BNP7787, a novel protector against platinum-related toxicities, does not affect the efficacy of cisplatin or carboplatin in human tumour xenografts.
BNP7787 (2',2'-dithio-bis-ethane sulphonate sodium), a water-soluble disulphide, is chemically and mechanistically different from other sulphur-containing chemoprotective agents. Presently, BNP7787 is under investigation for its protective properties with regard to the side-effects of platinum compounds. In this study, we evaluated BNP7787, mesna and amifostine for their effects on the antitumour activity of platinum compounds. Continuous exposure to BNP7787 did not affect the antiproliferative effects of cisplatin or carboplatin, but the efficacy of both compounds was reduced in the presence of mesna in vitro in two human ovarian cancer cell lines. BNP7787 or amifostine combined with cisplatin or carboplatin given in standard schedules for the treatment of nude mice bearing well-established OVCAR-3 xenografts did not interfere with platinum-induced inhibition of tumour growth. Of interest, BNP7787 or amifostine co-administered with carboplatin was significantly more effective than carboplatin alone (P<0.01). In the presence of amifostine, doses of cisplatin and carboplatin could be safely increased by factors of 1.6 and 1.5, respectively. Unlike in a previous study of BNP7787 in tumour-bearing rats, BNP7787 did not protect against additional weight loss following treatment with higher doses of cisplatin in OVCAR-3-bearing mice. Pharmacokinetics of (mixed) disulphides including BNP7787 and extractable mesna in deproteinised plasma revealed a rapid disappearance of BNP7787 and an AUC(5-60) value of mesna 9-fold lower than that calculated after an equivalent dose of mesna by weight. We can conclude that BNP7787 does not interfere with the antitumour activity of platinum compounds in vitro and in vivo. Clinical trials are underway to evaluate the protection of normal tissues by BNP7787 when combined with cisplatin.
Boven
E
E
Department of Medical Oncology, Vrije Universiteit Medical Centre, De Boelelaan 1117, Amsterdam, The Netherlands. e.boven@vumc.edu
Verschraagen
M
M
Hulscher
T M
TM
Erkelens
C A M
CA
Hausheer
F H
FH
Pinedo
H M
HM
van der Vijgh
W J F
WJ
D004999:Amifostine / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016190:Carboplatin / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007928:Lethal Dose 50; D015080:Mesna / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020011:Protective Agents / Q000494:pharmacology*; D011837:Radiation-Protective Agents / Q000494:pharmacology; D014183:Transplantation, Heterologous; D015431:Weight Loss
D000970:Antineoplastic Agents; D020011:Protective Agents; D011837:Radiation-Protective Agents; C027032:2,2'-dithiodiethanesulfonic acid; D016190:Carboplatin; D004999:Amifostine; D015080:Mesna; D002945:Cisplatin