Mechanisms of toxicity of hepsulfam in human tumor cell lines.
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.
Pacheco
D Y
DY
Laboratory of Pharmacology, AMC Cancer Research Center, Denver, Colorado 80214.
Cook
C
C
Hincks
J R
JR
Gibson
N W
NW
D000970:Antineoplastic Agents / Q000633:toxicity*; D002066:Busulfan / Q000633:toxicity; D002460:Cell Line; D003114:Colony-Forming Units Assay; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D007942:Leukemia, Experimental / Q000188:drug therapy*; D013451:Sulfonic Acids / Q000633:toxicity*
D000970:Antineoplastic Agents; D013451:Sulfonic Acids; D004247:DNA; C052475:hepsulfam; D002066:Busulfan