Do Anti-P-Glycoprotein Antibodies Have a Future in the Circumvention of Multidrug Resistance?

Abstract

Discovering how to circumvent or overcome cancer drug resistance has become the Holy Grail of experimental chemotherapists and clinicians. It is clear that patients' tumors can become resistant to all the therapies they receive, and outwitting the tumor cells' resistance mechanisms has become an increasingly difficult challenge. In recent years, we have learned that the phenomenon of multidrug resistance, characterized by cross-resistance to many natural product anticancer drugs, decreases drug accumulation and retention and that Pglycoprotein (Pgp) expression (7) may be an important factor in some of the clinical failures of cancer chemotherapy. A number of tumors have been shown to express Pgp either de novo or after chemotherapy (23), and recent results suggest that Pgp expression may be an important indicator of therapeutic outcome (4). While non-Pgp forms of natural-product multidrug resistance have been described experimentally (5,6), they have not yet been shown in patients' tumors, principally because appropriate reagents that detect them are presently unavailable. Accordingly, efforts directed at circumventing multidrug resistance are focused on inhibition or modulation of Pgp function or expression and include screening and rational design of Pgp-inhibitory chemicals, as well as the use of modulator combinations, inhibitory antibodies, and antisense oligonucleotides (7,8). Most experimental and clinical efforts to circumvent multidrug resistance have used drugs such as verapamil, quinidine, amiodarone, and cyclosporine that likely block the efflux function of Pgp (8). This approach has not yet proven satisfactory in the clinical setting in part because of the limitation of available modulators and because of their toxic effects (9,10). Planned or in progress are clinical trials of compounds (11,12) that appear to have a far more favorable therapeutic index than some of the first generation modulators (such as verapamil) and may be effective in maximizing the chemotherapy of drug resistant disease associated with the expression of Pgp. Among the other possibilities to circumvent Pgp-associated multidrug resistance, several would seem to hold promise for the near future. Application of modulator combinations, which has provided some encouraging preliminary results in cell culture (13,14), has the advantage of maximum inhibition of Pgp without the dose-limiting toxic effects seen with single modulator treatment. This approach, however, may also suffer from lack of specificity and nonspecific toxicity. By contrast, the use of anti-Pgp antibodies to circumvent Pgp-mutlidrug resistance offers the prospect of specificity, since the antibodies should only target Pgp; toxicity would only be that associated with the administration of protein. It is obvious that only an antibody that recognizes surface determinants of Pgp will have a chance of modulating Pgp-multidrug resistance in vivo. Anti-Pgp antibodies have been administered in vivo alone, in combination with anticancer drugs, and coupled to a toxin. Tsuruo et al. developed two antibodies that recognize surfaceexposed epitopes of Pgp (15) and showed that one, MRK-16 monoclonal antibody, blocked the growth of multidrug resistant human tumor xenografts in athymic mice (76). In this issue of the Journal, Pearson et al. (17) have taken the experiment one step further: using a transplantable human colon carcinoma cell line infected with a retrovirus carrying a complementary DNA containing the MDR1 gene (also known as PGY1), the authors also showed that MRK-16 monoclonal antibody was able to overcome Pgp-multidrug resistance in vitro and, more importantly, in xenografts in vivo when used in combination with vincristine. Of interest, neither the antibody alone nor vincristine alone were able to enhance the survival of mice bearing the Pgpexpressing xenografts. A preliminary account of similar findings was reported last year by Rittman-Grauer et al. (18) using the other antibody that recognizes surface determinants of Pgp, HYB-241. By contrast, Fitzgerald et al. (79) coupled MRK-16 monoclonal antibody to ricin and showed that this immunotoxin was effective in selectively killing tumor cells that expressed