[Ribamidyl (ribavirin) as a modulator of the biological action of arabinosylcytosine and methotrexate]. / Ribamidil (ribavirin) kak moduliator biologicheskogo deistviia arabinoziltsitozina i metotreksata.

Administration of ribamidyl (Rb) prior to Ara-C to intact mice or mice with implanted tumours enhanced Ara-C toxicity. The growth of tumours (plasmacytoma MOPC-21, adenocarcinoma of the small intestine (strain AKATON), mammary adenocarcinoma 755 (Ca 755) resistant to Ara-C or Rb was inhibited after coadministration of these drugs. The augmentation of toxic and antitumour effects of Ara-C by Rb is similar to the described effect of high doses of thymidine. This is in accordance with the enhancement of the intracellular pool of thymidine phosphates under the action of Rb. The toxicity of methotrexate in vivo was increased by coadministration with Rb. This effect may be connected with a decrease in purine precursors pool under the action of Rb.

Anti-parasite activity of nucleoside analogues in Leishmania tropica promastigotes.

Many nucleoside analogs were screened for anti-protozoa activity on Leishmania tropica in an in vitro culture system. 3'-Deoxyinosine and several tubercidin derivatives were found to be potent inhibitors for growth of the promastigote form of L. tropica. EC50 value of 3'-deoxyinosine was 4.43 X 10(-7)M. This compound was remarkably less toxic towards mouse mammary tumor FM3A cells (EC50, 1.25 X 10(-4) M). 3'-Deoxyinosine is metabolized by Leishmania promastigote to give 3'-deoxyinosine-5'-monophosphate, 3'-deoxy-adenosine(cordycepin)-5'-mono, di-, and triphosphates. This means that Leishmania can aminate the 6-position of 3'-deoxyinosine-5'-monophosphate, thereby converting it into a highly toxic compound.

Induced maturation of the human promyelocytic leukemia cell line, HL-60, by 2-beta-D-ribofuranosylselenazole-4-carboxamide.

The new synthetic nucleoside analogue, 2-beta-D-ribofuranosylselenazole-4-carboxamide, was evaluated for its effects upon the growth and maturation of the human promyelocytic leukemia cell line, HL-60. At a concentration of greater than or equal to 1 nm, this agent was found both to decrease HL-60 cell proliferation and to cause the cells to acquire an ability to phagocytose opsonized yeast and to reduce nitroblue tetrazolium dye, functions characteristic of mature myeloid cells. In addition, this agent at similar concentrations caused a marked depression of intracellular guanosine nucleotide pools and a reduction in the incorporation of [14C] hypoxanthine into guanylates. These results suggested that the selenazole nucleoside caused an inhibition of inosinate monophosphate dehydrogenase, a key enzyme of guanylate biosynthesis. We therefore measured the activity of this enzyme indirectly by simultaneous-UV-radioactivity HPLC as well as by a direct radiometric method and demonstrated markedly reduced enzyme activities by both assays in drug treated cells. Dose response studies indicated that concentrations of drug which caused greater than 30% inhibition of IMP dehydrogenase activity induced greater than 50% maturation of the cells. These observations with this new nucleoside analogue provide further support for the concept that production of guanosine nucleotides and the activity of IMP dehydrogenase have a role in regulating the terminal maturation of myeloid cells.

Rat hepatomas: chemotherapy with lycurim and pyrazofurin.

Hepatoma 8999 was sensitive to Lycurim [1,4-di-(methylsulfonyloxy-ethylamino)-1,4-dideoxy-ms-erythritol] with a mean lethal dose (LD50) of 8.1 X 10(-8) M for a 6-hour treatment in vitro. The drug dose lethal to 10% of the rats with Lycurim (10 mg/kg) injected ip 12 times into hepatoma 8999-bearing BUF rats at 10-day intervals provided a mean increase in life-span (ILS) of 156%. The more rapidly growing, less differentiated hepatoma 3924A was tenfold less sensitive to Lycurim in vitro, and three treatments in vivo (10 mg/kg given every 8 days) gave an ILS of only 18% in ACI/N rats. Because hepatoma 8999 had a high adenosine kinase activity, the effect of Pyrazofurin (PF; 3-beta-D-ribofuranosyl-4-hydroxypyrazole-5-carboxamide) was examined in vitro: The LD50 was 8.5 X 10(-8) M in a 6-hour exposure. In hepatoma 3924A, with a fifteenfold lower adenosine kinase, the LD50 was 22-fold higher. Three treatments with PF (4 mg/kg given every 2 days) in hepatoma 8999 caused an 18% ILS and no host toxicity, but in hepatoma 3924A no significant ILS was observed. Lycurim combined with PF (0.05 microM each) in hepatoma 8999 cells in vitro provided synergistic kill, but Lycurim and PF (0.3 and 1 microM, respectively) in hepatoma 3924A cells yielded summation. When 10 rats with hepatoma 8999 were treated 15 times with the optimal dose of Lycurim (7.5 mg/kg every 10 1/2 days), 1-year survivors numbered 7. Alternate doses of Lycurim (7.5 mg/kg) and PF (3 mg/kg) at 5-day intervals for 4 months to 10 rats gave an ILS of 152% with eight 1-year survivors and no host toxicity.