha IFN may enhance the toxicity of 5FU, the toxicity of this regimen remained manageable. Three partial responses were noted.
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PMID:Alpha-interferon in combination with 5-fluorouracil and leucovorin in metastatic colorectal cancer: a phase I study. 153 82

Treatment results in advanced colorectal cancer have improved during the last decade since the incorporation of agents like folinic acid, PALA, or interferon as active biomodulation of 5-fluorouracil (5-FU), the most potent drug in this disease. But essential prolongation of survival could not be demonstrated. To better define the need to initiate therapy and duration of treatment, a phase II study of high-dose folinic acid and 5-FU was initiated in patients with documented progression or severe tumor-related symptoms prior to start of therapy until best response was observed. The treatment plan was folinic acid 300 mg/m2 as a 10-minute intravenous infusion followed 50 minutes later by 5-FU 600 mg/m2 intravenous bolus days 1 to 3 every 3 to 4 weeks. Thirty-seven consecutive patients were treated during November 1986 and October 1987. Because of severe tumor-related symptoms, immediate treatment was considered mandatory in only eight patients. In the remaining 29 primarily asymptomatic patients, an observational period of a median duration of 8 weeks (range, 1-56) was possible before treatment seemed to be indicated. Most patients experienced some toxicity, mostly leukopenia and gastrointestinal side effects, of World Health Organization grades 3 and 4 during 156 treatment cycles (range, one to eight cycles). The calculated dose intensity was 535 mg/m2 5-FU per week. Of 36 evaluable patients, 14 responded at least with a partial remission (39%; confidence interval, 23% to 55%) of 7 months median duration. An additional 13 patients (36%) had stable disease, giving a rate of tumor stabilization in these progressive patients of 75%, for a median duration of 5.5 months. Median survival since start of therapy was 11 months. Results are comparable to data reported in the literature; survival and remission duration seem not to be mitigated in a patient population in which therapy was withheld until progression or symptoms occur. This patient population might be characterized by more homogeneously distributed risk factors.
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PMID:A 3-day schedule of 5-fluorouracil and folinic acid in metastatic progressive colorectal cancer and its impact in terms of palliation. 155 39

We conducted a phase I/II trial of 5-fluorouracil (5-FU)/folinic acid (FA) and alpha-2b interferon (IFN) in 43 previously untreated patients with measurable metastatic colorectal cancer. Patients had disease progression prior to therapy consistent of 5-FU 500 mg/m2 (level A) or 600 mg/m2 (level B) as starting dose administered as a 2-hour infusion, FA 200 mg/m2, and alpha-2b IFN 5MU/m2 subcutaneously. All drugs were given on days 1 to 5 and cycles were repeated after 3 to 4 weeks. The aim of the study was to define the maximal tolerable dose (MTD) of 5-FU for this schedule. In the absence of toxicity above MTD, defined as diarrhea and mucositis of World Health Organization grade 2 and leukopenia of World Health Organization, grade 3 5-FU was increased in increments of 100 mg/m2 for further cycles. Twenty-four patients were started on level A; 18 were started on level B. Forty-two patients were evaluable for toxicity, 32 for response. Three of 32 patients achieved a partial response; in 22 of 32 patients, tumor stabilization occurred. Forty percent of patients started on level A developed grade 2 diarrhea; 28% of patients developed grade 2 or 3 mucositis. Of 18 patients on level B, two patients experienced grade 4 mucositis (11%) and grade 3 or 4 diarrhea (11%). One drug-related death in the presence of sepsis occurred. Due to 11% of patients with grade 4 toxicity when started on 600 mg/m2 5-FU and 40% of patients with grade 2 diarrhea when started on level A, MTD as starting dose for 5-FU is 500 mg/m2 as a 2-hour infusion when used in combination with FA and IFN on a day 1 to 5 active schedule. We observed a wide range of 5-FU dose tolerated by individual patients. While some patients experienced severe, mainly gastrointestinal, toxicity on lower levels of 5-FU, others tolerated much higher 5-FU doses (11 patients, 700 mg/m2; 5 patients, 800 mg/m2; and one patient, 900 mg/m2). Our data suggest that double modulation of 5-FU by FA and IFN may not be superior to modulation of 5-FU with either drug alone.
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PMID:Interferon alpha-2b, 5-fluorouracil, and folinic acid combination therapy in advanced colorectal cancer: preliminary results of a phase I/II trial. 155 46

Preclinical data suggest that both folinic acid and interferon may enhance the efficacy of 5-fluorouracil (5-FU) in colorectal carcinoma. We therefore initiated a phase I trial evaluating the doses, safety, and pharmacokinetics of the combination of recombinant interferon (IFN) alpha-2b with folinic acid (FA) and 5-FU. Seventeen patients with colorectal cancer who failed local chemotherapy received 5-FU as a 4-hour infusion, preceded by a bolus of FA and IFN. The 5-FU dose was escalated over the range of 400 to 650 mg/m2/d for a period of 7 days. Folinic acid was administered as a bolus in a fixed dose of 200 mg/m2/d and IFN as 5 million U/d subcutaneously on days 1 to 7. A total of 89 courses of therapy were completed for the 17 patients, of which there were 10 paired courses with a combination of 5-FU and IFN or 5-FU alone, being performed to analyze the pharmacokinetics and modulation of 5-FU by IFN. The maximum tolerated dose of 5-FU using this combination and a 4-hour schedule was 600 mg/m2/d for 7 days. The dose-limiting toxicity of this regimen was diarrhea. Mucositis and myelosuppression was not a marked problem at dose levels of 400 and 500 mg/m2/d for 7 days. However, at a dose level of 600 to 650 mg/m2/d for 7 days, grade 3 and 4 (WHO) leukopenia occurred in 50% and mucositis occurred in 33%. At a given dose of 5 million U, IFN did not significantly influence 5-FU serum levels. Mean steady-state serum levels of 5-FU at 500 mg/m2 given as a 4-hour infusion were 16.55 +/- 9.34 mumol/L and 18.23 +/- 12.77 mumol/L with and without IFN, respectively. Mean area under the curve (mumol/L x min) was 4,008 +/- 2,133 and 5,114 +/- 2,567 with and without interferon, respectively. Objective responses were seen in one of 17 of these heavily pretreated patients and stable disease was seen in seven of 17 patients. The recommended dose of 5-FU for use of phase II studies is 500 mg/m2/d for 7 days. We conclude that the toxicity of 5-FU plus FA with and without IFN alpha-2b can be reduced by using a 4-hour infusion instead of a bolus.
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PMID:A phase I trial of interferon alpha-2b with folinic acid and 5-fluorouracil administered by 4-hour infusion in metastatic colorectal carcinoma. 155 47

Several reports on fluorouracil (5-FU) and alfa interferon (IFN-alpha) combination therapy in patients with advanced colorectal cancer have been published. In our study high-dose continuous infusion 5-FU (60 mg/kg per 48 hours), oral folinic acid (FA) (8 x 90 mg during 5-FU), and IFN-alpha three times weekly were combined. Because the addition of IFN-alpha has not been tested before, and serious toxicity of 5-FU plus IFN-alpha therapy has been reported, the IFN-alpha dose was escalated from 3 to 10 million units (MU)/dose in the first 11 patients. Grade 3 toxicity was noted in four patients, and consisted mainly of oral mucositis. No grade 4 toxicity occurred. Three partial responses were noted. Preliminary results of a phase II study, in which all patients received IFN-alpha at 10 MU/dose, show grade 3 and 4 toxicities in 24% and 4% of patients, respectively. This compares favorably with other trials in which 5-FU and IFN-alpha was used without FA.
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PMID:Fluorouracil continuous infusion plus alfa interferon plus oral folinic acid in advanced colorectal cancer. 155 49

Based on promising results with 5-FU/FA or 5-FU/IFN-alpha in colorectal cancer, a pilot study was initiated to evaluate the effects of the combination 5-FU/FA/interferon alfa (IFN-alpha) in patients with advanced pancreatic cancer. Patients received 9 million units (MU) IFN-alpha subcutaneously three times a week or 6 MU IFN-alpha once a week; 500 mg/m2 5-FU via an intravenous bolus 1 hour after the initiation of a 2-hour infusion of 500 mg/m2 of FA, once a week. Fourteen patients, all previously untreated with chemotherapy, were enrolled; 13 (two females/11 males) were evaluable for response and toxicity (one too early). The median performance status was 80% (range, 60 to 100) and the median age 62 years. Besides the inoperable primary tumor, metastatic sites were liver, lung, and peritoneum. Three of 13 patients had a partial remission, three of 13 patients a minor response, and four of 13 patients no change. Three patients had progressive disease. Until now, no complete remission was seen. Median duration of response was 4+ months; median survival has not been reached yet. Of all patients there were three instances of World Health Organization grade 3 toxicity: fatigue (one of 13), nausea (one of 13), and diarrhea (one of 13); grade 4 toxicity did not occur. Although overall toxicity was moderate, most patients experienced a reduction of well-being. Therefore in all patients the dose of IFN was reduced (from 3 x 9 MU/week to 1 x 6 MU/week). Our preliminary data suggest that biochemical modulation of 5-FU with FA and IFN-alpha (reduced dosage) is effective in pancreatic cancer with moderate toxicity, warranting further study.
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PMID:Combination fluorouracil, folinic acid, and interferon alfa-2a: an active regimen in advanced pancreatic carcinoma. 155 50


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