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Titolo:
EXPERIMENTAL ANTITUMOR-ACTIVITY AND PHARMACOKINETICS OF THE CAMPTOTHECIN ANALOG IRINOTECAN (CPT-11) IN MICE
Autore:
BISSERY MC; VRIGNAUD P; LAVELLE F; CHABOT GG;
Indirizzi:
RHONE POULENC RORER SA,CTR RECH VITRY ALFORTVILLE F-94403 VITRY SUR SEINE FRANCE INST GUSTAVE ROUSSY,CNRS URA 147,LAB PHARMACOTOXICOL & PHARMACOGENET F-94805 VILLEJUIF FRANCE
Titolo Testata:
Anti-cancer drugs
fascicolo: 4, volume: 7, anno: 1996,
pagine: 437 - 460
SICI:
0959-4973(1996)7:4<437:EAAPOT>2.0.ZU;2-4
Fonte:
ISI
Lingua:
ENG
Soggetto:
TOPOISOMERASE-I INHIBITOR; HUMAN TUMOR XENOGRAFTS; CELL LUNG-CANCER; PHASE-I; STEM-CELLS; AGENTS; MOUSE; ESTABLISHMENT; RESISTANCE; METABOLITE;
Keywords:
ANTITUMOR ACTIVITY; CPT-11; CAMPTOTHECIN ANALOG; IRINOTECAN; PHARMACOKINETICS; MICE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
48
Recensione:
Indirizzi per estratti:
Citazione:
M.C. Bissery et al., "EXPERIMENTAL ANTITUMOR-ACTIVITY AND PHARMACOKINETICS OF THE CAMPTOTHECIN ANALOG IRINOTECAN (CPT-11) IN MICE", Anti-cancer drugs, 7(4), 1996, pp. 437-460

Abstract

Irinotecan (CPT-11) is a semi-synthetic derivative of camptothecin currently in clinical trials. In vitro, CPT-11 presented preferential cytotoxicity toward some solid tumor cells (mouse colon 38 and pancreas 03; human pancreas MIA PaCa-2) as compared to leukemia cells (L1210), whereas SN-38, a metabolite of CPT-11, was not solid tumor selective. In vivo, schedule of administration studies in P388 leukemia and mammary adenocarcinoma 16/C (MA16/C) showed that CPT-11 was not markedly schedule dependent. In order to determine its spectrum of anticancer activity, CPT-11 was evaluated against a variety of mouse and human tumors. The end points used were total log cell kill (Lck) for solid tumorsand increase in life span (% ILS) for leukemia. Intravenous CPT-11 was found highly active against both early and advanced stage pancreaticductal adenocarcinoma 03 (P03), with 60% long-term survivors and 100%complete regressions, respectively. Other responsive tumors included:colon adenocarcinomas 38 and 51 (both 1.0 Lck); MA16/C (3.4 Lck); MA13/C (1.0 Lck); human Calc18 breast adenocarcinoma (2.8 Lck); Glasgow osteogenic sarcoma (1.8 Lck); Lewis lung carcinoma (1.4 Lck); B16 melanoma (1.4 Lck); P388 leukemia (170% ILS) and L1210 leukemia (64% ILS). Of interest, CPT-11 was active against tumors with acquired resistanceto vincristine (P388/Vcr), to doxorubicin (P388/Dox) and to docetaxel(Calc18/TXT). CPT-11 was also found highly active after oral administration in mice bearing P03 and MA16/C tumors. Pharmacokinetic evaluations performed i.v. at the highest non-toxic dosage in mice bearing P03tumors revealed CPT-11 peak plasma concentrations (C-max) of 8.9 mu g/ml and a terminal half-life of 0.6 h. The metabolite SN-38 plasma concentrations presented a C-max of 1.6 mu g/ml and a terminal half-life of 7.4 h. Although the CPT-11 tumor levels were similar to the plasma concentrations for early time points, drug levels decreased more slowly in the tumor compared to plasma (half-life, 5.0 h). SN-38 tumor levels reached concentrations in the range of 0.32-0.34 mu g/g and decayedwith a half-life of 6.9 h. No significant difference in plasma or tumor pharmacokinetics of either CPT-11 or SN-38 were noted after one or five daily i.v. injections. Overall, these data show that CPT-11 has good activity in experimental models, when administered both by the i.v. and the oral routes. Compared to humans, a similar schedule of administration independence was observed and similar CPT-11 levels could bereached at efficacious dosages although metabolite SN-38 levels were found higher in mice.

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Documento generato il 28/11/20 alle ore 04:42:57