New highly lipophilic camptothecin BNP1350 is an effective drug in experimental human cancer.

Abstract

BNP1350, 7-[(2-trimethylsilyl)ethyl]-20(S)-camptothecin, is a novel semi-synthetic, highly lipophilic, silicon-containing camptothecin and an inhibitor of topoisomerase I. It has been supercomputer engineered for superior oral bioavailability, superior lactone stability, broad anti-tumor activity, increased potency and insensitivity to Pgp/MRP/LRP drug resistance. We determined the efficacy of BNP1350 in experimental human colon cancer and compared its anti-tumor effects with those of CPT-11/SN-38. We also determined a possible influence of Pgp, MRP and LRP on the efficacy of BNP1350. The in vitro anti-proliferative capacity of the compounds using various exposure times was assessed in five colon cancer cell lines and indicated that BNP1350 was similarly effective or slightly more potent than SN-38. Four cell lines of other origin with sublines expressing Pgp, MRP and/or LRP showed that BNP1350 was significantly more effective than SN-38 (p < 0.05) and that the activity of BNP1350 was not reduced in multidrug-resistant cells. For in vivo experiments, BNP1350 was given 1.0 mg/kg i.p. or 1.5 mg/kg p.o. daily x 5 and CPT-11 20 mg/kg i.p. daily x 5 being equitoxic schedules in nude mice bearing s.c. human tumor xenografts. The schedules were studied in colon cancer xenografts COLO320, COLO205 or WiDr as well as in two Pgp-positive xenografts 2780AD and BRO/mdr1.1 and the parental Pgp-negative A2780 ovarian cancer xenografts and BRO melanoma xenografts. Growth inhibition of >50% was obtained for BNP1350 given i.p. in six out of the seven xenografts studied. BNP1350 was similarly effective when given i.p. or p.o. CPT-11 was as effective as BNP1350, except in BRO and BRO/mdr1.1 xenografts. Pgp expression in xenografts in vivo confirmed that there was no negative influence on the efficacy of BNP1350. In conclusion, BNP1350 shows a broad spectrum of activity in experimental human tumors and is a suitable candidate for oral treatment of cancer.

• Authors: A H Van Hattum, H M Pinedo, H M Schlüper, F H Hausheer, E Boven
• Journal: International journal of cancer (Int J Cancer) Vol. 88 Issue 2 Pg. 260-6 (Oct 15 2000) ISSN: 0020-7136 [Print] United States
• PMID: 11004678 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright 2000 Wiley-Liss, Inc.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents, Phytogenic
• Enzyme Inhibitors
• cositecan
• Irinotecan
• Doxorubicin
• Camptothecin

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (analysis)
• Animals
• Antineoplastic Agents, Phytogenic (therapeutic use)
• Camptothecin (analogs & derivatives, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy)
• Carcinoma, Small Cell (drug therapy)
• Colonic Neoplasms (drug therapy)
• Doxorubicin (therapeutic use)
• Drug Resistance, Multiple
• Enzyme Inhibitors (therapeutic use)
• Female
• Humans
• Irinotecan
• Lung Neoplasms (drug therapy)
• Melanoma (drug therapy)
• Mice
• Mice, Nude
• Neoplasms (drug therapy)
• Ovarian Neoplasms (drug therapy)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays