The development of increasing numbers of drugs with significant antineoplastic activity, improvements in our ability to measure the effects of these drugs on cell biologic functions, and the development of in vitro and in vivo models for combination chemotherapy have made rational development of combination and sequential chemotherapy for malignancy possible. Hydroxyurea (HU) is a drug which inhibits ribonucleotide reductase resulting in decreased intracellular deoxyribonucleotide triphosphate (dNTP) pools and decreased rates of DNA synthesis and repair. HU has been shown in vitro to significantly potentiate the antineoplastic activity of several classes of antineoplastic drugs including other antimetabolites, alkylating agents, and drugs which intercalate DNA or interfere with topoisomerase II function. Preliminary studies in this laboratory have shown that HU potentiation of the antineoplastic effects of cyclophosphamide (CY), 4'-(9-acridinylamino) -methanesulfon-M- anisidide (AMSA) and an epipodophyllotoxin (VP16) can be demonstrated in vivo in a rat model for acute leukemia, the LBN- ML. In this model the optimum sequences for HU potentiation of these drugs are determined. The differences in optimum sequencing of HU with CY versus AMSA have led to a testable hypothesis regarding the mechanism of these effects and to the design of a clinical trial for refractory human leukemia. The hypothesis is that HU administration subsequent to CY but prior to or simultaneously with AMSA or VP16 will maximize therapeutic benefit by simultaneously inhibiting the repair of CY induced DNA damage and increasing the binding sites of AMSA and VP16. To test this hypothesis we plan simultaneous and separate measures of cell kinetic and biochemical events induced by these drugs. Measurements of dNTP pool size reduction and DNA content distribution following HU, and alkaline elution and K+SDS determination of DNA single strand breaks and DNA protein cross links after CY, AMSA and VP16 will be correlated with the antineoplastic effects of specific sequences of these drugs in the rat. While these rat model studies are being conducted to refine the hypothesis, clinical trials demonstrating the feasibility of similar combinations and sequences for human malignancy will be done. The ultimate goal is more rational design of sequential combination chemotherapy for human malignancy, especially in high dose chemotherapy protocols employing bone marrow rescue where antineoplastic cytotoxic efficiency must be maximized.

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National Cancer Institute (NCI)
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Experimental Therapeutics Subcommittee 2 (ET)
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University of Nebraska Medical Center
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