pentostatin and fludarabine-phosphate

Patients with lymphoid malignancies such as chronic lymphocytic leukemia, particularly those who receive the newer purine analogs, are at increased risk for infectious morbidity and mortality. Defects in cell-mediated immunity appear to be a major predisposing factor in these patients. An expanding spectrum of pathogens associated with lymphocytopenia and depletion of CD4 has been described in the setting of therapy with purine analogs. During the past 2 years new knowledge about the immunosuppression related to that treatment has continued to accumulate.

Topics: Antimetabolites, Antineoplastic; Cladribine; Humans; Immune Tolerance; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Vidarabine Phosphate

This article details both the contribution of the purine nucleoside analogs to the current management of relapsed indolent non-Hodgkin's lymphoma (NHL) and the role of pentostatin (Nipent) in that management. Of the three purine nucleoside analogs, pentostatin has received the least attention with regard to the management of indolent NHL. Although data in the literature appear to indicate that fludarabine (Fludara) and 2-chlorodeoxyadenosine (cladribine [Leustatin]) are more active in NHL, this conclusion could be flawed because many of the studies investigating pentostatin in indolent NHL have contained a large number of patients previously treated with the other purine analogs. As these agents are most likely cross-resistant, it is unfair to conclude that pentostatin is less active. Recently, there has been interest in using a new, more protracted schedule of 2 mg/m2/d of pentostatin for 5 days. Although the schedule used in the trials conducted in indolent NHL might not be optimal, pentostatin has nevertheless shown significant activity in these disorders.

Topics: Adenosine Deaminase Inhibitors; Antibiotics, Antineoplastic; Cladribine; Humans; Lymphoma; Pentostatin; Vidarabine Phosphate

Topics: Alkaloids; Animals; Antineoplastic Agents; Azacitidine; Biphenyl Compounds; Chrysenes; Deoxycytidine; Echinomycin; Epirubicin; Etanidazole; Flavonoids; Gemcitabine; Guanidines; Humans; Idarubicin; Menogaril; Mitoguazone; Neoplasms; Nitroimidazoles; Nogalamycin; Organoplatinum Compounds; Paclitaxel; Pentostatin; Polymers; Propylene Glycols; Ribavirin; Sulfonylurea Compounds; Trimetrexate; Vidarabine Phosphate

Combination chemotherapy regimens achieve complete remissions in 60% to 80% of patients with non-Hodgkin's lymphomas; however, the majority of patients will relapse, and resistant disease remains a problem. Attempts to identify new, effective chemotherapy agents have primarily focused on the development of analogues that, unfortunately, have uniformly failed to provide a substantial therapeutic advantage. Drugs with a unique mechanism of action are more likely to be successful; among these are the purine analogues (e.g., fludarabine, 2'-deoxycoformycin, 2-chlorodeoxyadenosine) and agents that can reverse clinical drug resistance. The number of patients who can be cured can be increased only by incorporating new agents into front-line regimens through carefully designed clinical trials.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Humans; Lymphoma, Non-Hodgkin; Pentostatin; Vidarabine Phosphate

Topics: Adenine; Antibiotics, Antineoplastic; Antineoplastic Agents; Biphenyl Compounds; Depsipeptides; Echinomycin; Epirubicin; Flavonoids; Guanidines; Humans; Idarubicin; Imides; Isoquinolines; Menogaril; Naphthalimides; Nogalamycin; Organophosphonates; Pentostatin; Peptides, Cyclic; Polymers; Vidarabine Phosphate

Topics: Acetamides; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Flavonoids; Gallium; Humans; Mitolactol; Mitoxantrone; Organoplatinum Compounds; Pentostatin; Quinazolines; Ribavirin; Trimetrexate; Vidarabine Phosphate

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cladribine; Cyclophosphamide; Doxorubicin; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Prednisone; Vidarabine Phosphate

Topics: Antimetabolites, Antineoplastic; Cladribine; Drug Resistance; Humans; Leukemia, Hairy Cell; Pentostatin; Vidarabine Phosphate

Previous results from this laboratory demonstrated that treatment of mice with the adenosine analog tubercidin (Tub) reduced natural killer (NK) cell activity while stimulating antibody production whereas the deoxyadenosine analog, 2-fluoroadenine arabinoside-5'-monophosphate (FaraAMP), produced opposite effects; i.e., it stimulated NK cell activity at doses that inhibited antibody formation (Cancer Res. 48, 4799, 1988). Since NK cells have been reported to play a suppressor role in immunoglobulin induction, it was hypothesized that the actions of Tub and FaraAMP on antibody production occurred secondary to their opposing effects on NK cells. To test this hypothesis, abilities of these nucleoside analogs to modulate primary antibody response to sheep red blood cells were evaluated in a C57BL/6 mutant mouse lacking NK cell activity (the beige mutation. C57BL/6-bg/bg). As previously found with C3H/He mice. NK cell activity was inhibited (Tub, doses 2-6 mg/kg/day for 3 days) or stimulated (FaraAMP, doses 75-250 mg/kg/day for 3 days) in heterozygous mice C57BL/6-bg/+. In support of the hypothesis, these nucleosides had no effect on primary antibody formation in the homozygous mutant mice at doses that clearly stimulated (Tub) or inhibited (FaraAMP) this immune response in heterozygous C57BL/6-bg/+ animals. This results was corroborated in C57BL/6 wild-type mice by abrogation of NK cell activity using a monoclonal antibody to the NK cell surface glycophisingolipid, ganglio-n-tetraosylceramide. We conclude that under the conditions of drug administration, modulation of primary antibody formation by Tub and FaraAMP in mice occurs indirectly via NK cells. Similar experiments using the potent ADA inhibitor, deoxycoformycin, indicated that its enhancement of primary antibody formation is independent of NK cell activity.

Topics: Animals; Antibody Formation; Killer Cells, Natural; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Pentostatin; Purine Nucleosides; T-Lymphocytes, Regulatory; Tubercidin; Vidarabine Phosphate