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)

The establishment of reliable preclinical test is essential for the reasonable clinical trial. As a methodology for the screening of new active anticancer agents, disease oriented strategy using human tumor cell lines has been proposed in USA. The important questions in DOS are to determine the representative cell lines of specific cancer and it is also extremely important to decide the numbers of cell lines used for the screening. CPT-11, topoisomerase I inhibitor, developed in my country has been demonstrated to be active against lung cancer cell lines compared with mice tumors such as S-180 and P-388. However, no compound is demonstrated to be clinically active so far by this methodology. The criteria for the application of clinical trial are obscure and each drug company decides empirically by themselves. We have proposed to use PEI (predictive efficacy index) for the prediction of antitumor activity of new compounds. The clinical effect of new platinum analogue well correlated with this value. We have conducted phase II trial of 5-FU + LV against NSCLC without no prior chemotherapy. No responder was observed in the trial. Augmentive effect of leucovorin on the cytotoxicity of 5-FU and FdUrd was examined in vitro against NSCLC and colon cancer cell lines. Leucovorin stimulated the cytotoxicity of both drugs only against colon cancer cell lines. We tried to predict the response rate of new platinum derivative based on the data of bioassay of patient's serum administrated with platinum compounds. The predicted response rates of 254-S were 57-67% and 16-27% against SCLC and NSCLC, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Preclinical trials from the standpoint of clinical trials]. 185 17

CPT-11 is a new derivative of Camptothecin. Phase I clinical study of single administration with CPT-11 was carried out by a cooperative study group. Starting from 50 mg/m2 (n), dose was escalated to 350 mg/m2 (7n). Dose limiting factor was found to be a decrease in WBC counts (especially in neutrophils), and MTD was presumed to be 250 mg/m2 or more. Nadir of WBC counts was observed after about a week, and it took 2-3 weeks for recovery. The decrease in platelet number and hemoglobin content was mild. Other side effects included G-I toxicities, alopecia, etc. However, no toxic effects on the heart, kidney, lung were observed. SN-38, main metabolite of CPT-11, was observed in blood, and excreted rapidly. Anticancer effects were suggested with dose of 165 mg/m2 or more against colon cancer, gastric sarcoma, melanoma and lung cancer. It is suggested that the optimal dose schedule for an early Phase II study is 200 mg/m2 every 3-4 weeks. However, not only leukopenia but also marked G-I toxicities being noted in some cases, care should be taken for those side effects.
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PMID:[Phase I clinical study of CPT-11. Research group of CPT-11]. 240 54

Topoisomerase I inhibitors are a new therapeutic class whose clinical evaluation began a few years ago; Irinotecan (CPT-11) gave interesting results in colon cancer; side effects were neutropenia, diarrhea, vomiting and a cholinergic syndrome. Topotecan was useful in lung and ovarian cancer; side effects were mostly hematologic. Undergoing studies concern dose optimization, mode of administration and therapeutic associations.
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PMID:[Topoisomerase I inhibitors. Review of phase II trials with irinotecan (CPT-11) and topotecan]. 749 18

Chemically-induced colon cancer was used to test the sensitivity of tumors to chemotherapeutic agents. Thirty-four Sprague-Dawley rats received dimethylhydrazine (40 mg/kg) s.c. once weekly for 10 weeks to induce colon cancer. Twenty weeks after beginning the carcinogen treatment, a barium enema was performed to determine the size of colon tumors. The animals were divided into CDDP group and CPT-11 group, in which the maximum tolerable dose of each drug was given. After 5 weeks of treatment, the barium enema was repeated. "Response" was assessed on the basis of tumor doubling time. Response rates in the CDDP and CPT-11 groups were 6% and 35%, respectively. This reflects the clinical data of those drugs and confirms the results of our previous study. The present study may be a predictive model for screening anticancer drugs for human colorectal malignancy.
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PMID:[A model for sensitivity determination of anticancer agents against chemical-induced colon cancer in rats]. 766 71

The cytotoxicity of SN-38, the major metabolite of CPT-11 (7-ethyl-10-[4-(1-piperidino)-1- piperidino]carbonyloxycamptothecin, was compared among gastrointestinal carcinomas of every organ, and between primary and metastatic lesions of every organ-originated gastrointestinal carcinoma, by an in vitro anticancer drug sensitivity test using fixed-contact-sensitive plates. The rates of cases having a high response (percent survival 75% or lower) to SN-38 but a low response (percent survival above 75%) to cisplatin, mitomycin C (MMC), adriamycin (ADM) and 5-fluorouracil (5-FU) were 14.6, 19.4, 15.6 and 27.0%, respectively. While, the rates of cases having a high response to cisplatin, MMC, ADM and 5-FU but a low response to SN-38 were 7.3, 2.8, 9.4 and 13.5%, respectively. Each of the former rates were higher than each of the latter rates. In particular, the former rate for MMC was significantly higher than the latter rate (p = 0.04). Two cases with colon cancer showed a high response only to SN-38. The percent survival of primary lesions in colon cancer was significantly lower than that in stomach cancer. The rates of hepatocellular carcinoma cases having a high response to SN-38 but a low response to cisplatin, MMC, ADM and 5-FU were 16.7, 16.7, 0 and 25%, respectively. Only one case had a high response to 5-FU but a low response to SN-38. The percent survival of metastatic lesions in pancreatic cancer was significantly lower than that of primary lesions. From this study, we recommend the further clinical trial of CPT-11 for colon and hepato-cellular cancers.
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PMID:Cytotoxicity of CPT-11 for gastrointestinal cancer cells cultured on fixed-contact-sensitive plates. 767 Jan 39

In order to select a suitable combination chemotherapy with BOF-A2 from the view of both anti-tumor effect (IR) and decrease of side effect, we studied a combination significance of BOF-A2 with CPT-11 that promised for a new anticancer drug, CDDP or mitomycin C (MMC) that used widely to many cancer patients and interferon-alpha (IFN-alpha) against colon, stomach and renal cancer, respectively, by using xenografted nude mice. The combination therapy of BOF-A2 with CDDP was effective against stomach cancer (H-111) from the cellular change and decreased side effect. The combination therapy of BOF-A2 with MMC showed additive effect against stomach cancer (H-111) from IR and cellular changes. The combination effect of BOF-A2 with IFN-alpha was additive and synergistic against renal cancer (H-12). The combination therapy with CPT-11 was effective (IR > or = to 58%) from antitumor effect, additive from IR and synergistic from cellular change against lung cancer (H-74) and colon cancer (H-110), to which conventional drugs were generally insensitive and spontaneously tolerant. BOF-A2 was expected to be a promising new anti-cancer agent in the future clinical trial.
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PMID:[Combination chemotherapy of BOF-A2, a new 5-FU derivative, with various anticancer agents against human cancer xenografts in nude mice]. 806 Jan 37

A total of three topoisomerase I inhibitors, including topotecan, CPT-11 (irinotecan), and intoplicine, have been studied in both preclinical and clinical/clinical pharmacology studies. In in vitro testing against human tumor colony-forming units, all three compounds were significantly more effective when tested as a continuous exposure as compared with a 1-h exposure. The dose-limiting toxicities were different for all three of the agents, with neutropenia and thrombocytopenia being dose-limiting for topotecan; diarrhea, for CPT-11; and hepatotoxicity, for intoplicine. In these phase I studies a number of marginal responses were noted with topotecan; partial and marginal responses, with CPT-11 (particularly in patients with colon cancer); and no response, with intoplicine. The detailed pharmacology of all three agents documented a very short half-life for topotecan, an intermediate half-life for CPT-11, and a prolonged half-life for intoplicine. Based on our experience to date, these compounds (particularly CPT-11) have promise as useful additions to our tremendous therapeutic armamentarium.
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PMID:Preclinical and phase I trials of topoisomerase I inhibitors. 807 26

Irinotecan hydrochloride (CPT-11), topotecan, sobuzoxane, NC-190, and IST-622 are unique topoisomerase inhibitors and are investigational in Japan. CPT-11 is a water-soluble, semisynthetic derivative of camtothecin. CPT-11 shows its anticancer activity by inhibiting topoisomerase I activity, now a target of anticancer agents with major interest. Recent clinical trials reveal that CPT-11 is very effective in the treatment of cancer including lung cancer, cervical cancer, ovary cancer, stomach cancer, colon cancer, and non-Hodgkin's lymphoma. Major dose limiting toxicities are leukopenia and diarrhea, and are dose related. Topotecan is an another semisynthetic derivative of camtothecin and is also topoisomerase I inhibitor. Topotecan has undergone phase I clinical evaluations in USA, europe, and recently in Japan. DLF are leukopenia and neutropenia. Topotecan is more hydrophilic than its parent compound and shows lesser protein binding. Renal excretion appears to be the major route of elimination. Sobuzoxane (MST-16) is a unique derivative of dioxopiperazine, an inhibitor of topoisomerase II. In phase II studies, definite anticancer effects are observed in patients with non-Hodgkin's lymphoma and adult T-cell leukemia/lymphoma. Responses are seen even in pretreated cases. Leukopenia is also dose-limiting. Non-hematologic toxicities are mild and include alopecia and G.I. toxicities. NC-190 is a novel benzophenazine derivative with excellent antitumor activities against murine tumors. NC-190 also inhibits topoisomerase II. Now the drug is an early clinical phase II studies in Japan. Toxicities include bone marrow suppression, transient mild to moderate liver enzyme elevation, alopecia and mild G.I. toxicities. Tumor responses are occasionally encountered. IST-622 is a semisynthetic derivative of chartreusin. The drug is an inhibitor of topoisomerase II (and I in high concentration). IST-622 shows excellent, broad anticancer activity against murine tumors. The drug is well absorbed from small intestine. IST-622 is now in phase I clinical trial in Japan.
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PMID:[Topoisomerase inhibitors developing in Japan]. 842 86

We examined whether heat stress could enhance the sensitivity of human colon cancer WiDr cells to topoisomerase II-targeting anticancer agents, etoposide (VP-16) and teniposide (VM-26), and also determined the most effective timing for the drug administration after exposure to hyperthermia. Both topoisomerase II contents and topoisomerase II activity were significantly increased in WiDr cells 3 to 12 h after heat stress at 43 degrees C for 1 h, in comparison with those immediately after the heat stress. Cytotoxicity by VP-16 was most significantly enhanced 3 to 12 h after exposure to 43 degrees C for 1 h, but no synergistic effect was observed when the drug was administered immediately after the heat stress. A combination of VM-26 with heat stress, but not that of a topoisomerase I-targeting camptothecin derivative (CPT-11), or vincristine, showed a synergistic cytotoxic effect on WiDr cells. VP-16 alone induced cellular accumulation at the G2 + M phase, whereas the combination of VP-16 and heat stress further increased the cell population at the G2 + M phase, and decreased S-phase cells. A possible application of the combination of VP-16 and hyperthermia in clinical use is discussed.
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PMID:Biomodulation by hyperthermia of topoisomerase II-targeting drugs in human colorectal cancer cells. 856 2

Recently cytokines have been reported to potentiate the antiproliferative effects of chemotherapeutic agents against a variety of malignant tumors. We studied the antiproliferative effect of recombinant human interferon-alpha (rHuIFN-alpha) and CPT-11 on transplantable human colon cancer H-110 in nude mice. CPT-11 was administered to the H-110-bearing nude mice intraperitonealy every 4 days and rHuIFN-alpha was administered subcutaneously every day. The weight of the individual tumor was estimated by the tumor size. The cell cycle was analyzed by flow cytometry. The single administration of rHuIFN-alpha failed to show any antiproliferative activity. The antiproliferative effects of CPT-11 alone were observed in a dose and time dependent manner. This antiproliferative activity was markedly (p < 0.05) enhanced by combination with rHuIFN-alpha. Flow cytometric analysis revealed that treatment with rHuIFN-alpha accumulated cells in the S phase. rHuIFN-alpha can enhance the antiproliferative effects of CPT-11, probably through the accumulation of the tumor cells in the S phase.
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PMID:Interferon-alpha potentiates the antiproliferative activity of CPT-11 against human colon cancer xenografts in nude mice. 891 69


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