PHARMACODYNAMICS OF DOXORUBICIN IN HUMAN BLADDER-TUMORS

Intravesical doxorubicin treatment delivers high drug concentrations t o the bladder wall, Set the treatment produces only a variable and inc omplete response in superficial bladder cancer and insignificant activ ity in muscle-invading disease, This study evaluated the pharmacologic al basis for the clinical observations and potential prognostic indica tors of tumor sensitivity to doxorubicin, The pharmacodynamics of doxo rubicin were studied using histocultures of surgical specimens of seve n superficial (T-a and T-1) and nine invasive (T-2-T-4) tumors, After a 2-h exposure, drug treatment caused a concentration-dependent inhibi tion of proliferation, as measured by bromodeoxyuridine incorporation into DNA, Extensive cell death was observed at high concentrations (>1 0 mu M) in sensitive tumors, The IC50 values ranged from 0.14 to 5.2 m u M for superficial tumors and from 1.4 to >100 mu M for invasive tumo rs, A comparison of the IC50 and IC90 values with the drug concentrati ons previously determined in human bladder walls showed that IC50 was achieved in all T-a tumors, 67-100% of T-1 tumors, and one of the nine invasive tumors, whereas IC90 was achieved in all T-a tumors but none of the other tumors, To determine the biological basis of variable do xorubicin sensitivity among different tumors, we examined the relation ship of chemosensitivity with tumor pathology and with expression of m ultidrug resistance p-glycoprotein (Pgp) and p53 protein, The invasive , high-grade, highly proliferative, p53- and Pgp-positive tumors were more resistant than the superficial, lower-grade, p53- and Pgp-negativ e tumors, All tumors were negative for bcl-2, The rank order of these factors was p53 expression > tumor stage > grade > bromodeoxyuridine l abeling index > Pgp, Statistical analysis using the Akaike Information Criterion indicates that the two-parameter combination of p53 express ion with stage further improved the predictive value, The present stud y shows that: (a) there was a > 700-fold difference in doxorubicin sen sitivity among superficial and invasive tumors; (b) the variable and i ncomplete response of superficial bladder cancer to intravesical doxor ubicin therapy is likely due to the 35-fold variability in tumor chemo sensitivity and, to a lesser degree, the 4-fold variability in tissue pharmacokinetics; (c) the lack of response of invasive cancer to intra vesical doxorubicin therapy is likely the result of the inadequate dru g concentrations presented to the deep muscle layers and the low chemo sensitivity of the more aggressive tumors; and (d) the combination of p53 expression and high stage was the most significant predictor of do xorubicin sensitivity, whereas Pgp expression was the least important.