Comparison of melphalan toxicity in human lymphocytic cells and Chinese hamster cells in vitro: the relationship between DNA-DNA cross-link formation and clonogenic survival.

Human CCRF-CEM ('T' cell), EB3p ('B' cell) and RPMI-8226 (myeloma cell) lymphocytic cell lines were an order of magnitude more sensitive to melphalan (MEL) than Chinese hamster, V-79-753B, cells even though the amount of [14C]MEL they incorporated was less than 50% of that incorporated into the rodent cells: the D0 values were 0.16, 0.20 and 0.30 microgram/ml respectively compared with 1.6 micrograms/ml. Furthermore, MEL sensitivity was not related to the total thiol content of the cells. DNA-DNA cross-linking was not detectable in lymphocytic cells using the alkaline elution technique at doses of MEL used for clonogenic survival, whereas in Chinese hamster cells both parameters were assessable within the same dose range. At high concentrations of MEL there was a direct relationship between DNA-DNA cross-linking and drug dose in each lymphocytic cell line. Changes in the amounts of DNA-DNA cross-linking, at different MEL concentrations, increased directly with the sensitivity of the cells, viz. CCRF-CEM greater than EB3p greater than RPMI-8226. Calculated survival values for doses of MEL which produced measurable DNA-DNA cross-linking showed that there was a similar relationship between these parameters for the three lymphocytic cell lines which was different from that for Chinese hamster cells. It is concluded that the contribution of DNA-DNA cross-links in determining cell survival after MEL treatment is both quantitatively and possibly qualitatively different in human and rodent cells and that DNA-DNA cross-linking cannot be used as an indicator of MEL sensitivity in human lymphocytic cells unless parallel clonogenic survival studies are also undertaken.