Effects of Cytochalasin B in Culture and in Vivo on Murine Madison 109 Lung Carcinoma and on B16 Melanoma

Cytochalasin B (CB), at 100 or at 10 mg/kg single dose s.c. in carboxymethyl-cellulose (2%)/Tween-20 (1%) 24 h after s.c. challenge of B6D2F, mice with trocar implants of B16F10 tumor s.c, delayed the appearance of measurable tumor nodules by 157 and 93%, respectively, and extended host survival by 65 and 26%. Tumor growth was also delayed when CB treatment was given 1 day after the appearance of palpable tumor nodules. By in vivo bioassay, in vitro cloning, and dye exclusion measurements, solid tumor nodules treated in vivo with CB at either 100 or 10 mg/kg showed the same viability and tumorigenicity as did vehicle-treated nodules 4 and 6 days after drug treatment, at which time growth inhibition was still apparent. This indicates that growth inhibition by CB is not dependent on a gross cytotoxic effect. CD2Fi mice challenged s.c. with Madison 109 lung carcinoma cells and treated with CB s.c. at 100 or 150 mg/kg 24 h later showed a 66% delay in the median day of tumor nodule appearance. When administered under these conditions or at the time of nodule appearance, CB markedly inhibited the rate of tumor growth, prevented tumor invasion at day 23, extended life span by 23%, and significantly inhibited spontaneous lung metastases measured 28 days after tumor challenge. Maximum tolerated doses of CB administered i.p., s.c, or i.v. in suspension or in solution are defined. These results delineate the conditions under which CB can be tested for in vivo biological activities and establish that this microfilament-active natural product in a single-agent protocol inhibits local tumor growth and extends survival in B16F10 melanoma and Madison 109 lung carcinoma, and, in the latter model, inhibits invasion and spontaneous lung metastases by mechanisms that do not appear to depend on cytotoxicity. This work on formulation, tolerated doses iji vivo, and localized peritu-moral effects of CB now permits evaluation of systemic antitumor effects of cytochalasin B as a single agent. It also permits chemotherapy studies using CB as a potential amplifier of the activity of other antitumor agents in vivo.