CORRELATION OF HUMAN BLADDER-TUMOR HISTOCULTURE PROLIFERATION AND SENSITIVITY TO MITOMYCIN-C WITH TUMOR PATHOBIOLOGY

This study examined the in vitro proliferation and mitomycin C (MMC) s ensitivity of patient bladder tumors as a function of the tumor pathob iology. Surgical specimens of transitional cell carcinoma of the bladd er were maintained as histocultures on collagen gels. The thymidine la beling index (LI) was determined by autoradiography and the labeling f or proliferating cell nuclear antigen (PCNA) by immunohistochemistry. There was a linear correlation between the thymidine LI and the PCNA L I, but the PCNA LI were quantitatively lower than the thymidine LI. Th e mean thymidine LI were 30.9, 32.4 and 51.5% for the grade I, II and III tumors, 33.6 and 56.3% for the superficial (Tis, Ta and T1) and in vasive (T2-T4) tumors, and 28.9 and 50.9% for the diploid and aneuploi d tumors. Analysis of variance indicates that these differences were s tatistically significant. These data indicate that the proliferation o f tumor histocultures paralleled the tumor aggressiveness in vivo. The tumor sensitivity to MMC, measured by the inhibition of the thymidine LI of tumor cells, was studied in 31 tumors. At a 2 hour exposure, as is currently used in intravesical therapy, the MMC concentrations req uired for 50% inhibition of thymidine LI (IC50) showed a 120-fold inte rtumor variation (0.102 to 12.4 mu g./ml.). The sensitivity to MMC inv ersely correlated with tumor aggressiveness. The IC50 increased with t umor LI (p < 0.05). The mean IC50 were 2.61 and 5.79 mu g./ml. for sup erficial and invasive tumors (p < 0.05), 1.06, 3.05 and 4.49 mu g./ml. for grade I, II and III tumors (p < 0.05), and 2.53 and 4.31 mu g./ml . for diploid and aneuploid tumors (p = 0.14). These data indicate a l arge difference in sensitivity of human bladder tumors to MMC, with gr eater sensitivity for well-differentiated superficial tumors and lesse r sensitivity for undifferentiated, invasive tumors.