mofarotene and Body-Weight

The aromatic retinoid (arotinoid) Ro 40-8757 (4-[2-[p-(E)-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl]phenoxy]ethyl]-morpholine), a compound with antitumor activities, has been studied in a combination therapy with the cytostatic antitumor drug cyclophosphamide (CPA), and was found to protect bone marrow from the toxic effects of CPA. To evaluate its protective effects against CPA toxicities on lymphoid systems, we treated BDF1 mice with Ro 40-8757 orally for 1 to 5 weeks in combination with CPA intraperitoneally. After the combination treatment, mice were subjected to immunohistochemical analysis with antibodies against cell surface markers (Thy 1.2, Lyt-2, L3T4, Kappa chain, and Ia) and, in addition, general pathologic examinations were done. The protective effects of Ro 40-8757 on CPA toxicities were observed. The lymphocyte reductions (both in T cells and B cells) in lymphoid organs by CPA were apparently less severe. In particular, recovery of immature T cells in the thymic cortex was greater in combination treatment with Ro 40-8757 and CPA than in treatment with CPA alone. From these results, it can be concluded that Ro 40-8757 protects the lymphoid organs (thymus, spleen, and lymph node) from the immunotoxicity of CPA, and the protective effect is evident, especially in the thymic cortical lymphocytes.

Topics: Animals; Antigens, Surface; Antineoplastic Agents; Body Weight; Cyclophosphamide; Immunohistochemistry; Immunosuppressive Agents; Lymphoid Tissue; Male; Mice; Mice, Inbred Strains; Morpholines; Organ Size; Retinoids; Spleen; Thymus Gland; Time Factors

The arotinoid Ro 40-8757 is a novel compound that has significant therapeutic activity against chemically induced breast tumors in rats. The results of combination therapy with cyclophosphamide, plus the arotinoid showed that the anti-tumor effects were additive. However, all of the rats given CPA alone died between week 6 and week 10 of treatment. None of the animals in the group treated with the combination died. Administration of a single dose of Ro 40-8757 to non-tumor bearing mice resulted in a transient increase in bone-marrow-progenitor cells after 2 days and a decrease in splenic progenitors at day 4. Treatment of mice with the combination demonstrated that the marrow progenitors were protected from the toxic effects of CPA by the arotinoid. Direct addition of Ro 40-8757 to mouse bone-marrow cells in clonogenic assay cultures containing WEHI-3-conditioned medium plus erythropoietin showed no significant enhancement by the arotinoid. The results suggest that this compound may exert its protective effect through the hemopoietic micro-environment.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Body Weight; Bone Marrow; Cyclophosphamide; Drug Interactions; Female; Hematopoiesis; Hematopoietic Stem Cells; Mammary Neoplasms, Experimental; Morpholines; Rats; Rats, Sprague-Dawley; Retinoids