Correlation of human bladder tumor histoculture proliferation and sensitivity to mitomycin C with tumor pathobiology

Abstract

This study examined the in vitro proliferation and mitomycin C (MMC) sensitivity of patient bladder tumors as a function of the tumor pathobiology. Surgical specimens of transitional cell carcinoma of the bladder were maintained as histocultures on collagen gels. The thymidine labeling index (LI) was determined by autoradiography and the labeling for proliferating cell nuclear antigen (PCNA) by immunohistochemistry. There was a linear correlation between the thymidine LI and the PCNA LI, but the PCNA LI were quantitatively lower than the thymidine LI. The 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 invasive (T2-T4) tumors, and 28.9 and 50.9% for the diploid and aneuploid tumors. Analysis of variance indicates that these differences were statistically significant. These data indicate that the proliferation of 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 required for 50% inhibition of thymidine LI (IC50) showed a 120-fold intertumor variation (0.102 to 12.4 micrograms./ml.). The sensitivity to MMC inversely correlated with tumor aggressiveness. The IC50 increased with tumor LI (p < 0.05). The mean IC50 were 2.61 and 5.79 micrograms./ml. for superficial and invasive tumors (p < 0.05), 1.06, 3.05 and 4.49 micrograms./ml. for grade I, II and III tumors (p < 0.05), and 2.53 and 4.31 micrograms./ml. for diploid and aneuploid tumors (p = 0.14). These data indicate a large difference in sensitivity of human bladder tumors to MMC, with greater sensitivity for well-differentiated superficial tumors and lesser sensitivity for undifferentiated, invasive tumors.