Many
cancer therapeutic agents elicit resistance that renders them ineffective and often produces cross-resistance to other drugs. One of the most common mechanisms of resistance involves
P-glycoprotein (Pgp)-mediated
drug efflux. To address this problem, new agents have been sought that are less prone to inducing resistance and less likely to serve as substrates for Pgp efflux. An alternative to this approach is to deliver established agents as molecular transporter conjugates into cells through a mechanism that circumvents Pgp-mediated efflux and allows for release of free
drug only after cell entry. Here we report that the widely used chemotherapeutic agent
Taxol, ineffective against
Taxol-resistant human
ovarian cancer cell lines, can be incorporated into a releasable
octaarginine conjugate that is effective against the same
Taxol-resistant cell lines. It is significant that the ability of the
Taxol conjugates to overcome
Taxol resistance is observed both in cell culture and in animal models of
ovarian cancer. The generality and mechanistic basis for this effect were also explored with
coelenterazine, a Pgp substrate. Although
coelenterazine itself does not enter cells because of Pgp efflux, its
octaarginine conjugate does so readily. This approach shows generality for overcoming the multidrug resistance elicited by small-molecule
cancer chemotherapeutics and could improve the prognosis for many patients with
cancer and fundamentally alter search strategies for novel therapeutic agents that are effective against resistant disease.