Dependence on treatment time of melphalan resistance and DNA cross-linking in human melanoma cell lines.

In the human melanoma cell line MM127 , the melphalan survival curve was linear and exhibited reciprocity with respect to concentration and treatment time. The survival curve of an allogeneic line, MM253c1 , exhibited a shoulder and, on a concentration X time basis, was resistant to 1-hr compared with 4-hr treatment. This type of resistance, which was not found using chlorambucil, nitrogen mustard, or methyl methanesulfonate, could be overcome by simultaneous hyperthermia (42 degrees) but not by treatment with thymidine or caffeine. Both lines had similar levels of DNA interstrand cross-linking (perchlorate renaturation method) after 1-hr treatment, but MM253c1 cells were able to repair most of this damage during the next 23 hr. The cross-links formed in MM253c1 cells after 1 hr were predominantly heat sensitive and photoresistant , whereas those formed in MM127 cells were heat resistant and photosensitive. These results suggest that melphalan formed repairable (possibly diadeninyl or adeninyl - guaninyl ) cross-links in MM253c1 cells during the first hr of treatment and nonrepairable , possibly diguaninyl cross-links in MM127 cells at all stages of treatment. It appears therefore that the mode of action of melphalan and the effect of synergistic agents may not be identical in all cells.