Uptake and binding of 3'-(3-cyano-4-morpholinyl)-3'-deaminoadriamycin and 3'-(4-morpholinyl)-3'-deaminoadriamycin in...

3'-(3-Cyano-4-morpholinyl)-3'-deaminoadriamycin (CMA) and 3'-(4-morpholinyl)-3'-deaminoadriamycin (MA) are analogues of Adriamycin, with altered cytotoxic activity. CMA is 100- to 1500-fold more cytotoxic than Adriamycin and possesses unique DNA crosslinking activity. Intact MA does not crosslink DNA and has a cytotoxicity equivalent to Adriamycin, but it retains its activity in anthracycline-resistant cells. In this study, uptake and binding of [3H]CMA and [3H]MA in L5178Y lymphoblasts were examined. Both CMA and MA were rapidly taken up by cells at 37 degrees C and concentrated almost exclusively in the nucleus. All of the intracellular MA was TCA-soluble, but only 45% of this drug effluxed from the cells by 4 hr. More than 50% of CMA in the cells was TCA-insoluble, and approximately 40% effluxed from the cells by 4 hr through loss of the TCA-soluble fraction. CMA differed from other alkylating agents in that more than 97% of the bound drug was associated with DNA. The bound drug was partially lost from the DNA by a process that may have involved DNA repair.