ALLOSTERIC EFFECTORS OF HEMOGLOBIN AS MODULATORS OF CHEMOTHERAPY AND RADIATION-THERAPY IN-VITRO AND IN-VIVO

Introduction: A series of molecules designed to be allosteric effecter s of hemoglobin were examined for their potential as radiation sensiti zers in vitro and in vivo and for their potential as chemosensitizers in vivo as well as for their antimetastatic effect. Results: At a conc entration of 100 mu M for 1 h prior to, during and for 1.5 h after rad iation exposure, the allosteric effecters decreased the shoulder of th e radiation survival curve of normally oxygenated EMT-6 cells and incr eased the slope of the radiation survival curves of hypoxic EMT-6 cell s resulting in dose-modifying factors of 1.8 to 2.1. In vivo the allos teric effecters had antitumor activity against the Lewis lung carcinom a and produced primarily additive tumor growth delay when administered along with fractionated radiation therapy. When administered on days 4 through 18 after tumor implantation, the allosteric effectors. espec ially JP-7, RSR-13 and RSR-4, were highly effective antimetastatic age nts in animals bearing Lewis lung carcinoma. In cell culture, simultan eous exposure to the allosteric effectors (at 100 mu M) effectively se nsitized EMT-6 cells to the effects of 4-hydroperoxycylophosphamide, t hiotepa and carboplatin. The allosteric effectors were not very cytoto xic toward EMT-6 tumor cells from tumors treated in vivo with single d oses of each molecule nor were these agents very cytotoxic toward bone marrow CFU-GM taken from the same animals. Conclusions: It is likely that the allosteric effectors have a molecular target in addition to h emoglobin. Other possible targets include hydroxymethyl-glutaryl-COA r eductase or microsomal cytochrome b(5).