Synchronization and recruitment in acute leukemia

The in vivo effects of several chemotherapeutic agents on the mitotic cycle of leukemic blasts in the bone marrow were evaluated by serial measurements of cells in mitosis and in deoxyribonucleic acid (DNA) synthesis as indicated by ability to incorporate tritiated thymidine or tritiated deoxyuridine. 28 studies were done in 23 children and 1 adult. The changes in the marrow after a single injection of L-asparaginase, hydrocortisone, cyclophosphamide, cytosine arabinoside, methotrexate, and an exchange transfusion (62% of the total blood volume) were evaluated. L-asparaginase and hydrocortisone were found to arrest the entry of cells into the S period. Cyclophosphamide appeared to inhibit DNA synthesis, arrest cells in mitosis, and inhibit the entry of cells into the S period. Cytosine arabinoside, and methotrexate inhibited DNA synthesis. During the period of time the cells were inhibited in the S phase by these two drugs, cells continued to enter the S period. Thus partial synchronization was achieved after these two drugs. An exchange transfusion had no consistent effect on the mitotic cycle, but partial synchronization in the S period was seen in one patient. To take advantage of the ability of cystosine arabinoside, to synchronize leukemic cells in the S phase, a second cycle-dependent drug was given at the time the leukemic blasts were synchronized. The second cycle-dependent drugs evaluated were vincristine, methotrexate, and cytosine arabinoside given by intravenous drip over a 12 hr period. Recruitment was found after cytosine arabinoside alone, and after prior synchronization with cytosine arabinoside and then the administration of either of these drugs. The results of these studies indicate that a greater therapeutic advantage can be achieved by a second cycle-dependent drug after synchronization than after the second drug alone.