The proliferation rate paradox in antimitotic chemotherapy

Abstract

Cytotoxic cancer chemotherapy drugs are believed to gain selectivity by targeting cells that proliferate rapidly. However, the proliferation rate is low in many chemosensitive human cancers, and it is not clear how a drug that only kills dividing cells could promote tumor regression. Four potential solutions to this "proliferation rate paradox" are discussed for the microtubule-stabilizing drug paclitaxel: drug retention in tumors, killing of quiescent cells, targeting of noncancer cells in the tumor, and bystander effects. Testing these potential mechanisms of drug action will facilitate rational improvement of antimitotic chemotherapy and perhaps cytotoxic chemotherapy more generally.

FIGURE 1:

Chromatin morphology reports responses of dividing cancer cells to paclitaxel in a tumor. HT1080 human cancer cells expressing histone H2B-GFP were grown as xenograft tumors in window chambers in nude mice, treated with paclitaxel, and imaged by laser confocal microscopy. Cells that divided in drug proceeded from mitotic arrest to multiple micronuclei and apoptosis. Next to far right and far right, sequential images of the same cell from a movie. (From Orth et al., 2011.)

FIGURE 2:

Potential actions of paclitaxel on tumor cells. Green arrows show cell cycle transitions. Red arrows show the only well-characterized drug action—killing cancer cells that enter mitosis. Blue arrows show hypothetical mechanisms for killing quiescent cancer cells that would provide solutions to the proliferation rate paradox.