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.