APPARENT INTERACTION OF DIMETHYL-SULFOXIDE WITH CISPLATIN RELEASED FROM POLYMER DELIVERY DEVICES INJECTED SUBCUTANEOUSLY IN DOGS

Local tissue toxicity, systemic toxicity and platinum pharmacokinetics were evaluated in 6 normal healthy beagle dogs injected subcutaneousl y with two formulations of a polylactide biodegradable polymer (Atrige l (R)) system containing cisplatin. Dogs were injected 4 times at 30 d ay intervals at platinum dosages of 70, 105 and 157.5 mg/m(2) (dose es calation). Once pharmacokinetics were established, 29 dogs with sponta neous stage IIb appendicular osteosarcoma were treated with 4 injectio ns of the same polymer system containing cisplatin at 70 mg/m2 (20 dog s) and 100 mg/m(2) (9 dogs) to establish efficacy against micrometasta tic disease. Local tissue toxicity was variable. Systemic toxicity, as judged by clinicopathologic evaluation was not noted at any dose leve l or injection number. Interim (6 month) survival analysis revealed a median disease-free interval of 180 days. Consistent platinum release characteristics were found, however, the lack of toxicity and decrease d disease-free-interval raised concerns over the biologic activity of the cisplatin. Prior to completion of the study, it was discovered tha t dimethyl sulfoxide, the solvent used in the co-polymer system, may b e responsible for biologic inactivation of cisplatin. This was subsequ ently demonstrated in tissue culture assays. The clinical trial was su spended and dogs were treated with traditional chemotherapy.