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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA045529-02
Application #
3188626
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1988-07-01
Project End
1991-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Tracewell, W G; Trump, D L; Vaughan, W P et al. (1995) Population pharmacokinetics of hydroxyurea in cancer patients. Cancer Chemother Pharmacol 35:417-22
Vaughan, W P; Reed, E C; Edwards, B et al. (1994) High-dose cyclophosphamide, thiotepa and hydroxyurea with autologous hematopoietic stem cell rescue: an effective consolidation chemotherapy regimen for early metastatic breast cancer. Bone Marrow Transplant 13:619-24
Smith, D C; Vaughan, W P; Gwilt, P R et al. (1993) A phase I trial of high-dose continuous-infusion hydroxyurea. Cancer Chemother Pharmacol 33:139-43
Vaughan, W P; Bierman, P J; Reed, E C et al. (1992) High-dose hydroxyurea in autologous bone marrow transplantation: a promising ""new"" agent. Semin Oncol 19:110-5