ABSTRACT
We previously demonstrated a circadian rhythm in response to docetaxel chemotherapy in C3H/HeN mice bearing MA13/C mammary adenocarcinoma. We investigated the relation between this rhythm and the expression of BCL-2 in bone marrow and in tumor tissues. A circadian rhythm characterized BCL-2 expression in the bone marrow, which was hardly modified in tumor-bearing animals. BCL-2 acrophase coincided with the time of highest docetaxel tolerability and efficacy in this model. This suggests that BCL-2 protects the bone marrow from the drug toxicity, especially during the light phase.
Subject(s)
Adenocarcinoma/physiopathology , Circadian Rhythm/genetics , Gene Expression Regulation, Neoplastic/physiology , Genes, bcl-2 , Mammary Neoplasms, Experimental/physiopathology , Neoplasm Proteins/biosynthesis , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Adenocarcinoma/genetics , Adenocarcinoma/secondary , Animals , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/therapeutic use , Antineoplastic Agents, Phytogenic/toxicity , Bone Marrow/metabolism , Bone Marrow Diseases/chemically induced , Bone Marrow Diseases/prevention & control , Chronotherapy , Docetaxel , Male , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/genetics , Mice , Mice, Inbred C3H , Neoplasm Proteins/genetics , Neoplasm Transplantation , Taxoids/administration & dosage , Taxoids/therapeutic use , Taxoids/toxicityABSTRACT
Experimental tumor models constitute a prerequisite toward chronotherapy testing in cancer patients. Studies in experimental models are required to understand the relation between tumor rhythms and antitumor treatments efficacy. In healthy tissues, cell proliferation, and differentiation processes are regulated precisely and exhibit marked circadian rhythmicity. Experimental and human tumors can retain circadian rhythms or display altered oscillations. Healthy tissues can also display rhythm modifications, possibly related to cancer stage. Cellular rhythms modulate the metabolism of cytotoxic agents and the cellular response to them; hence, they determine the chronopharmacology of anticancer drugs. Circadian rhythms in host tolerability and/or cancer chemotherapy efficacy have been demonstrated with nontoxic doses of drugs in several experimental tumor models, while in other ones a circadian-time effect was only seen within a specific dose range. The usual coupling between tolerability and efficacy rhythms of anticancer agents has resulted in significant improvement of their therapeutic index. Results of laboratory animal studies have been extrapolated to the design of clinical cancer therapy trials involving a chronobiological approach.