The aim is to establish a rational basis for the use of the naturally-occurring nucleoside deoxycytidine as a potentially host-selective protective agent, and to implement phase I-II studies employing high-dose deoxycytidine in patients with refractory leukemia and solid tumors. These efforts are based on preclinical studies suggesting that supraphysiologic concentrations of deoxycytidine stimulate the growth of normal but not leukemic myeloid progenitor cells, and preferentially protect normal elements from the in vitro inhibitory effects of inhibitors of de novo pyrimidine biosynthesis (e.g., thymidine and 3-deazauridine) as well as cytosine arabinoside. Biochemical studies of high-dose deoxycytidine metabolism will be performed in human leukemic myeloblasts in order to determine whether the selective inability of deoxycytidine to protect these cells is related to impaired nucleotide formation (e.g., decreased deoxycytidine kinase activity) or augmented degradative processes (e.g., increased activity of cytidine deaminase, deoxycytidylate deaminase or 5'-nucleotidase). Soft agar cloning studies will be performed designed to compare the effects of deoxycytidine on pyrimidine antagonist-mediated growth inhibition in normal human (CFU-GM) and leukemic (L-CFU) myeloid progenitor cells. The objective will be to identify deoxycytidine and pyrimidine antagonist dose relationships and schedules exerting a selective cytotoxic effect toward leukemic cells while sparing their normal counterparts. In conjunction with these preclinical studies, a phase I study of high-dose deoxycytidine will be initiated with the aim of establishing the safety and feasibility of achieving high plasma deoxycytidine concentrations exhibiting a selective protective effect toward normal elements in in vitro studies. Shortly thereafter, a phase I study of continuously-administered cytocine arabinoside in conjunction with a fixed dose of deoxycytidine will be implemented, also with the aim of achieving plasma cytosine arabinoside and deoxycytidine concentrations exerting a selective cytotoxic effect toward leukemic cells in preclinical studies. A subsequent phase I study of thymidine and 3-deazauridine administered with high-dose deoxycytidine will also be designed. The ultimate aim of this proposal will be to make dose recommendations for phase II studies employing high-dose deoxycytidine in conjunction with pyrimidine antagonists in patients with refractory leukemia and solid tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA035601-06
Application #
3173204
Study Section
Project Start
1987-09-01
Project End
1990-02-28
Budget Start
1988-03-07
Budget End
1989-02-28
Support Year
6
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Grant, S; Pettit, G R; Howe, C et al. (1991) Effect of the protein kinase C activating agent bryostatin 1 on the clonogenic response of leukemic blast progenitors to recombinant granulocyte-macrophage colony-stimulating factor. Leukemia 5:392-8
Grant, S; Bhalla, K; McCrady, C (1991) Effect of tetrahydrouridine and deoxytetrahydrouridine on the interaction between 2'-deoxycytidine and 1-beta-D-arabinofuranosylcytosine in human leukemia cells. Leuk Res 15:205-13
Grant, S; Boise, L; Westin, E et al. (1991) In vitro effects of bryostatin 1 on the metabolism and cytotoxicity of 1-beta-D-arabinofuranosylcytosine in human leukemia cells. Biochem Pharmacol 42:853-67
McCrady, C W; Staniswalis, J; Pettit, G R et al. (1991) Effect of pharmacologic manipulation of protein kinase C by phorbol dibutyrate and bryostatin 1 on the clonogenic response of human granulocyte-macrophage progenitors to recombinant GM-CSF. Br J Haematol 77:5-15
Grant, S (1990) Biochemical modulation of cytosine arabinoside. Pharmacol Ther 48:29-44
Grant, S; Bhalla, K; Arlin, Z et al. (1990) The effect of a prolonged in vitro exposure to 1-beta-D arabinofuranosylcytosine and deoxycytidine on the survival of normal (CFU-GM) and leukemic (L-CFU) human myeloid progenitor cells in suspension culture. Exp Hematol 18:41-8
Bhalla, K; Cole, J; MacLaughlin, W et al. (1987) Effect of deoxycytidine on the metabolism and cytotoxicity of 5-aza-2'-deoxycytidine and arabinosyl 5-azacytosine in normal and leukemic human myeloid progenitor cells. Leukemia 1:814-9
Bhalla, K; Grant, S (1987) Effect of deoxycytidine on the in vitro response of human leukemia cells to inhibitors of de novo pyrimidine biosynthesis. Cancer Chemother Pharmacol 19:226-32
Bhalla, K; MacLaughlin, W; Cole, J et al. (1987) Deoxycytidine preferentially protects normal versus leukemic myeloid progenitor cells from cytosine arabinoside-mediated cytotoxicity. Blood 70:568-71
Bhalla, K; Cole, J; MacLaughlin, W et al. (1986) Deoxycytidine stimulates the in vitro growth of normal CFU-GM and reverses the negative regulatory effects of acidic isoferritin and prostaglandin E1. Blood 68:1136-41

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