Comparison of the Mechanism of Action of Busulfan with Hepsulfam, a New Antileukemic Agent, in the LI 210 Cell Line1

1,7-1 Irpiatirti ¡ol d¡sull'amati-(hepsulfam, NSC 329680) is a new antileukemic agent with close structural similarity to busulfan. The mecha nism of action of hepsulfam is not known and it has recently been entered into Phase I clinical trials by the National Cancer Institute. Waud et al. have recently shown that hepsulfam has good antitumor activity against mouse 1.1210 leukemia in vivo (Waud el al., Proc. Am. Assoc. Cancer Res., 29:333,1988). In contrast, busulfan was inactive against this model tumor system. In the present study, we have compared the in vitro cytotoxicity of hepsulfam with that of busulfan and we also examined the ability of these compounds to induce DNA damage in the I 1210 leukemia cell line. Our results show that 1,12111 leukemia cells were 7-fold more sensitive to hepsulfam than busulfan. Only hepsulfam produced an ap preciable quantity of DNA interstrand cross-linking in 1.12 III cells, with the peak of cross-link formation being delayed 12 h following a 2-h drug treatment. In contrast, both compounds also produced DNA-protein cross-linking, again with the formation of peak levels being delayed 612 h after drug treatment. At equimolar concentrations, hepsulfam pro duced a greater quantity of DNA interstrand cross-links and DNA-protein cross-links than busulfan. In contrast, busulfan produced a greater quan tity of DNA-protein cross-links, when compared to hepsulfam at equitoxic concentrations.