NEUTRAL METOCLOPRAMIDE INDUCES TUMOR-CYTOTOXICITY AND SENSITIZES IONIZING-RADIATION OF A HUMAN LUNG ADENOCARCINOMA AND VIRUS-INDUCED SARCOMA IN MICE

Radiation induced cytotoxicity was potentiated by neutralized metoclop ramide (nMCA; Neu-Sensamide(TM), Oxigene Inc) when a human lung adenoc arcinoma (H2981) transplanted into acid mice and an adeno-type 12 viru s induced mouse sarcoma (A12B3) inoculated into CBA mice were exposed in vivo to low dose radiation at single doses of 1 and 2 Gy respective ly. However, when the radiation dose was increased to 6, 10 or 18 Gy ( single dose) and combined with a single dose nMCA (2 mg/kg), tumor cyt otoxicity was not sensitized by the combination treatment. A fractiona ted dose of ionizing radiation (3 x 1 Gy) in combination with nMCA at a repeated dose of 3 x 10 mg/kg body weight (1 dose/day, i.m.) signifi cantly increased cytotoxicity in H2981 compared with radiation given a lone. nMCA alone also had a statistically significant dose dependent c ytotoxic effect on H2981 growth when it was administered as repeated d oses (8 doses) at 2 mg/kg or 10 mg/kg (1 dose every second day), and a similar result was achieved at 20 mg/kg but not at 2 and 10 mg/kg in the A12B3 tumor. In addition, the tumor volume at the start of treatme nt was important for the anti-tumor effect of nMCA (i.e. the larger in itial tumor volume gave less effect on tumor growth). Taken together, our data propose that the mode of action of nMCA is different from rad iation, and hence the two mechanisms are at least additive when in com bination with lower radiation doses. The data further suggest that the cytotoxic mechanism is consistent with potentiating apoptosis because low and repeated doses of radiation (1-2 Gy), which are known to incr ease cytotoxicity by apoptosis, are sensitized by nMCA but not high do ses and nMCA has more potent anti-tumor effects against H2981 tumors w hich have a higher constitutive apoptotic fraction of cells than A12B3 .