Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Irinotecan (7-ethyl-10-[4-[1-piperidino]-1-piperidino]carbonyloxycampothecin) , also known as CPT-11, is a promising semi-synthetic derivative of camptothecin with significant activity against a range of tumor types. The pharmacokinetic behaviour of its principal and presumedly active metabolite, SN-38 (7-ethyl-10-hydroxy-camptothecin), displays wide inter-patient variation. During the high-performance liquid chromatographic (HPLC) analysis of plasma samples collected from a patient given CPT-11, we observed several unidentified peaks that were not present in pre-infusion samples. In this paper we describe the manner in which one of these was determined to be a beta-glucuronide of SN-38. The total plasma concentrations of this metabolite were quantified following digestion with beta-glucuronidase and were found to be greater than those of SN-38 in the patient studied. The elimination phases of the plasma concentration profile of SN-38 and its glucuronide were parallel, suggesting that the transformation of SN-38 to the glucuronide is the rate-limiting step in the elimination of SN-38 and could play a key role in its pharmacokinetics.
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PMID:Identification and kinetics of a beta-glucuronide metabolite of SN-38 in human plasma after administration of the camptothecin derivative irinotecan. 776 55

Although many advances have been made in the management of neuroblastoma, the prognosis of patients with advanced neuroblastoma remains poor, and constant efforts are being made to search for newer effective drugs. CPT-11 is a newly developed derivative of camptothecin and shows a unique anti-tumor activity by inhibiting DNA topoisomerase I. In this study the effects of CPT-11 on a human neuroblastoma xenograft, TNB9, were investigated according to the standard Battelle Columbus Laboratories protocol. TNB9 is one of the most malignant strains of neuroblastoma, showing a homogeneously staining resion (HSR) on chromosome 20 and 80-fold amplification of the N-myc gene. This study disclosed that CPT-11 was highly effective against TNB9. Maximum inhibition rate (IR) was 72.5% at a standard dose and 52.8% even at half the dose. No nude mouse used in this study lost weight after an administration of CPT-11. Plasma pharmacokinetics of CPT-11 administered in this experimental model were compared to that in clinical patients. Our data suggested that CPT-11 might be a promising new drug in the treatment of high-risk neuroblastoma patients and encouraged us to employ CPT-11 in the protocol of the Study Group of Japan.
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PMID:Effects of CPT-11 (a unique DNA topoisomerase I inhibitor) on a highly malignant xeno-transplanted neuroblastoma. 793 75

CPT-11 is a derivative of camptothecin, a topoisomerase-I inhibitor with marked cytotoxic activity. We examined the cytotoxicity of CPT-11 and its metabolite SN-38 for primary gastrointestinal carcinoma and various recurrent carcinomas which were cultured on contact-sensitive plates (CSPs). The response rate of seven gastrointestinal carcinomas for either CPT-11 or SN-38 was 71% (5/7). The response was higher than those for other anticancer agents, including adriamycin (ADM), cisplatinum (CDDP) and 5-fluorouracil (5-FU). The mean percent survival of these tumor cells was 69% when incubated with 25 ng/ml of SN-38, which was the lowest survival for all the anticancer drugs tested. IN the case of recurrent carcinomas, the response rate to either CPT-11 or SN-38 was 60% (3/5), and was higher than the rates for MMC, CDDP or 5-FU. The mean percent survival of the recurrent carcinoma cells was 76% in the presence of 25 ng/ml SN-38, and this was once again the lowest survival rate. CPT-11 had a stronger inhibitory effect against one carcinoma than SN-38 when a clinical drug concentration was added to the culture medium, suggesting that CPT-11 itself was cytotoxic. IN addition, one carcinoma with a low response to CDDP also showed no response to CPT-11, but was very occurred because of decreased conversion of CPT-11 to SN-38. Our results suggest that CPT-11 may be a useful agent for the treatment of both primary gastrointestinal cancer and various recurrent carcinomas.
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PMID:Cytotoxicity of CPT-11 and SN-38 for gastrointestinal and recurrent carcinomas cultured on contact-sensitive plates. 801 40

The topoisomerase I inhibitors are an exciting new class of antineoplastic agents currently under clinical development. Analogues of camptothecin with improved toxicity profiles and antitumor activity included CPT-11 and topotecan. CPT-11 has demonstrated activity against a variety of tumor types, particularly colon and lung cancer. Early results with topotecan against ovarian and lung cancer are also encouraging. Combination trials with other antineoplastic agents including cisplatin and etoposide, and early clinical trials with new topoisomerase I inhibitors, such as 9-aminocamptothecin, are underway.
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PMID:Topoisomerase I inhibitors. An overview of the camptothecin analogs. 804 Jan 44

CPT-11 (irinotecan hydrochloride, 7-ethyl-10-[4-(piperidino)-1-piperidino] carbonyloxy-camptothecin) is a semisynthetic camptothecin derivative developed in Japan. The inhibitory activity of CPT-11 against human tumor colony-forming units from freshly explanted human tumors was explored using a soft agar cloning system. Final CPT-11 concentrations of 0.3-3.0 micrograms/ml were used for a 1 h exposure. At a concentration of 3.0 micrograms/ml antitumor activity was seen against colorectal, ovarian, nonsmall-cell lung, breast cancer and mesothelioma colony-forming units. CPT-11 should have activity against a broad spectrum of tumors in patients.
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PMID:Activity of CPT-11 (irinotecan hydrochloride), a topoisomerase I inhibitor, against human tumor colony-forming units. 804 3

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

A 62-year-old man was hospitalized in March 1990 due to upper abdominal discomfort and anorexia. The chest X-ray revealed an upper anterior mediastinal tumor, and abdominal ultrasound showed lymphadenopathy. Endoscopic examination of the stomach revealed a large, irregular ulcer, which was histologically confirmed to be malignant lymphoma by biopsy. Serum anti-HTLV-1 antibody was positive. A diagnosis of ATLL (lymphoma type) was made. The usual therapy for this disease, including the LSG4 and RCM protocols, was only transiently effective. Therefore, the patient was treated with CPT-11 (40 mg/m2) by intravenous infusion on 3 consecutive days with weekly repetition in November 1990. Complete remission was obtained after 2 weeks of treatment, and was maintained for 5 months. This case suggests that CPT-11 may be effective for the treatment of ATL.
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PMID:[Successful treatment of chemotherapy-resistant adult T cell leukemia/lymphoma by irinotecan hydrochloride (CPT-11)]. 813 1

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11; Irinotecan), a semisynthetic analogue of camptothecin (CPT) with broad preclinical antitumor activity, has demonstrated impressive activity in phase II trials in Japan in advanced small and non-small cell lung, colorectal, cervical, and ovarian carcinomas, as well as in refractory lymphomas and leukemias. In this phase I and pharmacological study, 90-min infusions of CPT-11 were administered every 3 weeks at doses ranging from 100 to 345 mg/m2 to patients with solid malignancies. Acute, severe, and refractory vomiting, diarrhea, and/or abdominal cramps associated with flushing, warmth, and diaphoresis occurred in the immediate posttreatment period at the 240-mg/m2 dose level in several patients who were not treated with premedications. The characteristics and temporal nature of these toxicities, the prompt resolution of symptoms following treatment with diphenhydramine, and the successful use of a premedication regimen consisting of ondansetron and diphenhydramine in preventing these acute effects suggest that vasoactive substances are involved in the mediation of these acute toxicities. With the routine use of these premedications, there was no single toxicity type that limited the escalation of CPT-11 doses. Instead, a constellation of severe hematological and gastrointestinal effects precluded the repetitive administration of CPT-11 at doses above 240 mg/m2, the maximum tolerated dose and recommended phase II dose on this schedule. Major responses were observed in patients with advanced colorectal, cervical, and renal cancers. The disposition of total CPT-11 in plasma was fit by a biexponential kinetic model with renal elimination accounting for 37 +/- 4% (SE) of total drug disposition. The Cmax for the active metabolite of CPT-11, 7-ethyl-10-hydroxycamptothecin (SN-38), was achieved at 2.2 +/- 0.1 h after treatment, and mean residence times for both CPT-11 and SN-38 were long, 9.1 and 10.0 h, respectively. Compared with topotecan, another CPT analogue under development, a larger proportion of total drug exposure was accounted for by the active lactone (closed-ring) forms of CPT-11 and SN-38; areas under the time-versus concentration curve for their respective lactone were 44 and 50% of areas under the time-versus-concentration curve for total CPT-11 and SN-38. Although intermittent dosing schedules appear to be superior to single dosing schedules for CPT and some CPT analogues in preclinical tumor models, the maintenance of biologically relevant concentrations of SN-38 for relatively long durations may negate the potential pharmacological benefits of intermittent and continuous administration schedules for CPT-11.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Phase I and pharmacological study of the novel topoisomerase I inhibitor 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) administered as a ninety-minute infusion every 3 weeks. 827 79


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