osteoprotegerin and Leukopenia

Hematopoietic growth factors are used to reverse chemotherapy-induced leukopenia. However, some factors such as granulocyte macrophage colony-stimulating factor (GM-CSF) induce osteoclast-mediated bone resorption that can promote cancer growth in the bone. Accordingly, we evaluated the ability of GM-CSF to promote bone metastases of breast cancer or prostate cancer in a mouse model of chemotherapy-induced leukopenia. In this model, GM-CSF reversed cyclophosphamide-induced leukopenia but also promoted breast cancer and prostate cancer growth in the bone but not in soft tissue sites. Bone growth was associated with the induction of osteoclastogenesis, yet in the absence of tumor GM-CSF, it did not affect osteoclastogenesis. Two osteoclast inhibitors, the bisphosphonate zoledronic acid and the RANKL inhibitor osteoprotegerin, each blocked GM-CSF-induced tumor growth in the bone but did not reverse the ability of GM-CSF to reverse chemotherapy-induced leukopenia. Our findings indicate that it is possible to dissociate the bone-resorptive effects of GM-CSF, to reduce metastatic risk, from the benefits of this growth factor in reversing leukopenia caused by treatment with chemotherapy.

Topics: Animals; Antineoplastic Agents, Alkylating; Bone Density Conservation Agents; Bone Neoplasms; Breast Neoplasms; Cyclophosphamide; Diphosphonates; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Imidazoles; Leukopenia; Male; Mice; Mice, Nude; Osteoclasts; Osteoprotegerin; Prostatic Neoplasms; RANK Ligand; Zoledronic Acid

It is suggested that Scr-index for radiation-induced apoptosis in leukocytes in vitro be determined prior to combined therapy of urinary bladder cancer in order to estimate its efficacy. It was identified by studying leukocytes of peripheral blood from patients in whony white blood cells DNA level decreased after exposure to 2 Gy and 3-hr incubation at 37 degrees C. Values over 1.0 predicted relatively longer relapse-free survival. Scr-index of over 1.20 pointed to an insignificant decrease in leukocyte count during therapy. When it ranged 1.00-0.75, leukocyte count fell by approximately 25%; S(cr)-index below 0.55 indicated grade III blood poisoning.

Topics: Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Chemotherapy, Adjuvant; Cystectomy; Disease-Free Survival; Female; Humans; Leukocyte Count; Leukopenia; Male; Mathematical Computing; Middle Aged; Neoplasm Invasiveness; Osteoprotegerin; Prognosis; Radiation-Sensitizing Agents; Radiotherapy, Adjuvant; Survival Analysis; Treatment Outcome; Urinary Bladder Neoplasms