Effects of N-Trifluoroacetyladriamycin-14-O-Hemiadipate and Radiation on L1210 Cells

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Abstract
N-Trifluoroacetyladriamycin-14-O-hemiadipate (AD 143) is the most active among the 14-O-hemiester adriamycin-trifluoroacetamide derivatives and has been selected for preclinical studies. We now report its ability to enhance the kill by ionizing radiation of murine leukemic cells in culture. A 1-h exposure to either 1.28-12.8 .mu.g/ml of AD 143 or to 0.16-1.62 .mu.g/ml of adriamycin (ADR) was followed at 0 h by graded doses (0-1 Krad) of radiation, and cell viability was assessed by soft agar cloning technique. Regression analyses of the dose-response curve has shown that both compounds, at the concentrations employed, decrease the reciprocal of the slope D0 from 97 rad for radiation alone, to 66-56 rad for Ad 143 (1.28-5.12 .mu.g/ml) plus radiation, or to 85-61 rad for ADR (0.16-0.65 .mu.g/ml) when used with radiation. ADR, however, had a significant "shoulder"-modifying effect. The Dq remained essentially unchanged after AD 143 pretreatment. Quantitation of synergism (superadditivity), additivity, and antagonism was performed by isobologram analysis and by a computerized method based on the "median effect principle." Both approaches have shown that synergism of AD 143 or ADR with radiation becomes apparent with dose escalation. This effect is discernible at significantly lower levels of AD 143 than of ADR, corresponding to < LD50 measured by clonogenic assay.