Dose-response relationships of chronic adriamycin toxicity in rabbits.

Doxorubicin was administered chronically to 55 female New Zealand White rabbits in order to determine a chronic dose-response relationship for doxorubicin-induced cardiomyopathy, skeletal myopathy and nephropathy. Systolic time interval recording as a measure of cardiac function in doxorubicin-induced cardiomyopathy in the rabbit is compared to histologic grading of the cardiomyopathy. Histologic evidence of cardiomyopathy was not seen at cumulative doses less than 100 mg/m2 but incidence and severity of cardiomyopathy increased with increasing doxorubicin dosage. The most severe lesions were seen at cumulative doses in excess of 400 mg/m2. The dose-response of skeletal myopathy paralleled that of cardiomyopathy but the severity of histologic abnormalities and the incidence of skeletal myopathy was less than half that of cardiomyopathy at all dose levels. Nephropathy was a consistent finding at cumulative doses of doxorubicin in excess of 100 mg/m2.

Systolic time interval recordings in rabbits with congestive cardiomyopathy induced by chronic anthracycline administration.

Systolic time interval recordings were performed serially on 104 healthy female New Zealand White rabbits and 51 rabbits with congestive heart failure (CHF) induced by chronic anthracycline drug therapy. The results were analyzed and the comparisons were made with studies of systolic time interval recordings of CHF in persons. In the rabbit, CHF is manifested by prolongation of the isovolumic contraction time, the preejection period (PEP), and by shortening of the left ventricular ejection time (LVET). The ratio of PEP/LVET was a sensitive indicator of left ventricular failure, with values in excess of 0.466 reflecting significant cardiac dysfunction at the 95% confidence level. The mean PEP/LVET = 0.337 +/- 0.66 in healthy rabbits and PEP/LVET = 0.502 +/- 0.075 in rabbits with CHF. The PEP index increased from 0.057 +/- 0.007 in healthy rabbits to 0.074 +/- 0.007 in rabbits with heart failure. The LVET index decreased from 0.173 +/- 0.007 in healthy rabbits to 0.166 +/- 0.010 in rabbits with CHF.

Systolic time interval recordings as a measure of cardiac function in the healthy rabbit: reference values.

Results of systolic time interval recordings obtained serially on 104 female New Zealand White rabbits were analyzed for reproducibility, variation with respect to changes in heart rate (HR), and interrelationship of the various systolic time intervals. A table of values for systolic time intervals in the healthy rabbit was constructed. The preejection period (PEP), left ventricular ejection time (LVET), and PEP/LVET ratio were 0.040 +/- 0.008 s, 0.119 +/- 0.014 s, and 0.337 +/- 0.066 respectively. The major systolic time intervals, PEP and LVET, varied with respect to HR according to the regression equations: PEP = 0.057--0.000078 HR and LVET = 0.175--0.000251 HR. The QS2 interval, S1S2 interval and isovolumic contraction time also varied with changes in HR.

Comparison of methyl-CCNU and CCNU in patients with advanced forms of Hodgkin's disease, lymphosarcoma nad reticulum cell sarcoma.

In May 1972, the Cancer and Leukemia Group B initiated a randomized study comparing the effectiveness of CCNU and methyl-CCNU in patients with advanced malignant lymphomas, including Hodgkin's disease (HD), lymphosarcoma (LYS) and reticulum cell sarcoma (RCS). A single dose of 100 mg/m2 of CCNU or 150 mg/m2 of methyl-CCNU was given orally every 6 weeks. In patients with leukopenia or thrombocytopenia, due to prior treatment, this dose was reduced to 70 mg/m2 of CCNU and 100 gm/m2 of methyl-CCNU. Of 109 evaluable patients, 60 received CCNU and 49 received methyl-CCNU. Response rates (complete and partial) to CCNU and methyl-CCNU were respectively 42% (14/33) and 15% (3/20) in HD, 21% (3/14) and 21% (3/14) in LYS, 15% (2/13) and 27% (4/15) in RCS. Responses to methyl-CCNU, but not to CCNU, were seen only in patients who developed significant hematologic toxicity. Responses to both drugs were generally of short duration due to the advanced stage of the disease. Renal, hepatic or neurological toxicity was not observed. In conclusion, CCNU proved to be superior to methyl-CCNU for the treatment of advanced HD. CCNU was also observed to be of higher activity in Hodgkin's than in non-Hodgkin's lymphomas.

Persistent lymphocytosis with chromosomal evidence of malignancy.

An inappropriate, sustained and absolute lymphocytosis in a young man was investigated using technics which attempted to define the more detailed features of these cells and their T and B subpopulations. The results of the tests for lymphocyte RFC (E) and complement (EAC) rosette formation, immunofluorescence, in vitro phytohemagglutin (PHA) stimulation and 14C-cyclo-phosphamide binding assays, when evaluated in a combined and interrelated fashion, indicated that the lymphocytosis was mainly but not solely, due to an absolute elevation in circulating T lymphocytes. Moreover, an aneuploid cell line with 47 chromosomes, presumably T cells, also was detected in PHA-stimulated cultures. These data, associated with the patient's anemia, lymphocyte-infiltrated bone marrow, hepatosplenomegaly, pharyngeal lymphoid tumor and the clonal proliferation of lymphocytes bearing an abnormal karyotype, furnish evidence that the lymphocytosis is more than an unremitting leukemoid reaction and is potentially neoplastic. The detection of the chromosomal abnormality at this patient's age and point in disease may make him especially unique in that he could be a clinical prototype for other patients with lymphoreticular tumors which remain undetected at their onset.