Function of the anthracycline amino group in cellular transport and cytotoxicity.

Using a number of derivatives of doxorubicin (Adriamycin) and daunomycin, we have examined how substitution of the anthracycline amine affected net cellular accumulation and cytotoxic potency in HL-60 leukemia cells. Octanol/buffer partitioning demonstrated that each of the derivatives had an amino group titratable between pH 5 and 8, with the exception of derivatives containing a cyanomorpholino-substituted amine, which had a significantly lower pKa value. The steady state cellular drug levels for the Adriamycin and daunomycin series decreased in the following order: N,N-dimethyl-greater than morpholino-greater than parent greater than cyanomorpholino-. Thus, the net cellular accumulation of an anthracycline was found to be influenced by the basicity of the amino group; drugs with a non-basic amino group exhibited reduced uptake. Soft agar clonogenic assays showed the following order of cytotoxicity for both series: cyanomorpholino-much greater than parent greater than morpholino-approximately equal to N,N-dimethyl-. The data demonstrate an inverse correlation between uptake and potency; thus, differences in net cellular accumulation do not account for the order of anthracycline potency.

Performance evaluation: continuous lumbar epidural anesthesia skill test.

The evaluation of skills in anesthesiology residents is usually subjective and lacks demonstrable reliability. Therefore, an objective criterion-referenced skill test for measuring performance of continuous lumbar epidural anesthesia was developed. For such a test to be useful, it is necessary to demonstrate agreement among rater-observers. Eight performances of continuous lumbar epidural anesthesia were recorded on video tape and simultaneously rated by nine anesthesiology faculty observers to determine inter-rater reliability. Inter-rater agreement was analyzed by determining coefficient kappa for each item and the entire test. Coefficient kappa for the entire test was 0.82 indicating a high degree of agreement between raters on the performance or nonperformance of various items. Development and utility of skill tests are discussed.

Release of xenotropic type C RNA virus in response to lipopolysaccharide: acitivity of lipid-A portion upon B lymphocytes.

The present studies demonstrate that lipopolysaccharide (LPS) causes the release of endogenous xenotropic type-C RNA virus from BALB/c spleen cells. The evidence suggests that virus release is stimulated by the lipid-A portion of LPS and primarily involves an action of LPS on B lymphocytes. LPS had little or no effect on virus release by T lymphocytes, macrophages, or fibroblasts. These results indicate that the differentiated state of the cell plays an important role in the regulation of endogenous virus release.