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 modified by buthionine sulfoximine (BSO), a specific inhibitor of glutathione (GSH) synthesis. In the present study, the effects of BSO on the rhythms of CDDP toxicity and antitumor efficacy were investigated in mice bearing a transplantable pancreatic adenocarcinoma (PO3). B6D2F1 mice were inoculated with two 4 mm3 tumor fragments, one in each flank, then were synchronized with an alteration of 12 h of light (L) and 12 h of darkness (D) (LD 12:12). Three weeks later, a single dose of CDDP (12 mg/kg i.v.) was injected at 3 h, 7 h, 11 h, 15 h, 19 h, or 23 h after light onset (HALO) with or without prior BSO (450 mg/kg i.p. 4 h 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 of CDDP as gauged by body weight loss or survival varied significantly according to CDDP dosing time. Body weight loss was least in mice receiving 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 period of survival or body weight change from 24 h 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 toxicity nor the ultradian rhythm in the toxicity of BSO-CDDP combination. The results suggest that rhythms in target tissues for drug actions can be manipulated with biochemical modulators, thus partly escaping central clock control.