Prolonged adjuvant tamoxifen: A beginning not the end

Biochemical modulation is a special type of combination chemotherapy which aims to selectively improve the therapeutic index by increasing the antitumor effect and protecting against toxic side effects. Bio-chemical modulation seems to be an attractive way to circumvent quantitative and qualitative heterogeneity of tumors. In the past decade a number of biochemical modulation approaches have been tested to improve the activity of 5-fluorouracil (5FU). 5FU itself has only modest anticancer activity but has been shown to be a very attractive target for biochemical modulation. A number of the combinations have been ineffective in the clinic despite extensive testing in a number of schedules. Some other combinations were initially tested in an inappropriate schedule, but were active when applied in another schedule. The latter was made possible by a systematic preclinical development of combinations with a proper translation to the clinic accompanied by pharmacodynamic evaluation. This review describes a number of biochemical modulation combinations, both inactive and active. The main conclusion is that properly applied biochemical modulation schedules may lead to successful use in the clinic.