The effects of the folic acid antagonists and 2,6-diaminopurine on neoplastic disease.With special reference to acute leukemia

Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition

“…Rather, hFRβ uses the same residues that make contacts with the pterin of FOL, with the exception of H151, to make a series of new contacts with the diaminopteridine. We also determined a structure of hFRβ in complex with MTX, an antifolate that varies from AMT via the addition of a methyl at the N10 position, and we see little distinction in the binding modes of these two diaminopteridinecontaining antifolates (9). Taken together, our structural models of four hFR complexes suggest that folate receptors are able to recognize molecules that consist of an aromatic system capable of stacking between Y101 and W187, a largely hydrophobic linker with length matched to the central portion of the binding cleft, and a glutamyl moiety that makes specific polar contacts at the exit of the binding pocket.…”

“…Folic acid and its reduced derivatives, including 5-methyltetrahydrofolate and 10-formyltetrahydrofolate, are transported via two widely expressed facilitative transporters, the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT), and via a family of glycosyl-phosphatidylinositol (GPI)-anchored receptors with limited expression profiles generally described as folate receptors (FRs) (3)(4)(5)(6)(7). For >60 y, folate analogs that inhibit intracellular folate-using enzymes, termed antifolates, have been developed to treat a variety of cancer types and inflammatory diseases (8)(9)(10)(11)(12)(13)(14). More recently, the emphasis in folatemediated drug therapy has shifted to obtain a better understanding of transport mechanisms of antifolates because dose-limiting toxicities arise from their transport via RFC, and possibly PCFT, into normal cells (6,11,(15)(16)(17).…”

Clinical Effects of the Dichloro and Monochlorophenyl Analogues of Diamino Pyrimidine: Antagonists of Folic Acid12

“…It is of interest, however, that high antagonist 1 This investigation was supported by research grants from the American Cancer Society, the Damon Runyon Memorial Fund for Cancer Research, the Lasker Foundation and the Grant Foundation, and by Grant C-1889 from the National Cancer Institute of the National Institutes of Health of the United States Public Health Service. 2 We wish to express our appreciation to Dr. George Because the 4-amino derivatives of folic acid inhibit the growth of tumors and leukemias in animals and in man (2), Clarke, Buckley, Sternberg, Stock, Rhoads, and Hitchings (3) tested a series of diamino-pyrimidines for their influence on transplantable mouse tumors, and observed that one of this group, 2,4-diamino-5-(3',4'-dichlorophenyl) -6-methylpyrimidine (DDMP) inhibited the growth of the Sarcoma 180. The drug also produced inhibition in the growth of leukemia (4) and the Ehrlich ascites tumor (5) in mice, and modified the development of the chick embryo (6).…”

“…Two children and two adults who received DDMP to the point of toxicity then developed alopecia. Skin pigmentation has been reported as occurring after prolonged administration of A-methopterin (10) and alopecia also is a previously noted complication of therapy with the 4-amino antagonists of folic acid (2).…”

Amethopterin: A Toxic Tumour Growth Inhibitor

“…This variation was substantially reduced by giving the injections three times a day. Reports of the rapid excretion of pteroylglutamic acid analogues quoted by Burchenal et al (1951) and the findings of Swenseid, Swanson, Miller and Bethell (1950) support the view that the maintenance of an effective blood level would be favoured by reducing the intervals between injections. The subcutaneous route was chosen for the same reason.…”