The response of hypoxic B16 melanoma cells to in vivo treatment with chemotherapeutic agents.

Survival curves are presented for the treatment of B16 melanomas with a range of single doses of cyclophosphamide (CY), 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), or 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl)-1-nitro-sourea (MeCCNU). When these four drugs are assessed in terms of the tumor cell kill at the lethal dose to 10% of the mice, MeCCNU is found to be much the most effective, followed by CCNU, and then CY and BCNU together. The superiority of MeCCNU is possibly related to the fact that it seems to be longer lived in the mice than are the other drugs. Combined drug and irradiation experiments have indicated that CY kills both oxygenated and hypoxic cells in the tumor, leaving proportions equal to those in the tumor prior to treatment, whereas BCNU preferentially spares the hypoxic cells. Since hypoxic cells constitute a population of cells that is at a distance from blood vessels, this result suggests that CY treatment of B16 melanomas is not limited by an inability of the drug to diffuse to cells away from blood vessels.