Human T-cell Acute Leukemia Cell Research Articles

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 μg/ml × 24 h) completely restored dCTP pools but only partially protected against thymidine cytotoxicity (100–1000μg/ml × 24 h) and thymidine-carboplatin sensitization (up to 60 μg 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 μg deoxyadenosine/ml partially prevented cytotoxicity and carboplatin sensitization by 300 μg 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.

Thymidine-cisplatin vs thymidine-carboplatin interactions in human T-cell acute leukemia

Thymidine is shown to sensitize JM human T-cell acute leukemia cells to cisplatin killing in vitro with dose modifying factors of 1.72, 1.62, and 1.76 at 200, 500, and 1000 μg thymidine/ml × 24 h. The magnitude of thymidine-cisplatin sensitization increases with longer thymidine exposures (500 μg/ml) up to 16 h but is not further increased at 24 h. For a 25 h thymidine exposure, enhancement is greater for cisplatin (3 μg/ml × 1 h) starting 12–24 h into the thymidine exposure vs starting at 0–8 h ( p ⩽ 0.0004). Results are precisely the same for simultaneous studies using carboplatin except that (1) thymidine enhances carboplatin cytotoxicity more than cisplatin killing, (2) enhancement of carboplatin killing varies little with the timing of carboplatin administration during a 25 h thymidine exposure. These findings are discussed relative to their clinical applicability.