pentostatin and Lymphoma--Large-B-Cell--Diffuse

One dose of pentostatin was added to a standard cyclophosphamide (CY) based transplant regimen in two patients in an attempt to decrease the rate of non-engraftment in haploidentical allogeneic BMT. Despite a normal cardiac history and evaluation prior to transplant, both patients suffered fatal cardiac toxicity within 48 h of receiving the chemotherapy. This phenomenon was further investigated in an animal model. Laboratory rats were treated with progressive doses of CY in a range that produces acute cardiac toxicity. Successive groups of rats were treated with either pentostatin or fludarabine and CY at 400 mg/kg. Neither pentostatin nor fludarabine alone produced early mortality. However, a marked increase in early mortality was noted in those animals treated with pentostatin and high-dose CY. The addition of fludarabine did not increase the early toxicity of CY. Autopsy revealed no gross or microscopic abnormalities in the animals. The implications of adding agents that interfere with adenosine metabolism to CY based transplant regimens is discussed.

Topics: Adult; Animals; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Carmustine; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Synergism; Etoposide; Fatal Outcome; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Methylprednisolone; Pentostatin; Prednisone; Rats; Rats, Inbred Lew; Salvage Therapy; Shock, Cardiogenic; Ventricular Fibrillation; Vidarabine; Vincristine

The association of a genetic deficiency of adenosine deaminase (ADA) with immunodeficiency disease has emphasized the importance of deoxyadenosine and adenosine metabolism for human lymphocyte function. However, information concerning the endogenous production and metabolism of deoxyadenosine and adenosine in normally growing human T and B lymphoblasts is lacking. In the present experiments, we used a diverse series of cell lines deficient in individual enzymes of purine metabolism to quantitate the de novo formation of deoxyadenosine and adenosine in human T lymphoblasts (CEM), B lymphoblasts (WI-L2), and histiocytic lymphoma cells (DHL-9). The B lymphoblasts and histiocytic lymphoma cells generated deoxyadenosine at a rate of 60 to 80 pmol/hr/10(7) cells. This value was several fold greater than the rate of production of deoxyadenosine by T cells (6 to 7 pmol/hr/10(7) cells). Deoxyadenosine synthesis required ribonucleotide reductase activity, and was maximal during the S-phase of the cell cycle. The T and B lymphoblasts formed relatively similar amounts of adenosine (870 to 1620 pmol/hr/10(7) cells) throughout the cell cycle. In ADA-deficient cells, a major fraction of the deoxyadenosine synthesized de novo was excreted into the extracellular space. These results establish that the endogenous synthesis and metabolism of deoxyadenosine (but not adenosine) is distinctly different in T and B lymphoblasts.

Topics: Adenosine; Adenosine Deaminase; Adenosine Deaminase Inhibitors; B-Lymphocytes; Cell Line; Coformycin; Deoxyadenosines; Humans; Interphase; Lymphocyte Activation; Lymphoma, Large B-Cell, Diffuse; Pentostatin; T-Lymphocytes