IMMUNOCHEMOTHERAPY OF HUMAN COLON-CARCINOMA XENOGRAFTS IN NUDE-MICE USING COMBINATIONS OF IDARUBICIN MONOCLONAL-ANTIBODY CONJUGATES

Tumour cell heterogeneity is probably a principal cause of treatment failure and represents a formidable barrier for effective antibody-targeted chemotherapy. Idarubicin (Ida), a more potent and less cardiotoxic analogue of daunomycin, has been demonstrated to specifically target and eradicate homogeneous, cloned, murine tumour cell populations in vitro and in vivo when coupled to monoclonal antibodies (MoAb); however, the antitumour activity of Ida-MoAb conjugates against human tumour xenografts remains to be established. In this study, the value of cotargeting conjugates to different human tumour-associated antigens within a solid tumour has been assessed by comparing the effects of combinations of Ida-anti-colon carcinoma MoAb conjugates with any one Ida-anti-colon carcinoma MoAb conjugate used alone. Individual Ida-MoAb conjugates have previously been evaluated for their specific binding and cytotoxicity to one of two different human colon carcinoma xenografts (Colo 205 or LIM2210) in vitro, although their efficacy alone or in combination required assessment in vivo. Combinations of the most effective Ida-MoAb conjugates were demonstrated to enable a greater number of complete tumour regressions than the most efficacious Ida-MoAb conjugate administered alone in vivo; some combinations inhibited control tumour growth by up to 95%. This study suggests that Ida-MoAb conjugates can be effective against subcutaneous human tumours in nude mice, although it is unlikely that any single conjugate will eradicate all the tumour cells in a solid tumour, and the value of 'cocktails' of drug-MoAb conjugates against some xenografts (i.e. LIM2210) appears to be limited.