New highly lipophilic camptothecin BNP1350 is an effective drug in experimental human cancer
| Autor: | A H, Van Hattum, H M, Pinedo, H M, Schlüper, F H, Hausheer, E, Boven |
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| Rok vydání: | 2000 |
| Předmět: |
Ovarian Neoplasms
Lung Neoplasms Mice Nude Irinotecan Antineoplastic Agents Phytogenic Xenograft Model Antitumor Assays Drug Resistance Multiple Mice Doxorubicin Carcinoma Non-Small-Cell Lung Neoplasms Colonic Neoplasms Tumor Cells Cultured Animals Humans Camptothecin Female ATP Binding Cassette Transporter Subfamily B Member 1 Carcinoma Small Cell Enzyme Inhibitors Melanoma |
| Zdroj: | International journal of cancer. 88(2) |
| ISSN: | 0020-7136 |
| Popis: | 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 (p0.05) 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 of50% 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. |
| Databáze: | OpenAIRE |
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