In vitro studies on the mechanism of action of hepsulfam in chronic myelogenous leukemia patients.
In the present study we have characterized the cytotoxicity and DNA damage induced by hepsulfam and busulfan in cells isolated from both chronic myelogenous leukemia (CML) patients and normal donors. hepsulfam inhibited colony-forming units-granulocyte, macrophage to a greater extent than busulfan in peripheral blood cells (PBCs) isolated from CML patients. Normal PBCs were equally sensitive to both agents and were more sensitive than the cells isolated from CML patients. Hepsulfam induced DNA interstrand cross-links in PBCs and bone marrow from both CML and normal volunteers, whereas busulfan produced few or no DNA interstrand cross-links. In addition, hepsulfam induced higher levels of DNA interstrand cross-linking than busulfam in three samples isolated from CML patients in blast crisis. Busulfan did however cause a small number of DNA strand breaks to be formed in human cells. Both agents produced similar levels of DNA-protein cross-links in PBCs from CML patients. These results suggest that the mechanism of DNA reactivity of hepsulfam and busulfan differ and that hepsulfam may prove useful in the treatment of CML.
Hincks
J R
JR
Laboratory of Pharmacology, AMC Cancer Research Center, Denver, Colorado 80214.
Adlakha
A
A
Cook
C A
CA
Johnson
C S
CS
Furmanski
P
P
Gibson
N W
NW
D000970:Antineoplastic Agents / Q000494:pharmacology; D002066:Busulfan; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D013451:Sulfonic Acids / Q000494:pharmacology*
D000970:Antineoplastic Agents; D013451:Sulfonic Acids; C052475:hepsulfam; D002066:Busulfan