Use of vasoactive agents to increase tumor perfusion and the antitumor efficacy of drug-monoclonal antibody conjugates.

The effects of both alpha 1- and beta-adrenergic blocking agents on the vascular perfusion of tumors were studied with the ultimate goal of improving diagnosis and therapy of solid tumors with the use of monoclonal antibody (MAb) conjugates. With the use of a subcutaneously growing murine thymoma, it was demonstrated that nonselective and cardioselective beta-adrenergic blocking agents were capable of increasing threefold tumor-to-blood and tumor-to-liver perfusion of 125I-labeled MAbs. Subsequently, these beta-adrenergic blocking agents were found to increase the antitumor efficacy of idarubicin (Ida)-MAb conjugates. Conjugate-treated mice that also received beta-adrenergic blocking agents had a smaller mean tumor size and a greater number of regressions than mice receiving Ida-MAb conjugate alone. By contrast, prazosin HCl, an alpha 1-adrenergic blocking agent, and Cyclospasmol, a peripheral vasodilator, did not enhance the tumor perfusion and antitumor efficacy of 125I- or Ida-conjugated MAbs, and no vasoactive agent enhanced the antitumor effect of Ida when used alone. By their selective action on normal blood vessels, vasoactive drugs can change the tumor-to-normal tissue perfusion ratio, thereby enhancing the access of drug-MAb conjugates to tumors and increasing the effectiveness of tumor therapy with the use of drug-MAb conjugates.