M. G. Nair

Antitumor Efficacy of Classical Non-Polyglutamylatable Antifolates that Inhibit Dihydrofolate Reductase

The non-polyglutamylatable dihydrofolate reductase (DHFR) inhibitors γ-methylene-l0 deazaaminopterin (MDAM) and 7-methylene-l0ethyl-10-deazaaminopterin (MEDAM)1,2 exhibited striking activity relative to methotrexate (MTX) against the growth of a number of human tumor cell lines in culture3,4. Since both MDAM and MEDAM are nonpolyglutamylatable and therefore could be cleared more efficiently from tissues than MTX, it was of interest to undertake a comparative study of the in vivo activity and toxicity of these compounds and MTX in normal and tumor bearing animals. These investigations were carried out with MEDAM using normal and ip implanted L1210 and P388 leukemic mice as the animal model using a number of experimental protocols. MDAM and MEDAM were previously shown to inhibit recombinant human DHFR at equivalent magnitude as MTX 1,2. They were neither substrates nor inhibitors of CCRF-CEW human leukemia cell folypolyglutamate synthetase (FPGS) and they competed more efficiently for folinic acid transport than MTX in H35 hepatoma cells. Both MDAM and MEDAM were excellent inhibitors of the growth of H35 hepatoma, CCRF-CEM human leukemia and Manca human lymphoma cells in culture. In NCI’s human tumor disease oriented in vitro screen, MDAM and MEDAM exhibited a wide spectrum of sensitivity and their activities were superior to MTX in a large number of tumor cells (Table I).

New thiophene substituted 10-deazaaminopterins: synthesis and biological evaluation.

Analogues of 10-deazaaminopterin (10-DAM) and 4-amino-4-deoxy-10-deazapteroyl-gamma-methylene glutamic acid (MDAM) in which the benzene ring was replaced with a thiophene ring have been synthesized and evaluated for their antitumor activity. These analogues were N-([5-(2,4-diamino-6-pteridinyl)ethyl]-2-thenoyl)-L- glutamic acid (1) and N-([5-(2,4-diamino-6-pteridinyl)ethyl]-2-thenoyl)-gamma-meth ylene glutamic acid (2).

Evaluation of the Anti-Arthritic Activity and an Alternate Synthesis of a Thiophene-Substituted 10-Deazaaminopterin

The antifolate methotrexate (MTX) has become an established treatment in patients with rheumatoid arthritis (RA). Although the mechanism of action of this drug in RA is still unknown, its efficacy has been demonstrated in short-term placebo-controlled studies, comparative trials, and open prospective studies as well as in animal models of rheumatoid arthritis. In a recent long-term study the effectiveness of methotrexate in the treatment of RA has been demonstrated in patients who have received the drug for more than seven years1. While a sustained clinical response is seen with long-term MTX treatment, the most common reason for withdrawal from the drug is toxicity.