Eradication of colorectal xenografts by combined radioimmunotherapy and combretastatin A-4 3-O-phosphate

Solid tumors have a heterogeneous pathophysiology, which has a major impact on therapy. Using SW1222 colorectal xenografts grown in nude mice, we have shown that antibody-targeted radioimmunotherapy (RIT) effectively treated the well-perfused tumor rim, producing regressions for similar to 35 days, but was less effective at the more hypoxic center, By 72 h after RIT, the n umber of apoptotic cells rose from an overall value of 1% in untreated tumo rs to 35% at the tumor periphery and 10% at the center. The antivascular ag ent disodium combretastatin A-4 3-O-phosphate (CA4-P) rapidly reduced tumor blood now to 621 of control values by 1 h, 23% by 3 h, and between 32-36% from 6 to 24 h after administration. This created central hemorrhagic necro sis, but a peripheral rim of cells continued to grow, and survival was unaf fected. Changes in the pattern of perfusion across the tumor over time were zonal. Untreated mice showed perfusion throughout the tumor, with greatest activity at the rim. There was an overall reduction at 1 h, and total cess ation of central perfusion from 3 h onward. A narrow peripheral rim of perf usion was always present, which increased in intensity and extent between 6 and 24 h, either through reperfusion or new vessel growth. Combining these two complementary therapies (7.4 MBq I-131-labeled anti-carcinoembryonic a ntigen IgG i,v, plus a single 200 mg/kg dose of CA4-P i,p,) produced comple te cures in five of six mice for >9 months. Allowing maximal tumor localiza tion of antibody (48 h) before blood now inhibition by CA4-P increased tumo r retention by two to three times control levels by 96 h without altering n ormal tissue levels, as confirmed by gamma counting and phosphor image anal ysis. The success of this combined, synergistic therapy was probably the re sult of several factors: (a) the killing of tumor cells in the outer, radio sensitive region by targeted radiotherapy; (b) enhancement of RIT by entrap ment of additional radioantibody after combretastatin-induced vessel collap se; and (c) destruction of the central, more hypoxic and radioresistant reg ion by CA4-P, This work demonstrates the need to consider cancer treatment in a biologically heterogeneous setting, if results are to he effectively t ranslated to the clinic.