Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D01061 (CPT-11)
 1,899 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In interdisciplinary oncotherapy by radiation and chemical substances, the injurious effects of radiation on the normal skin are occasionally modified by combined chemical substances. In the present experiment, the possible modifying effects of Peplomycin (PEP, 30 mg/kg body weight) and Camptothecin-11, an inhibitor of DNA topoisomerase I (CPT-11, 15 and 50 mg/kg body weight), on radiation skin injury were studied. Macroscopic changes on the thigh skin of male ICR hairless mice (at 8 weeks of age) induced by 10 Gy X-ray irradiation alone and the combined treatment with the anticancer substances were estimated by a modified scoring first reported by Lowy and Baker. Intraperitoneal administration of PEP significantly enhanced radiation skin injury; while CPT-11 (15 mg/kg), within the clinical dose range and in the similar molarities to that of PEP, did not show any appreciable modification effect. Treatment with CPT-11 (50 mg/kg) showed a radiation enhancement without significant difference. The chemotherapeutic radioenhancement ratios of the combined treatments of X-ray and PEP or CPT-11 (15 or 50 mg/kg) were 1.49, 1.17 or 1.34, respectively. Treatment with PEP at the accepted dose showed a radiation enhancement, while CPT-11 did not show any radiation enhancement within the clinical dose.
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PMID:Effect of peplomycin or camptothecin-11 on X-ray skin injuries of ICR hairless mice. 808 65

CPT-11 (irinotecan) is a water-soluble analogue of camptothecin (CPT), an antitumor drug extracted from the Chinese tree Camptotheca acuminata. SN-38 is an active metabolite of CPT-11 that contributes significantly to its activity. The antitumor effects of CPT-11 and SN-38 are exerted through a novel mechanism of action; inhibition of DNA topoisomerase I. CPT-11 and its metabolite have demonstrated potent inhibitory activity against a variety of cancer cell lines in vitro and against several murine and human tumors grafted in mice in vivo, including those that express multidrug resistance. CPT-11 has also shown synergistic activity in combination with 5-fluorouracil and cisplatin in vitro. No irreversible or unusual toxicities were observed with CPT-11 in animal toxicity studies. In summary, the preclinical profile of CPT-11 confirmed this drug to be an attractive candidate for clinical development.
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PMID:Preclinical evaluation of CPT-11 and its active metabolite SN-38. 863 48

Mutations and reduced expression of DNA topoisomerase I (topo I) gene have been shown to be important in the acquisition of resistance to camptothecin and its analogues in vitro, but their significance has not been verified in vivo. We investigated possible topo I gene mutations and topo I mRNA expression levels in 127 samples obtained from 56 patients with lung tumors, including patients who had developed clinical resistance to topo I inhibitors. No mutations were detected in any of the samples examined and expression levels did not differ significantly between clinically resistant cases and others. However, the topo I mRNA expression level was significantly higher in small cell lung carcinomas than in non-small cell lung carcinomas (P < 0.05). These results suggest that topo I mRNA levels may affect CPT-11 sensitivity in human lung cancer. However, topo I gene mutations and reduced topo I mRNA expression may not be the main mechanism of clinically acquired resistance to camptothecin analogues in vivo.
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PMID:No alteration in DNA topoisomerase I gene related to CPT-11 resistance in human lung cancer. 904 64

CPT-11 is a camptothecin derivative with a broad spectrum of antitumor activity, both in vitro and in vivo. Like camptothecin, CPT-11 is a selective DNA topoisomerase I inhibitor. Phase I trials were conducted in Europe to determine the dose and schedule for phase II trials. These phase I trials assessed the toxicity of CPT-11 in 235 patients and tested three administration schedules: a single infusion once every 3 weeks; a weekly infusion for 3 out of 4 weeks; and a daily infusion for 3 consecutive days every 3 weeks. The maximum tolerated dose (MTD) was 115 mg/m2 in the daily schedule and 145 mg/m2 in the weekly schedule. When the drug was administered once every 3 weeks, diarrhea became the dose-limiting toxicity at doses above 350 mg/m2. This schedule offered the highest dose intensity and the best tolerability profile, and was the most convenient for outpatient treatment. Finally, using this schedule, concomitant administration of high-dose loperamide allowed the dose of CPT-11 to be increased to 750 mg/m2. An ongoing phase I trial is investigating the combination of CPT-11 and 5-fluorouracil (5-FU) in various solid tumors. Although the MTD has not yet been reached, preliminary results show no pharmacokinetic interaction between the two drugs, contrary to a previous Japanese study. Based on the results of the three phase I trials, CPT-11 350 mg/m2 as an intravenous infusion over 30 minutes once every 3 weeks was recommended for phase II trials, which started in Europe in 1992. To date, CPT-11 has shown remarkable efficacy in colorectal cancer, even in patients resistant to 5-FU. Interesting results have also been obtained in pancreatic, cervical and lung cancers. Future trials will explore the place of CPT-11 in combination with other cytotoxic agents or radiotherapy.
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PMID:CPT-11: the European clinical development. 922 29

This article reviews the clinical pharmacokinetics of a water-soluble analogue of camptothecin, irinotecan [CPT-11 or 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy-camptoth eci n]. Irinotecan, and its more potent metabolite SN-38 (7- ethyl-10-hydroxy-camptothecin), interfere with mammalian DNA topoisomerase I and cancer cell death appears to result from DNA strand breaks caused by the formation of cleavable complexes. The main clinical adverse effects of irinotecan therapy are neutropenia and diarrhoea. Irinotecan has shown activity in leukaemia, lymphoma and the following cancer sites: colorectum, lung, ovary, cervix, pancreas, stomach and breast. Following the intravenous administration of irinotecan at 100 to 350 mg/m2, mean maximum irinotecan plasma concentrations are within the 1 to 10 mg/L range. Plasma concentrations can be described using a 2- or 3-compartment model with a mean terminal half-life ranging from 5 to 27 hours. The volume of distribution at steady-state (Vss) ranges from 136 to 255 L/m2, and the total body clearance is 8 to 21 L/h/m2. Irinotecan is 65% bound to plasma proteins. The areas under the plasma concentration-time curve (AUC) of both irinotecan and SN-38 increase proportionally to the administered dose, although interpatient variability is important. SN-38 levels achieved in humans are about 100-fold lower than corresponding irinotecan concentrations, but these concentrations are potentially important as SN-38 is 100- to 1000-fold more cytotoxic than the parent compound. SN-38 is 95% bound to plasma proteins. Maximum concentrations of SN-38 are reached about 1 hour after the beginning of a short intravenous infusion. SN-38 plasma decay follows closely that of the parent compound with an apparent terminal half-life ranging from 6 to 30 hours. In human plasma at equilibrium, the irinotecan lactone form accounts for 25 to 30% of the total and SN-38 lactone for 50 to 64%. Irinotecan is extensively metabolised in the liver. The bipiperidinocarbonylxy group of irinotecan is first removed by hydrolysis to yield the corresponding carboxylic acid and SN-38 by carboxyesterase. SN-38 can be converted into SN-38 glucuronide by hepatic UDP-glucuronyltransferase. Another recently identified metabolite is 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxy-camptothecin (APC). This metabolite is a weak inhibitor of KB cell growth and a poor inducer of topoisomerase I DNA-cleavable complexes (100-fold less potent than SN-38). Numerous other unidentified metabolites have been detected in bile and urine. The mean 24-hour irinotecan urinary excretion represents 17 to 25% of the administered dose. Recovery of SN-38 and its glucuronide in urine is low and represents 1 to 3% of the irinotecan dose. Cumulative biliary excretion is 25% for irinotecan, 2% for SN-38 glucuronide and about 1% for SN-38. The pharmacokinetics of irinotecan and SN-38 are not influenced by prior exposure to the parent drug. The AUC of irinotecan and SN-38 correlate significantly with leuco-neutropenia and sometimes with the intensity of diarrhoea. Certain hepatic function parameters have been correlated negatively with irinotecan total body clearance. It was noted that most tumour responses were observed at the highest doses administered in phase I trials, which indicates a dose-response relationship with this drug. In the future, these pharmacokinetic-pharmacodynamic relationships will undoubtedly prove useful in minimising the toxicity and maximise the likelihood of tumour response in patients.
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PMID:Clinical pharmacokinetics of irinotecan. 934 1

Inactivation of p16INK4, an inhibitor of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6), may be essential for oncogenesis in non-small cell lung cancer (NSCLC). We examined the sensitivity of two clones of p16INK4-transfected NSCLC cell line with homozygous deletion of p16INK4, A549/p16-1 and 2, to DNA topoisomerase I (topo I) inhibitors. A549/p16-1 and -2 showed 7.7- and 9.1-fold increases in sensitivity to CPT-11 (11,7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin ), respectively, compared with A549 cells. Ectopic p16INK4-expressing cells also showed approximately 4.0-fold increase in sensitivity to SN-38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of CPT-11, compared to the parent cells. The topo I-mediated DNA relaxation activities of ectopic p16INK4-expressing cells were approximately 5 times higher than those of the parent cells. Northern and western blot analyses indicate that these increased topo I activities of ectopic p16INK4-expressing cells were due to an elevated topo I mRNA level and an increase in topo I protein. The chemosensitivity to topo I inhibitors, topo I mRNA level, protein content and activity of a p16INK4 revertant, lacking functional p16INK4, tended to be restored toward those of the parental phenotype to some extent. These results suggest that p16INK4 expression is closely associated with the increased sensitivity of ectopic p16INK4-expressing NSCLC cells to topo I inhibitors. The up-regulation of topo I mRNA level, protein content and activity may be responsible for this hypersensitivity.
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PMID:p16INK4 expression is associated with the increased sensitivity of human non-small cell lung cancer cells to DNA topoisomerase I inhibitors. 941 64

CPT-11 (irinotecan) is a DNA topoisomerase I inhibitor active against metastatic colorectal carcinoma. We investigated, in a human colon carcinoma cell line, HT-29, the effects of CPT-11 and 5-fluorouracil (5FU) combinations. A strong synergism between CPT-11 and 5FU was observed after sequential exposure and only additivity or antagonism after simultaneous exposure. When cells were first exposed to 5FU, the product of cellular CPT-11 concentrations versus time (CxT) was 6895 +/- 1020 pmol x hr/10(6) cells, while it was 3875 +/- 121 pmol x hr/10(6) cells with CPT-11 alone (p < 0.01). The same phenomenon was observed with SN-38: 148.2 +/- 49.5 versus 83.4 +/- 23.6 pmol x hr/10(6) cells (p < 0.05). Consequently, the formation of protein-DNA complexes was 1.4 times greater with 5FU pretreatment than with CPT-11 alone (p = 0.03). Moreover, the incorporation of 5FU derivatives into DNA was multiplied by a factor of 1.5 24 hr after CPT-11 exposure. When cells were first incubated with CPT-11, the decrease in thymidylate synthase (TS) activity was identical to that obtained after 5FU exposure (1.09 to 0.023 pmol/min/mg protein), but this decrease persisted for 24 hr (0.014 pmol/min/mg protein) (p = 0.035). At the same time, a 1.8-fold increase in the incorporation of 5FU derivatives into DNA and a 2-fold increase in DNA-protein complex formation were evidenced. With the two sequential associations, we observed a persistent S-phase arrest, as compared with CPT-11 alone. These results suggest that CPT-11 and 5FU combinations are of clinical interest, and mechanisms of interaction between the two drugs seem to be multifactorial.
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PMID:Cellular interactions of 5-fluorouracil and the camptothecin analogue CPT-11 (irinotecan) in a human colorectal carcinoma cell line. 951 77

The induction of severe diarrhea limits the usefulness of the DNA topoisomerase I inhibitor irinotecan (CPT-11) in the treatment of advanced colon cancer. We investigated whether oral administration of the new synthetic bacterial lipopeptide, JBT 3002, encapsulated in phospholipid liposomes could prevent damage to the intestinal epithelium and lamina propria and thus allow for the parenteral administration of high-dose irinotecan to mice with established syngeneic CT-26 colon cancer liver metastases. Treatment of mice with four daily i.p. injections of 100 mg/kg irinotecan was effective against liver metastases but also resulted in loss of body weight and early death. Histopathological examination of the intestines after this treatment revealed loss of villi, epithelial vacuolation, decrease in the number of cells in the crypts in S-phase, increase in the number of apoptotic cells, and reduction in the number of lymphocytes in the lamina propria. In contrast, treatment of mice with the same irinotecan regimen after oral administration of JBT 3002 produced highly significant inhibition of liver metastases without detectable damage to the intestines. Studies that used irinotecan administered once a week for 3 weeks after pretreatment with oral JBT 3002 demonstrated significantly intensified eradication of established CT-26 liver metastases compared with treatment with once-weekly irinotecan alone. Histological studies revealed that the liver metastases in mice treated with oral JBT 3002 and i.p. irinotecan contained a higher number of macrophages than metastases in mice treated with either drug alone. In vitro studies revealed that irinotecan produced direct antiproliferative effects but JBT 3002 did not. Tumor cells exposed to both irinotecan and macrophages activated by JBT 3002 were highly susceptible to lysis. These data show that oral administration of JBT 3002 can prevent irinotecan-induced gastrointestinal toxic effects and maintain the integrity of the lamina propria, thus allowing for intensification of irinotecan therapy against liver metastases from colon cancer.
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PMID:Prevention of intestinal toxic effects and intensification of irinotecan's therapeutic efficacy against murine colon cancer liver metastases by oral administration of the lipopeptide JBT 3002. 974 19

DX-8951f, a water-soluble and non-pro-drug analogue of camptothecin, exhibits a strong inhibitory action on DNA topoisomerase I (Topo I) and in vitro cytotoxicity against various human cancer cell lines. In order to elucidate the mechanisms of its cytotoxicity, we established a DX-8951f-resistant cell line, SBC-3/DXCL1, from human small cell lung cancer cells (SBC-3) by stepwise exposure to DX-8951f. SBC-3/DXCL1 cells were approximately 400 times more resistant to DX-8951f than parent cells. The SBC-3/DXCL1 cells showed a high degree of cross-resistance to other Topo I inhibitors such as CPT-11, SN-38 and camptothecin, but not to non-Topo I targeting agents such as cisplatin, adriamycin, etoposide, and vincristine. The mechanisms of resistance of SBC-3/DXCL1 cells to DX-8951f were examined. Intracellular accumulation of DX-8951f by SBC-3 and SBC-3/DXCL1 cells did not differ significantly. Although the Topo I activity of nuclear extracts obtained from SBC-3/DXCL1 cells was the same as that of the parent cells, the Topo I of SBC-3/DXCL1 cells was resistant to the inhibitory effects of DX8951f and SN-38. Immunoblotting using anti-Topo I antibody demonstrated similar protein levels of Topo I in SBC-3 and SBC-3/DXCL1 cells. The active Topo I protein of SBC-3/DXCL1 was eluted by a high concentration of NaCl (0.4 N) compared with that of SBC-3 (0.3 N). DX-8951f stabilized the DNA-Topo I cleavable complex from SBC-3 cells, as measured by Topo I-mediated cleavage assay. In SBC-3/DXCL1 cells, DX-8951f also stabilized the DNA-Topo I complex, but with a 10-fold lower efficiency. These results suggest that a qualitative change in Topo I contributes, at least partially, to the resistance to DX-8951f in SBC-3/DXCL1 cells. Therefore, SBC-3/DXCL1 cells may have a unique mechanism of resistance to Topo I-directed antitumor drugs.
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PMID:Characterization of a human small-cell lung cancer cell line resistant to a new water-soluble camptothecin derivative, DX-8951f. 991 87

Non-P-glycoprotein-mediated multidrug-resistant C-A120 cells that overexpressed multidrug resistance protein (MRP) were 10.8- and 29. 6-fold more resistant to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and SN-38, respectively, than parental KB-3-1 cells. To see whether MRP is involved in CPT-11 and SN-38 resistance, MRP cDNA was transfected into KB-3-1 cells. The transfectant, KB/MRP, which overexpressed MRP, was resistant to both CPT-11 and SN-38. 2-[4-Diphenylmethyl)-1-piperazinyl]ethyl-5-(trans-4,6-dimethyl-1,3 , 2-dioxaphosphorinan-2-yl)-2, 6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate P-oxide (PAK-104P) and MK571, which reversed drug resistance in MRP overexpressing multidrug-resistant cells, significantly increased the sensitivity of C-A120 and KB/MRP cells, but not of KB-3-1 cells, to CPT-11 and SN-38. The accumulation of both CPT-11 and SN-38 in C-A120 and KB/MRP cells was lower than that in KB-3-1 cells. The treatment with 10 microM PAK-104P increased the accumulation of CPT-11 and SN-38 in C-A120 and KB/MRP cells to a level similar to that found in KB-3-1 cells. The ATP-dependent efflux of CPT-11 and SN-38 from C-A120 and KB/MRP cells was inhibited by PAK-104P. DNA topoisomerase I expression, activity, and sensitivity to SN-38 were similar in the three cell lines. Furthermore, the conversion of CPT-11 to SN-38 in KB-3-1 and C-A120 cell lines was similar. These findings suggest that MRP transports CPT-11 and SN-38 and is involved in resistance to CPT-11 and SN-38 and that PAK-104P reverses the resistance to CPT-11 and SN-38 in tumors that overexpress MRP.
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PMID:ATP-Dependent efflux of CPT-11 and SN-38 by the multidrug resistance protein (MRP) and its inhibition by PAK-104P. 1022 May 71


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