Modulation of nicotinamide adenine dinucleotide and poly(adenosine diphosphoribose) metabolism by the synthetic "C" nucleoside analogs, tiazofurin and selenazofurin. A new strategy for cancer chemotherapy.

Abstract

Tiazofurin (2-8-D-ribofuranosylthiazole4-carboxamide) and selenazofurin (2-%-D-ribofuranosylselenazole4-crboxmiude) are synthetic 'C" nucleosides whose antineoplastic activity depends on their conversion to tiazofurin-adenine dinucleotide and selenazofurin-adenine dinucleotide which are analogs of NAD. The present study was conducted to determine whether these nucleoside analogs and their dinucleotide derivatives interfere with NAD metabolism and in particular with the NADdependent enzyme, poly(ADP-ribose) polymerase. Incubation of L1210 cells with 10 gM tiazofurin or selenazofurin resulted in inhibition of cell growth, reduction of cellular NAD content, and interference with NAD synthesis. Using 114Clnicotinamide to study the uptake of nicotinamide and its conversion to NAD, we showed that the analogs interfere with NAD synthesis, apparently by blocking formation of nicotinamide mononucleotide. The analogs also serve as weak inhibitors of poly(ADPribose) polymernse, which is an NAD-utilizing, chromatinbound enzyme, whose function is required for normal DNA repair processes. Continuous incubation of L1210 cells in tiazofurin or selenazofurin resulted in progressive and synergistic potentiation of the cytotoxic effects of DNA-damaging agents, such as 1,3-bis(2-chloroethyl)-1-nitrosourea or N-methyl-N'-nitro-N-nitrosoguanidine. These studies provide a basis for designing chemotherapy combinations in which tiazofurin or selenazofurin are used to modulate NAD and poly(ADP-ribose) metabolism to synergistically potentiate the effects of DNA strand-disrupting agents.

Role of nicotinamide adenine dinucleotide and adenosine triphosphate in glucocorticoid-induced cytotoxicity in susceptible lymphoid cells.

“…The results are presented in Table IV. When control cells that were never exposed to steroids were elutriated and analyzed, the fraction containing the high percentage of (17). Because our studies suggest that dexamethasone cytotoxicity involves NAD depletion, we reasoned that combined treatment of cells with tiazofurin and dexamethasone might produce a more rapid cytotoxic effect by interfering with synthesis as well as increasing consumption of NAD.…”

Effectiveness of Tiazofurin (NSC 286193) in Treating Disseminated Tumor Cells and Micrometastases in Mice

“…This analogue (TAD) inhibits the NAD*-dependent enzyme inosine-5-monophosphate dehydrogenase (IMP-dehydrogenase), which is a rate-limiting enzyme [28] of the guanosine triphosphate (GTP) biosynthesis. The in terference with IMP-dehydrogenase in inhibiting the conversion of inosine to guanine results in the de pletion of guanine nucleotides (GTP and dGTP pools) and in the consequent inhibition of DNA, RNA syn thesis and thus the cell growth [10,12,25,26,29], The TAD also serves as a weak inhibitor of another NADdependent enzyme, the poly(ADP-ribose)polymerase, whose function -together with that of the NAD -is required for normal DNA repair processes. It was demonstrated that sensitivity of murine tumors to the pharmacologic effects of tiazofurin correlates with the intracellular levels of TAD [6].…”

Cancer chemotherapy: new strategies for success.

“…For example, in the pathway outlined above, the use of agents to inhibit synthesis of NAD or other metabolites should serve to enhance chemotherapeutic efficacy. We have recently shown that one of the metabolic effects of tiazofurin is to inhibit NAD synthesis, and this compound significantly potentiates the cytotoxic effects of BCNU (83). Another agent that interferes with NAD synthesis, 6-aminonicotinamide (84,85), can be combined with tiazofurin and BCNU to mediate even further synergistic antitumor effects in tissue culture and in vivo.…”