pentostatin and hypoxanthine-arabinoside

The amount of 9-beta-D-arabinofuranosyladenine (ARA-A) and 9-beta-D-arabinofuranosylhypoxanthine (ARA-Hx) present in ocular tissues of rabbits was determined following therapy with ARA-A alone and when ARA-A was used in combination with 2'-deoxycoformycin (dCF). Topical therapy was initiated three days after infection of the corneas of rabbits with herpes simplex virus type 1. Ocular tissues were harvested after two days of therapy and analyzed by high performance liquid chromatography. Combination topical therapy with ARA-A and dCF significantly increased the tissue content of ARA-A in all tissues examined except retina, as compared to therapy with ARA-A alone. The ARA-A content of the two ocular tissues most often subject to acute herpes infections, the conjunctiva and cornea, was increased from 29.9 +/- 11.7 to 144.0 +/- 53.3 pmoles/mg dry weight and from 15.4 +/- 6.1 to 231.8 +/- 30.8 pmoles/mg dry weight, respectively. Except for the aqueous humor, the total arabinoside content of each tissue was not significantly altered by combination therapy, merely the ratio of ARA-A to ARA-Hx was changed. These studies demonstrate that combination topical therapy with ARA-A and an inhibitor of ARA-A catabolism, dCF, can effectively result in elevated amounts of ARA-A in ocular tissues.

Topics: Animals; Arabinonucleosides; Chromatography; Coformycin; Eye; Keratitis, Dendritic; Pentostatin; Rabbits; Ribonucleosides; Vidarabine

A plaque-reduction assay was used to examine the susceptibility of five phosphonoformic acid-resistant variants of herpes simplex virus type 1 to arabinosylnucleosides and aphidicolin. These viruses were cross-resistant to arabinosylhypoxanthine and to arabinosyladenine when tested in the absence of deoxycoformycin, a deaminase inhibitor. In the presence of deoxycoformycin, no cross-resistance between arabinosyladenine and phosphonoformic acid was observed. The two variants tested were cross-resistant to arabinosylthymine, and all five variants were collaterally susceptible to aphidicolin inhibition.

Topics: Antiviral Agents; Aphidicolin; Arabinonucleosides; Coformycin; Diterpenes; DNA-Directed DNA Polymerase; Drug Resistance, Microbial; Foscarnet; Pentostatin; Phosphonoacetic Acid; Simplexvirus; Thymidine; Thymidine Kinase; Vidarabine

Combinations of Virazole plus arabinofuranosylhypoxanthine (ara-Hx) and Virazole plus arabinofuranosyladenine (ara-A) were investigated in KB or BHK cells infected with types 1 or 2 herpes viruses. Combinations of Virazole and ara-Hx exhibited significant synergy as evaluated graphically (isobolograms) or by fractional inhibitory concentration (FIC) indices. Optimal ratios for the combination were 1:1 to 1:10 for Virazole to ara-Hx. At these ratios, FIC indices in the range of 0.5-0.2 were commonly observed. Combinations of Virazole and ara-A were antagonistic when observed in the presence of pentostatin, an adenosine deaminase inhibitor. In the absence of pentostatin, the minimum inhibitory concentration (MIC) of ara-A and degree of synergy with Virazole were variable.

Topics: Animals; Arabinonucleosides; Cell Line; Cell Survival; Coformycin; Cricetinae; Dose-Response Relationship, Drug; Drug Antagonism; Drug Evaluation, Preclinical; Drug Synergism; Humans; Pentostatin; Ribavirin; Ribonucleosides; Simplexvirus; Vidarabine

It has been suggested that, by inhibiting the adenosine deaminase (ADA)-mediated catabolism of 9-beta-D-arabinofuranosyladenine (ara-A), 2'-deoxycoformycin (DCF) would increase the half-life (t1/2) of ara-A, a compound with known antileukemic activity. To test this hypothesis, we collected serial plasma samples from five patients with refractory acute lymphoblastic leukemia who participated in a Phase I trial of i.v. DCF 915 mg/sq m) in combination with i.v. single-dose ara-A (120-250 mg/sq m). In four of these patients, of whom three were known to have achieved greater than 98% ADA inhibition, a mean ara-A t1/2 of 227 min was achieved. Extrapolated peak levels (i.e., following infusion of ara-A) ranged from 1.5 to 7.4 micrograms/ml (mean, 4.2 micrograms/ml). Elimination of drug appeared to follow a single-compartment model. In two patients who received ara-A without prior DCF and in a third patient who had significant residual ADA activity despite DCF, ara-A was unmeasurable within 5 min of the end of infusion. These data confirm that the kinetics of ara-A catabolism can be altered by inhibition of ADA and suggest that more than one dose of DCF may be necessary for complete inhibition of the enzyme and optimal pharmacological modulation of ara-A.

Topics: Adolescent; Adult; Arabinonucleosides; Child, Preschool; Coformycin; Drug Evaluation; Drug Therapy, Combination; Female; Half-Life; Humans; Hypoxanthines; Kinetics; Leukemia, Lymphoid; Male; Pentostatin; Ribonucleosides; Vidarabine