PHARMACOLOGICAL MODULATION OF CISPLATIN TOXICITY RHYTHMS WITH BUTHIONINE SULFOXIMINE IN MICE BEARING PANCREATIC ADENOCARCINOMA (PO3)

In a previous report, we showed that the circadian rhythm of cisplatin (cis-diamminedichloroplatinum, CDDP) toxicity in healthy mice was mod ified by buthionine sulfoximine (BSO), a specific inhibitor of glutath ione (GSH) synthesis. In the present study, the effects of BSO on the rhythms of CDDP toxicity and antitumor efficacy were investigated in m ice bearing a transplantable pancreatic adenocarcinoma (PO3). B6D2F1 m ice were inoculated with two 4 mm(3) tumor fragments, one in each flan k, then were synchronized with an alternation of 12h of light (L) and 12h of darkness (D) (LD 12:12). Three weeks later, a single dose of CD DP (12 mg/kg iv) was injected at 3h, 7h, 11h, 15h, 19h, or 23h after l ight onset (HALO) with or without prior BSO (450 mg/kg ip 4h earlier). The antitumor activity of CDDP as assessed by tumor weight change and tumor growth delay was weak in this tumor model irrespective of prior BSO administration or CDDP dosing time. Nevertheless, toxic effects o f CDDP as gauged by body weight loss or survival varied significantly according to CDDP dosing time. Body weight loss was least in mice rece iving CDDP alone at the mid-to-late active span. Survival rate was 97% in mice treated with CDDP alone and 47% in those receiving prior BSO (chi(2) = 23.6, p < .0001). BSO pretreatment further shifted the perio d of survival or body weight change from 24h to (10 + 24)h, an effect similar to that earlier reported in healthy mice. Thus, PO3 tumor at a measurable stage altered neither the circadian rhythm in CDDP toxicit y nor the ultradian rhythm in the toxicity of BSO-CDDP combination. Th e results suggest that rhythms in target tissues for drug actions can be manipulated with biochemical modulators, thus partly escaping centr al clock control.