pentostatin and Body-Weight

For 3 consecutive days, the nucleoside cordycepin (3'-deoxyadenosine) was administered as 1-hr iv infusions (0, 1, 4, 8, 10, or 20 mg/kg/day) to dogs. These doses were given 1 hr after a bolus iv injection (0.25 mg/kg/day) of 2'-deoxycoformycin (dCF), a potent inhibitor of adenosine deaminase. The hypothesis was that dCF would affect the toxicity of cordycepin. Plasma adenosine deaminase activity was strongly inhibited during the dose period and for 5 days following the final dose of dCF. Dogs given cordycepin alone showed no drug-related toxicities. In dogs given only dCF, drug-related toxicity to lymphoid tissue (lymphopenia and thymus lymphoid depletion), thrombocytopenia, and decreases in food consumption were observed. Cordycepin in combination with dCF produced symptoms associated with severe gastrointestinal toxicity (decreased body weights, emesis, diarrhea, decreased food consumption, and necrosis of the gastrointestinal tract) and bone marrow toxicity (lymphopenia, thrombocytopenia, and depletion of hematopoietic cells). The gastrointestinal tract and bone marrow were sites associated with dose-limiting toxicities. In surviving dogs, most of the effects were reversible by Day 30. The maximum tolerated dose of cordycepin administered in combination with dCF was 8 mg/kg/day (160 mg/m2/day) given daily for 3 days.

Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Body Weight; Bone Marrow; Deoxyadenosines; Dogs; Dose-Response Relationship, Drug; Drug Combinations; Enzyme Inhibitors; Gastrointestinal Diseases; Infusions, Intravenous; Injections, Intravenous; Leukocyte Count; Lymphoid Tissue; Pentostatin; Platelet Count; Thrombocytopenia

Mice were administered the adenosine deaminase inhibitor 2'-deoxycoformycin by daily intraperitoneal injection for five days and evaluated 24 h, 72 h and 6 days after the final dose. Spleen weight was decreased in treated mice for up to 6 days after treatment whereas body weight was significantly affected only at 24 h in mice administered 4 micrograms 2'-deoxycoformycin/g of body weight. The number and relative percentage of circulating lymphocytes were decreased 24 and 72 h after the last injection. Lymphoproliferative responses to T cell mitogens were suppressed for at least 72 h post-treatment whereas the mixed lymphocyte response was normal at 24 h but was depressed at 72 h post-treatment. Conversely, natural killer cell activity was greater in treated mice than in controls for the entire observation period. Data from cell surface marker analysis provided indirect evidence that natural killer effector cells lack sensitivity to 2'-deoxycoformycin. The antibody responses of mice treated with 2 or 4 micrograms 2'-deoxycoformycin/g over four days prior to or after immunization with sheep erythrocytes were suppressed or enhanced, respectively, compared to controls. These results indicate selective effects of 2'-deoxycoformycin on immune function and suggest that subpopulations of lymphocytes differ in the degree of sensitivity to 2'-deoxycoformycin.

Topics: Adenosine Deaminase Inhibitors; Animals; Antibody Formation; Antigens, Surface; Blood Cell Count; Body Weight; Coformycin; Female; Immunity; Killer Cells, Natural; Lymphocyte Culture Test, Mixed; Lymphocytes; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Nucleoside Deaminases; Organ Size; Pentostatin; Ribonucleosides; Spleen

Pregnant mice were administered 2'-deoxycoformycin (2dCF), a potent inhibitor of adenosine deaminase activity, by intraperitoneal injection on day 7 or 15 of gestation or from day 8-12 or 14-18 of gestation. A total dose of 0.5 or 2.0 micrograms 2dCF/g of maternal body weight was given to the dams. In a separate study, pups born to nontreated dams were given 5 intraperitoneal injections totaling 0.5, 2.0 or 4.0 micrograms 2dCF/g beginning at 4 weeks of age. Administered doses of 2dCF were at levels known to profoundly suppress adenosine deaminase levels in adult mice. Pups born to dams injected with 2dCF from day 14-18 all died within 48 h of birth whereas other injection schedules had no effect on birth rate or survival of pups. In utero 2dCF exposure had little effect on immune function in offspring. On the other hand, body, spleen and thymus weight, and splenic cellularity were decreased in weanling mice 24 h after the last injection of 4 micrograms/g 2dCF. Proliferative responses of splenocytes to T cell mitogens and alloantigens were likewise suppressed at both 2.0 and 4.0 micrograms/g 2dCF. Suppression of proliferative responses in treated weanling mice were no longer apparent at 7 weeks of age although splenic cellularity and weight remained lower than control values. These results are similar to those we have reported for 8 week old mice given similar doses of 2dCF, with the exception of elevated levels of NK cell activity in older 2dCF-treated mice and suggest that there may be age-related differences in the sensitivity of certain cell populations to the effects of 2dCF.

Topics: Adenosine Deaminase Inhibitors; Animals; Antibody Formation; Body Weight; Cells, Cultured; Coformycin; Embryonic and Fetal Development; Female; Immune System; Immunosuppressive Agents; Killer Cells, Natural; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Pentostatin; Pregnancy; Ribonucleosides; Spleen

Adult AKR/J mice were treated with 10 micrograms/g or 100 micrograms/g 2'-deoxycoformycin, an adenosine deaminase inhibitor with chemotherapeutic potential. The thymus and adrenal glands were decreased in weight more than any other organ. Histologic and cytofluorographic analyses indicated preferential depletion of peanut-agglutinin-positive, cortical thymocytes, as well as acute, dose-dependent damage to the adrenal cortex and medulla. The effect of 2'-deoxycoformycin on the thymus was proven to be independent of the adrenal glands by use of adrenalectomized mice. Dose-dependent liver necrosis, hemolysis, and leukemoid reactivity were observed. These findings illustrate a differential sensitivity of thymocyte subpopulations and suggest, in addition, preferential sensitivity of certain nonlymphoid tissues to 2'-deoxycoformycin administered in vivo.

Topics: Adenosine Deaminase; Adrenal Glands; Animals; Body Weight; Coformycin; Disease Models, Animal; Erythrocyte Count; Female; Kidney; Liver; Lymph Nodes; Mice; Mice, Inbred AKR; Nucleoside Deaminases; Organ Size; Pentostatin; Ribonucleosides; Spleen; T-Lymphocytes; Thymus Gland

Transplantable BALB/c and AKR lymphomas of different cell surface immunologic phenotypes have distinctive patterns of response to the ADA inhibitor DCF in vivo and in vitro. BAL 9, a lymphoma of the Lyt-1+,2+ T cell phenotype, was the most sensitive to DCF in vivo, and its DNA synthesis was inhibited more than 95% when cultured in the presence of dAr and DCF in vitro. This was correlated with a 10-fold increase in dATP content. The ADA and AMPDA activities were both high. Two lymphomas of the Lyt-1-,2+ T cell phenotype, BAL 5 and AKTB - lt , as well as two B cell phenotype lymphomas, A20 .3 and AKTB -lb, were all moderately inhibited in their in vivo growth if enough DCF was administered. However, their DNA synthesis in vitro was only inhibited 8 to 24% by dAr and DCF, there was only a twofold increase in the accumulation of dATP, and ADA and AMPDA activities were both low in the two BALB/c lymphomas tested. BAL 13, the only lymphoma of the Lyt-1+,2- phenotype examined, was completely resistant to DCF in vivo and in vitro. When cultured in the presence of dAr and DCF there was a transient increase in dATP content, followed by an abrupt decline. AMPDA activity was five to seven times greater than in the other lymphomas tested. ADA activity was moderate. The activities of 5' nucleotidase and of adenosine kinase were low and approximately equal in all the BALB/c lymphomas. These results suggest that the response to DCF by lymphomas of various immunologic phenotypes can be correlated with their nucleoside metabolism. The sensitivity of BAL 9 and the resistance of BAL 13 to DCF are correlated with their tendency to accumulate dATP and with their AMPDA and ADA activity ratios. The moderate sensitivity to DCF in vivo of the other T and B cell lymphomas, however, could not be clearly explained by any of the in vitro parameters thus far investigated, and this suggests that mechanisms inhibiting lymphoma proliferation other than dATP accumulation may be operating.

Topics: Adenosine Deaminase; Animals; Azacitidine; Body Weight; Coformycin; Deoxyadenosines; DNA; Lymphoma; Mice; Mice, Inbred AKR; Mice, Inbred BALB C; Neoplasm Transplantation; Nucleoside Deaminases; Organ Size; Pentostatin; Phenotype; Ribonucleosides; Spleen; T-Lymphocytes; Thymus Gland

Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Adenosylhomocysteinase; Animals; Body Weight; Coformycin; Deoxyadenine Nucleotides; Deoxyadenosines; Dose-Response Relationship, Drug; Humans; Hydrolases; Mice; Mice, Inbred Strains; Nucleoside Deaminases; Organ Size; Pentostatin; Phosphotransferases; Phosphotransferases (Alcohol Group Acceptor); Ribonucleosides; Thymus Gland

Topics: Adenosine Deaminase; Animals; Body Weight; Coformycin; Immunosuppressive Agents; Lymph Nodes; Lymphocyte Activation; Lymphopenia; Male; Mice; Mice, Inbred C57BL; Mitogens; Organ Size; Pentostatin; Ribonucleosides; Spleen; Thymus Gland