PROLIFERATION INDEXES AS MOLECULAR PHARMACODYNAMIC END-POINTS IN EVALUATION OF ANTICANCER DRUG EFFECT IN HUMAN SOLID TUMORS

Purpose. The present study compared proliferative indices, i.e, incorp oration of DNA precursor (i.e, thymidine or TdR, and bromodeoxyuridine or BrdU) and expression of proliferating cell nuclear antigen (PCNA), as molecular pharmacodynamic endpoints in evaluation of anticancer dr ug effect in human solid tumors.Methods. Tumor specimens obtained from patients were grown as histocultures. After treatment with doxorubici n, mitomycin C, and/or paclitaxel, cells labeled by [H-3]TdR were iden tified using autoradiography, and cells labeled by BrdU and PCNA were identified using immunohistochemical techniques. Drug effect was measu red as reduction of DNA precursor-labeled cells or PCNA-expressing cel ls. Results. The results indicate that (a) the two DNA precursors, TdR and BrdU, labeled the same cells and resulted in identical pharmacody namics, (b) the pharmacodynamics established using inhibition of DNA p recursor incorporation were qualitatively and quantitatively different from the pharmacodynamics established using inhibition of PCNA expres sion, (c) the inhibition of PCNA expression was erratic in some tumors , and (d) the differences in pharmacodynamics established using the tw o end points are drug-specific, with greater differences for paclitaxe l than for mitomycin C. Conclusions. The erratic results measured by t he PCNA labeling method suggest that this method may be less reliable than the conventional DNA precursor labeling method. The finding of id entical pharmacodynamics of doxorubicin and paclitaxel established usi ng BrdU and [H-3]TdR indicates that the two precursors are interchange able. Because the methodology for detecting BrdU incorporation require s less time and does not require the use of radioactivity, we conclude that inhibition of BrdU incorporation represents a useful endpoint fo r evaluating the antiproliferative activity of anticancer drugs in hum an solid tumors.