Figure 6.

Dose-response ranges for tamoxifen in breast cancer therapy. This figure demonstrates the NMDRC, also called flare, in tamoxifen treatments. As the circulating dose of tamoxifen increases when treatment starts, patients initially experience flare, i.e. growth of the tumor (546), followed by a decrease in tumor size as the circulating levels of tamoxifen rise into the therapeutic range (676, 677). High doses of tamoxifen are acutely toxic (546). Starting from the highest concentrations, where acute toxicity is observed, and going to lower concentrations on the X-axis, the acute toxicity diminishes towards zero growth, i.e. therapeutic stasis (green baseline). This occurs at approximately 1E-05 m, the lowest observed effect level (LOEL) for toxicity. The vertical arrows show the results of applying three or four 10-fold safety factors to the LOEL for the high-dose toxicity of tamoxifen, and would calculate a safe or reference dose for tamoxifen in the region of flare, the least safe region of exposure in actual practice. Above the diagram of dose response ranges is estimated ER occupancy by tamoxifen. This was calculated from the affinity constant of tamoxifen for ERs determined in human breast cancer cells (Ki = 29.1 nM; Ref 678); flare appears to correspond to low receptor occupancy (blue axis), therapeutic range with mid and upper-range receptor occupancy, and acute toxicity well above 99% receptor occupancy. (678).