New highly lipophilic camptothecin BNP1350 is an effective drug in experimental human cancer.
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.
Van Hattum
A H
AH
Department of Medical Oncology, Academic Hospital Vrije Universiteit, Amsterdam, The Netherlands.
Pinedo
H M
HM
Schlüper
H M
HM
Hausheer
F H
FH
Boven
E
E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D018288:Carcinoma, Small Cell / Q000188:drug therapy; D003110:Colonic Neoplasms / Q000188:drug therapy; D004317:Doxorubicin / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; C406143:cositecan; D000077146:Irinotecan; D004317:Doxorubicin; D002166:Camptothecin