Deoxyribonucleoside triphosphate pools and thymidine chemosensitization in human T-cell leukemia.
Thymidine kills cells by depleting dCTP stores. The present experiments tested whether deoxycytidine, by replenishing dCTP pools, could prevent thymidine cytotoxicity and thymidine's enhancement of carboplatin killing in two human T-cell acute leukemia cell lines. MOLT3 and JM cells were exposed to combinations of thymidine, deoxycytidine, and carboplatin and then assessed for survival, the magnitude of thymidine-carboplatin chemosensitization, and changes in deoxyribonucleoside triphosphate pools. For both cell lines, deoxycytidine (up to 144.5 micrograms/ml x 24 h) completely restored dCTP pools but only partially protected against thymidine cytotoxicity (100-1000 micrograms/ml x 24 h) and thymidine-carboplatin sensitization (up to 60 micrograms carboplatin/ml during the last hour of thymidine). This contrasts with complete protection in prior studies using other cell types. Thymidine alone markedly increased dTTP and dGTP pools and decreased dCTP; dATP pools underwent a sharp decline which has not been observed before in any cell line. In subsequent studies 0.0336-137.3 micrograms deoxyadenosine/ml partially prevented cytotoxicity and carboplatin sensitization by 300 micrograms thymidine/ml. Together, deoxycytidine and deoxyadenosine completely prevented thymidine-carboplatin sensitization even though dATP and dCTP pools were not entirely returned to normal. These findings are discussed in regard to the unusual sensitivity of T-cell malignancies to thymidine toxicity, mechanisms of cytotoxicity and chemosensitization by thymidine, and the possibility of thymidine selectively sensitizing T-cell malignancies to killing by alkylating agents.
Cohen
J D
JD
Division of Hematology-Oncology, Denver Veterans Administration Medical Center, CO 80220.
Robins
H I
HI
Katz
T B
TB
Miller
E M
EM
Kuzminsky
S R
SR
Javid
M J
MJ
D016190:Carboplatin / Q000008:administration & dosage; D003839:Deoxyadenosines / Q000378:metabolism; D003841:Deoxycytidine / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000378:metabolism*; D006801:Humans; D015458:Leukemia, T-Cell / Q000378:metabolism* / Q000473:pathology; D013936:Thymidine / Q000378:metabolism / Q000633:toxicity*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D003839:Deoxyadenosines; D003854:Deoxyribonucleotides; D003841:Deoxycytidine; D016190:Carboplatin; D013936:Thymidine