Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1,7-Heptanediol disulfamate (hepsulfam, NSC 329680) is a new anti-cancer agent which is currently undergoing phase I clinical trials. The mechanism of action of this compound is not clear at this time. We have recently shown that hepsulfam was more toxic to L1210 leukemia cells than was busulfan. Consistent with the difference in toxicity, we found that hepsulfam induced DNA interstrand cross-links in L1210 mouse leukemia cells, whereas busulfan did not. In the present study, we have found that hepsulfam was more cytotoxic to two human leukemia cell lines (HL-60 and K562) and to two human colon carcinoma cell lines (BE and HT-29) than was busulfan. As in L1210 cells, hepsulfam induced a higher level of DNA interstrand cross-links than busulfan. Both compounds induced DNA-protein cross-links. Hepsulfam was also more cytotoxic to the human leukemia cell lines when the concentrations were reduced 10-fold and the duration of drug exposure was increased to 12-h This more accurately reflects the drug exposures that human leukemia cells may encounter in vivo. Under these 12-h drug exposures, hepsulfam was still able to form DNA interstrand and DNA-protein cross-links, whereas busulfan was only able to form DNA-protein cross-links. These results show that busulfan and hepsulfam react with DNA differently and that hepsulfam is a more potent cytotoxic agent.
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PMID:Mechanisms of toxicity of hepsulfam in human tumor cell lines. 225 4

1,7-Heptanediol disulfamate (hepsulfam, NSC 329680) is a new antileukemic agent with close structural similarity to busulfan. The mechanism 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 L1210 leukemia in vivo (Waud et 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 L1210 leukemia cell line. Our results show that L1210 leukemia cells were 7-fold more sensitive to hepsulfam than busulfan. Only hepsulfam produced an appreciable quantity of DNA interstrand cross-linking in L1210 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 6-12 h after drug treatment. At equimolar concentrations, hepsulfam produced a greater quantity of DNA interstrand cross-links and DNA-protein cross-links than busulfan. In contrast, busulfan produced a greater quantity of DNA-protein cross-links, when compared to hepsulfam at equitoxic concentrations.
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PMID:Comparison of the mechanism of action of busulfan with hepsulfam, a new antileukemic agent, in the L1210 cell line. 276 82