title: Deoxyribonucleoside triphosphate pools and thymidine chemosensitization in human T-cell leukemia.
abstract: 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.
authors.affiliation: Division of Hematology-Oncology, Denver Veterans Administration Medical Center, CO 80220.
authors.forename: J D
authors.initials: JD
authors.lastname: Cohen
authors.forename: H I
authors.initials: HI
authors.lastname: Robins
authors.forename: T B
authors.initials: TB
authors.lastname: Katz
authors.forename: E M
authors.initials: EM
authors.lastname: Miller
authors.forename: S R
authors.initials: SR
authors.lastname: Kuzminsky
authors.forename: M J
authors.initials: MJ
authors.lastname: Javid
mesh_terms: 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
chemical_list: D003839:Deoxyadenosines; D003854:Deoxyribonucleotides; D003841:Deoxycytidine; D016190:Carboplatin; D013936:Thymidine