EXPERIMENTAL ANTITUMOR-ACTIVITY AND PHARMACOKINETICS OF THE CAMPTOTHECIN ANALOG IRINOTECAN (CPT-11) IN MICE

Irinotecan (CPT-11) is a semi-synthetic derivative of camptothecin cur rently in clinical trials. In vitro, CPT-11 presented preferential cyt otoxicity toward some solid tumor cells (mouse colon 38 and pancreas 0 3; human pancreas MIA PaCa-2) as compared to leukemia cells (L1210), w hereas SN-38, a metabolite of CPT-11, was not solid tumor selective. I n vivo, schedule of administration studies in P388 leukemia and mammar y adenocarcinoma 16/C (MA16/C) showed that CPT-11 was not markedly sch edule dependent. In order to determine its spectrum of anticancer acti vity, CPT-11 was evaluated against a variety of mouse and human tumors . The end points used were total log cell kill (Lck) for solid tumors and increase in life span (% ILS) for leukemia. Intravenous CPT-11 was found highly active against both early and advanced stage pancreatic ductal 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 os teogenic sarcoma (1.8 Lck); Lewis lung carcinoma (1.4 Lck); B16 melano ma (1.4 Lck); P388 leukemia (170% ILS) and L1210 leukemia (64% ILS). O f interest, CPT-11 was active against tumors with acquired resistance to vincristine (P388/Vcr), to doxorubicin (P388/Dox) and to docetaxel (Calc18/TXT). CPT-11 was also found highly active after oral administr ation in mice bearing P03 and MA16/C tumors. Pharmacokinetic evaluatio ns performed i.v. at the highest non-toxic dosage in mice bearing P03 tumors 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 conc entrations presented a C-max of 1.6 mu g/ml and a terminal half-life o f 7.4 h. Although the CPT-11 tumor levels were similar to the plasma c oncentrations for early time points, drug levels decreased more slowly in the tumor compared to plasma (half-life, 5.0 h). SN-38 tumor level s reached concentrations in the range of 0.32-0.34 mu g/g and decayed with a half-life of 6.9 h. No significant difference in plasma or tumo r pharmacokinetics of either CPT-11 or SN-38 were noted after one or f ive daily i.v. injections. Overall, these data show that CPT-11 has go od activity in experimental models, when administered both by the i.v. and the oral routes. Compared to humans, a similar schedule of admini stration independence was observed and similar CPT-11 levels could be reached at efficacious dosages although metabolite SN-38 levels were f ound higher in mice.