pentostatin and Candidiasis

The antifungal activity of the nucleoside analog 3'-deoxyadenosine (cordycepin) was studied in a murine model of invasive candidiasis. When protected from deamination by either deoxycoformycin or coformycin, both of which are adenosine deaminase inhibitors, cordycepin exhibited potent antifungal efficacy, as demonstrated by prolongation of survival and a decrease in CFU in the kidneys of mice treated with cordycepin plus an adenosine deaminase inhibitor. The antifungal effect was seen with three different Candida isolates: Candida albicans 64, a relatively fluconazole-resistant clinical isolate of C. albicans (MIC, 16 micrograms/ml), and the fluconazole-resistant Candida krusei. Cordycepin and related compounds may provide another avenue for the discovery of clinically useful antifungal drugs.

Topics: Adenosine Deaminase Inhibitors; Animals; Antifungal Agents; Candidiasis; Deoxyadenosines; Disease Models, Animal; Drug Interactions; Drug Resistance, Microbial; Enzyme Inhibitors; Male; Mice; Mice, Inbred ICR; Pentostatin; Survival Analysis

Deoxycoformycin (dCF), a potent inhibitor of adenosine deaminase (ADA), was explored for its antineoplastic potential in 28 patients with advanced lymphoid malignancy. Both normal and malignant B lymphocytes have low levels of ADA activity, and low doses of dCF profoundly inhibit this enzyme in the peripheral blood of patients with chronic lymphocytic leukemia (CLL). The low doses of dCF administered in this trial (4 mg/m2) were not associated with prohibitive toxicity. Five of 28 patients had an objective response. Four additional patients had clinical improvement. No significant difference in the pretreatment ADA activity existed between responding patients and treatment failures. The demonstration of responses to dCF following failure on standard alkylating agents suggests that dCF may not be cross-resistant with current agents used to treat CLL. Additional studies should be pursued using low-dose dCF in patients with advanced malignancy.

Topics: Adenosine Deaminase Inhibitors; B-Lymphocytes; Candidiasis; Coformycin; Conjunctivitis; Drug Administration Schedule; Gastrointestinal Diseases; Herpesviridae Infections; Humans; Leukemia, Lymphoid; Liver Function Tests; Lymphoma, Non-Hodgkin; Middle Aged; Nucleoside Deaminases; Pentostatin; Respiratory Tract Infections; Ribonucleosides