pentostatin and Ventricular-Fibrillation

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

Adenosine receptor activation has been assumed to play a role in the cardioprotective effect of ischemic preconditioning. The actions of adenosine are terminated by the naturally occurring substance adenosine deaminase. We determined whether 2'-deoxycoformycin (DCF), a potent inhibitor of adenosine deaminase, could mimic the effect of preconditioning in nonpreconditioned rats and potentiate the salutary effect of preconditioning in preconditioned rats. We assessed the effect of DCF on myocardial infarct size and the incidence of ventricular arrhythmias in four groups of anesthetized rats: control (nonpreconditioned) + vehicle, control + DCF, preconditioned + vehicle, and preconditioned + DCF. All rats underwent 90 minutes of coronary artery occlusion followed by 4 hours of reperfusion, while preconditioned rats received three cycles of 3-minute episodes of ischemia and 5 minutes of reperfusion before the 90-minute occlusion. Following 4 hours of reperfusion, area at risk was determined by intravenous injection of blue dye during a brief coronary occlusion, and area of necrosis was determined by incubation of heart slices in triphenyltetrazolium chloride. In the nonpreconditioned control rats receiving vehicle, myocardial infarct size expressed as a percentage of the area at risk averaged 44.8 +/- 7.6%. Pretreatment with DCF had no effect on infarct size (49.4 +/- 4.9%) in the nonpreconditioned control rats. Both the preconditioned+vehicle (19.2 +/- 7.8%) and the preconditioned + DCF (17.9 +/- 5.1%) groups had a significant reduction in infarct size (p < 0.05 versus control + vehicle and control + DCF), with no significant difference in infarct size between the two preconditioned groups. The incidence of ventricular tachycardia (VT) during the 90 minutes of ischemia was significantly attenuated in both preconditioned groups (p < 0.05 versus controls).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Deaminase Inhibitors; Animals; Female; Heart Rate; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Necrosis; Pentostatin; Rats; Rats, Sprague-Dawley; Tachycardia, Ventricular; Ventricular Fibrillation