We have described the synthesis and remarkable antitumor activity of 3-Deazaguanine (DG, NSC 261726) and its derivatives. DG in experimental animal models exhibited highly significant tumor growth inhibitory properties against a series of slow and rapid growing mammary adenocarcinomas including those which are used as models for post-operative breast cancer. DG is activated by HGPRTase and is incorporated into RNA and DNA. The antitumor properties of DG are believed to be due to the consequences of its incorporation in DNA. As a result of these studies, DG is undergoing Phase-1 clinical evaluation. The present studies are aimed to improve the therapeutic effectiveness of DG either by drug combination regimens or by the development of its derivatives which will inhibit the synthesis of DNA specifically. Two sets of drug combination studies involving DG and Acivicin, and TDG and Acivicin are proposed. The studies are based on the rationale that: (i) as a result of biochemical effects of Acivicin, the increased levels of PRPP in tumor tissue will help anabolise DG and TDG more effectively (as both of these derivatives are activated by HGPRTase which requires PRPP for activation process); (ii) the inhibition of nucleotide de novo biosynthesis caused by Acivicin will increase the reliance of metabolically active tumor tissue on salvage pathway even more for its survival, thereby promoting the utilization of DG and TDG. The conditions for optional increase of PRPP, with regard to dose and exposure time of Acivicin will be established in in vitro and in vivo by assaying the intracellular PRPP concentrations. Thereafter, the schedules for combination chemotherapy will be devised to achieve the maximum potentiation for growth inhibition. Synthesis of 2'-deoxy-3-deazaguanosine (DGdR) and 6-thio-2'-deoxy-3-deazaguanosine (TDGdR) have been accomplished with the object to inhibit the synthesis of DNA specifically. DGdR and TDG have exhibited significant growth inhibitory properties against a number of transplantable tumors. A comprehensive evaluation of these agents in NCI recommended panel of tumors is proposed in order to establish the spectrum and conditions for maximum antitumor effects. The biochemical studies are proposed in which the effects of these derivatives on macromolecular synthesis, on nucleotide pool levels and nucleotide interconversion will be examined in order to establish the mode of action and site of growth inhibition. Radiolabelled precursor's incorporation and HPLC methodology will be adopted or developed for these studies. We will also study the metabolism of these drugs by HPLC procedures where metabolites will be quantitated and characterized with the help of authentic samples already prepared in our laboratory.