Acquired immunodeficiency syndrome (AIDS) is a progressively fatal disease that is believed to be the result of infection by the lymphotrophic virus HIV. Hundreds of drugs have been screened for activity against the HIV, and the ones that have been found effective in vitro are all members of the dideoxynucleosides. It has recently come to the attention of researchers that the intracellular anabolism of these nucleosides into active nucleotides (triphosphates) has different efficiencies in different cell types and showed varying degrees of competition with the endogenous metabolites. We have recently demonstrated that dipyridamole, a potent membrane nucleoside transport inhibitor, can augment the anti-tumor activity of a nucleoside analog cytarabine (araC) if administered in a sequential regimen. The mechanism of synergy resides in the ability of dipyridamole to increase cellular exposure to the active metabolite araCTP by preventing araC efflux. We plan to test the applicability of this type of sequential regiment in augmenting the anti-viral activity of a prototype anti-=viral nucleoside 2',3' -dideoxycytidine. Since the HIV has been shown to replicate in lymphocytes, macrophages, and bone marrow cells, we plan to use these cells as our experimental models. Our plan of action includes; a) demonstrating that their is a specific nucleoside transport system in each of the cell types; b) showing that such a nucleoside transport system is responsible for 2'3' -dideoxycytidine uptake into these immune effector cells; c) proving that this membrane nucleoside transport system is inhibitable by dipyridamole; d) confirming that dipyridamole can trap high concentrations of 2'3' -dideoxycytidine and its triphosphate within the immune effector cells for extended periods; and e) showing that prolonged entrapment of 2'3' -dideoxycytidine within cells is associated with improved anti-viral activity. Dipyridamole is a good drug to use because it has already been shown to be well tolerated in cardiac patients requiring anti-platelet therapy. In addition to the important therapeutic implications, this study will also provide valuable information on nucleoside metabolism in immune cells which is important in certain autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI029153-01
Application #
3143889
Study Section
(ARR)
Project Start
1989-09-30
Project End
1992-07-31
Budget Start
1989-09-30
Budget End
1990-07-31
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Purdue University
Department
Type
Schools of Veterinary Medicine
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Chan, T C; Chang, C J; Koonchanok, N M et al. (1993) Selective inhibition of the growth of ras-transformed human bronchial epithelial cells by emodin, a protein-tyrosine kinase inhibitor. Biochem Biophys Res Commun 193:1152-8
Chan, T C; Shaffer, L; Redmond, R et al. (1993) Permeation and metabolism of anti-HIV and endogenous nucleosides in human immune effector cells. Biochem Pharmacol 46:273-8
Konger, R L; Chan, T C (1993) Epidermal growth factor induces terminal differentiation in human epidermoid carcinoma cells. J Cell Physiol 156:515-21
Chan, T C; Boon, G D; Shaffer, L et al. (1992) Antiviral nucleoside toxicity in canine bone marrow progenitor cells and its relationship to drug permeation. Eur J Haematol 49:71-6