Topical chemotherapy of intradermal Walker 256 carcinosarcoma with diaziquone and doxorubicin in the rat

A model for metastatic skin cancer using intradermal injection of Walker 256 carcinosarcoma has been developed in the rat. Using this model, antitumor activity of topically applied doxorubicin and diaziquone in Vanicream, Plastibase, and dimethyl sulfoxide (DMSO) as vehicles was compared with intraperitoneal injection of the drugs at the same doses beginning 4 days after injection of tumor cells. Doxorubicin applied topically at 0.5 mg/day for 4 days in Vanicream or Plastibase exhibited no antitumor activity, while i.p. administered doxorubicin at 0.5 mg/day for 4 days inhibited tumor growth at day 20 by 66%. Diaziquone applied topically at 0.1 mg/day for 4 days in Vanicream, Plastibase, or DMSO inhibited tumor growth at day 20 by 66, 86, and 43%, respectively, and cured animals of the skin tumor at a dose of 0.5 mg/day. Diaziquone administered i.p. at 0.5 mg/day for 4 days was lethal to rats, and at 0.1 mg/day it produced 93% inhibition of tumor growth at day 20. Diaziquone applied topically at 0.1 mg/day for 4 days in Plastibase cured rats of advanced tumor when treatment was begun 12 days after injection of tumor cells. The area under the plasma radioactivity time curve over 5 h for a single 0.64-mg dose of topically applied [ring-14C]diaziquone in DMSO was 0.01% that of the same dose of [ring-14C]diaziquone administered i.p. in non-tumored rats. The decrease in WBC count following topical application of diaziquone at a dose of 0.1 mg/day for 4 days, compared to the same dose of diaziquone administered i.p., was 62% in Vanicream, 81% in Plastibase and 33% in DMSO. Topical diaziquone was non-toxic to normal skin in the rat and in the domestic pig. It is concluded that topical application of diaziquone offers a therapeutic advantage over systemic treatment for metastatic cancer of the skin.