One of the proposed mechanisms for multidrug resistance in cancer cells is the activation of efflux pumps using p-glycoprotein which pump the drugs out of the tumor cells. Naturally, the desire to use p-gp blockers to reverse this resistance arose.
This gave rise to the concept of the usage of the calcium channel blockers, specifically Verapamil and Desverapamil, in the reversal of multidrug resistant tumor cells.
First-generation agents (eg, cyclosporin, verapamil) were limited by unacceptable toxicity, whereas second-generation agents (eg, valspodar, biricodar) had better tolerability but were confounded by unpredictable pharmacokinetic interactions and interactions with other transporter proteins. Third-generation inhibitors (tariquidar XR9576, zosuquidar LY335979, laniquidar R101933, and ONT-093) have high potency and specificity for P-gp. Furthermore, pharmacokinetic studies to date have shown no appreciable impact on cytochrome P450 3A4 drug metabolism and no clinically significant drug interactions with common chemotherapy agents.
However, only a few phase II and phase II trials are running with the third generation agents and they are yet to show major impact.
Reference:
1. Thomas H, Coley HM. Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein. Cancer Control. 2003 Mar-Apr;10(2):159-65. Review. PubMed PMID: 12712010.
2. Mansouri A, Henle KJ, Nagle WA. Multidrug resistance: prospects for clinical management. SAAS Bull Biochem Biotechnol. 1992 Jan;5:48-52. Review. PubMed PMID: 1375033.
