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 × 5 and CPT‐11 20 mg/kg i.p. daily × 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. Int. J. Cancer 88:260–266, 2000. © 2000 Wiley‐Liss, Inc.

Novel camptothecin derivative BNP1350 in experimental human ovarian cancer: Determination of efficacy and possible mechanisms of resistance

“…Oral bioavailability in mice was presumably 67%. 8 Furthermore, BNP1350 retained prolonged lactone stability at physiological pH which has been confirmed in patient plasma. 7 BNP1350 is currently in phase I clinical trials.…”

“…LRP expression was determined with the mouse MAb LRP-56 (IgG2b) 24 and BCRP expression was assessed using the MAb BXP-34. 25 As positive controls, the following cell lines were included: 2780AD (Pgp), GLC4/ADR (MRP1), 2R120 (LRP) 8 and the MCF-7 MR cell line, 26 overexpressing BCRP.…”

“…7 In addition, its activity was not affected by the presence of the multidrug-resistance proteins Pgp, MRP1 or LRP. 8 I.p. administered BNP1350 exhibited Ͼ50% growth inhibition in 6 out of 7 different human tumor xenografts studied.…”

Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)

“…Cancer cells that express BCRP are not resistant to camptothecin itself, or to the camptothecin analogs BNP1350, DX8951f, or NX211 (Ishii et al, 2000;Maliepaard et al, 2001b;Van Hattum et al, 2001;Van Hattum et al, 2002). Studies of SN-38-and irinotecan-resistant PC-6 sublines, which overexpress BCRP, also demonstrated that these cells were not resistant to the clinically promising water-soluble camptothecin analog DX-8951f (Ishii et al, 2000).…”

“…In the drug-resistant human ovarian cancer lines T8 and MX3, developed by exposure of Igrov1 cells to topotecan and mitoxantrone, respectively, resistance associated with overexpression of BCRP was completely abrogated by GF120918 at a nontoxic dose of 100 nm . Reversal of resistance to the promising hydrophilic topoisomerase I inhibitor DX9581f by GF120918, in cells overexpressing BCRP, is variable and may depend on the cell line (Ishii et al, 2000;Van Hattum et al, 2001). …”