ENHANCEMENT OF RADIOIMMUNOTHERAPY BY DRUGS MODIFYING TUMOR BLOOD-FLOWIN A COLONIC XENOGRAFT MODEL

Radioimmunotherapy (RIT) is hampered clinically by poor tumour localiz ation of antibody. In order to enhance localization we have investigat ed the concomitant use of RIT with 2 drugs, flavone-8-acetic acid (FAA ) and its analogue 5,6-dimethylxanthenone-4-acetic acid (XAA), which b oth reduce tumour blood flow and induce immunomodulation. A single i.v . does of 0.5 mCi (18.5 MBq) intact I-131 anti-CEA antibody significan tly delayed growth and prolonged survival over that of untreated contr ols, in an established LS174T colon xenograft model in nude mice. The adjuvant use of a single i.p. dose of either FAA or XAA, given 24 or 4 8 hr after I-131-A5B7 to allow maximum tumour levels of antibody to be attained before drug-induced blood-flow inhibition, significantly enh anced the RIT. FAA caused entrapment of antibody within the tumour in relation to the time allowed for localization before drug administrati on. Repeated doses of FAA prolonged tumour growth inhibition but did n ot enhance the therapy achieved after a single dose. Although both dru gs alone induced massive tumour necrosis of all but a thin peripheral rim of viable cells, tumour regrowth was inhibited for a few days only , with no effect on survival. Drug-induced tumour necrosis, immunomodu lation and retention of higher doses of I-131-A5B7 within the tumour m ay contribute to the enhanced RIT produced by this combined therapy. ( C) 1994 Wiley-Liss, Inc.