Gurpreet S. Ahluwalia

Metabolism and action of amino acid analog anti-cancer agents

The preclinical pharmacology, antitumor activity and toxicity of seven of the more important amino acid analogs, with antineoplastic activity, is discussed in this review. Three of these compounds are antagonists of L-glutamine: acivicin, DON and azaserine; and two are analogs of L-aspartic acid: PALA and L-alanosine. All five of these antimetabolites interrupt cellular nucleotide synthesis and thereby halt the formation of DNA and/or RNA in the tumor cell. The remaining two compounds, buthionine sulfoximine and difluoromethylornithine, are inhibitors of glutathione and polyamine synthesis, respectively, with limited intrinsic antitumor activity; however, because of their powerful biochemical actions and their low systemic toxicities, they are being evaluated as chemotherapeutic adjuncts to or modulators of other more toxic antineoplastic agents.

Particulate cyclic 3′,5′-nucleotide phosphodiesterase and calmodulin of cardiac muscle

Cyclic AMP and cyclic GMP phosphodiesterase and calmodulin were measured in purified subcellular fractions of cardiac muscle. Phosphodiesterase activity solubilized by sonication of the nuclear fraction yielded a major 6.6 S form which was calcium-sensitive and cyclic GMP-specific. Phosphodiesterase activity occurring in the nuclear fraction could be further enriched by subfractionation on sucrose density gradients in the presence of MgCl2.

Metabolites of tiazofurin as mediators of its biochemical and pharmacologic effects

Tiazofurin (2-β-D-ribofuranosylthiazole-4-carboxamide) was synthesized by the medicinal chemists at ICN as one of a series of potential antiviral compounds [1,2]. In fact, the agent does exhibit a modest to moderate degree of activity against several pathogenic viruses [2,3]. However, at the time, this activity apparently was not judged sufficient to warrant development of the drug towards clinical trials. With the advent of managerial changes at ICN, Dr. Kenneth Paull of the National Cancer Institute made arrangements with Dr. Roland Robins, the chemist who had designed tiazofurin, to screen that compound and a number of related nucleosides for antineoplastic activity. These studies revealed that tiazofurin was effective against the L1210 and P388 leukemias and prompted a broader examination of the compound’s oncolytic potential. Surprisingly, tiazofurin proved to be effective against the subcutaneous Lewis lung carcinoma, a transplantable tumor resistant to the vast majority of standard and experimental chemotherapeutic drugs. Moreover, cures were achieved over a broad range of doses of the compound [4]. It was these studies, then, that prompted the development of tiazofurin toward clinical trials as an antitumor drug.