pentostatin and Bacterial-Infections

Topics: Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Bacterial Infections; Bone Marrow Transplantation; Clinical Trials as Topic; Coformycin; Combined Modality Therapy; Humans; Interferons; Kidney Failure, Chronic; Leukemia, Myeloid, Acute; Multiple Myeloma; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary; Palliative Care; Pentostatin

Topics: Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Bacterial Infections; Bone Marrow Transplantation; Clinical Trials as Topic; Coformycin; Combined Modality Therapy; Humans; Interferons; Kidney Failure, Chronic; Leukemia, Myeloid, Acute; Multiple Myeloma; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary; Palliative Care; Pentostatin

By pharmacological manipulation of endogenous adenosine, using chemically distinct methods, we tested the hypothesis that endogenous adenosine tempers proinflammatory cytokine responses and oxyradical-mediated tissue damage during endotoxemia and sepsis. Rats were pretreated with varying doses of pentostatin (PNT; adenosine deaminase inhibitor) or 8-sulfophenyltheophylline (8-SPT; adenosine receptor antagonist) and then received either E. coli endotoxin (lipopolysaccharide; 0.01 or 2.0 mg/kg) or a slurry of cecal matter in 5% dextrose in water (200 mg/kg). Resultant levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-10 were measured in serum and in liver and spleen. Untreated, 2 mg/kg lipopolysaccharide elevated serum TNF-alpha, IL-1beta, and IL-10. PNT dose dependently attenuated, without ablating, the elevation in serum TNF-alpha and IL-1beta and raised liver and spleen IL-10. PNT also attenuated elevation of TNF-alpha in serum, liver, and spleen at 4 and 24 h after sepsis induction, and 8-SPT resulted in higher proinflammatory cytokines. Modulating endogenous adenosine was also effective in exacerbated (8-SPT) or diminished (PNT) tissue peroxidation. Survival from sepsis was also improved when PNT was used as a posttreatment. These data indicate that endogenous adenosine is an important modulatory component of systemic inflammatory response syndromes. These data also indicate that inhibition of adenosine deaminase may be a novel and viable therapeutic approach to managing the systemic inflammatory response syndrome without ablating important physiological functions.

Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Animals; Bacterial Infections; Blood; Chronic Disease; Endotoxemia; Enzyme Inhibitors; Inflammation; Interleukin-1; Interleukin-10; Liver; Male; Pentostatin; Peroxides; Purinergic P1 Receptor Antagonists; Rats; Rats, Sprague-Dawley; Spleen; Theophylline; Tumor Necrosis Factor-alpha

Pentostatin (dCF), an inhibitor of adenosine deaminase, has shown activity in the treatment of several lymphoid malignancies, even in the earliest phase I trials. An analysis of the first 300 patients treated in such trials shows a high incidence of severe infection (8%) during the relatively brief period of treatment. Of 24 patients in whom infection was diagnosed, 17 had no evidence of myelosuppression. The causative organisms included viruses, fungi, and bacteria of both high and low pathogenicity. Two-thirds of the infections were fatal. It is suggested that dCF may cause a syndrome similar to severe combined immunodeficiency during the course of treatment. Patients treated with dCF who show evidence of infection, even in the absence of neutropenia, should receive vigorous and rapid diagnostic evaluation to establish the cause of their infection, and aggressive treatment of suspected organisms.

Topics: Adolescent; Adult; Aged; Bacterial Infections; Child; Coformycin; Drug Evaluation; Female; Herpes Zoster; Humans; Leukemia; Lymphoma; Male; Middle Aged; Mycoses; Neoplasms; Pentostatin; Ribonucleosides