title: Modulation of bone microenvironment with zoledronate enhances the therapeutic effects of STI571 and paclitaxel against experimental bone metastasis of human prostate cancer.
abstract: Prostate cancer cells metastasize to the bone where their interaction with osteoclasts and osteoblasts can lead to alterations in the structure of the bone. We determined whether the systemic administration of the bisphosphonate, zoledronate, could prevent bone lysis and halt the proliferation of human prostate cancer cells injected into the tibia of nude mice. Zoledronate did not affect the in vitro proliferation of human prostate cancer PC-3MM2 cells. The in vivo administration of zoledronate produced significant bone preservation but did not inhibit the progressive growth of PC-3MM2 cells. The systemic administration of STI571 (imatinib mesylate, Gleevec), an inhibitor of phosphorylation of the platelet-derived growth factor receptor, in combination with paclitaxel, produced apoptosis of tumor cells and bone- and tumor-associated endothelial cells. The systemic administration of zoledronate with STI571 and paclitaxel produced a significant preservation of bone structure, a decrease in tumor incidence and weight, and a decrease in incidence of lymph node metastasis. This therapeutic activity was correlated with inhibition of osteoclast function, inhibition of tumor cell proliferation, and induction of apoptosis in tumor-associated endothelial cells and tumor cells. Cancer is a heterogeneous disease that requires multimodality therapy. The present data recommend the combination of a bisphosphonate agent with protein tyrosine kinase inhibitor and an anticycling drug for the treatment of prostate cancer bone metastasis.
authors.affiliation: Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Sun-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Hisanori
authors.initials: H
authors.lastname: Uehara
authors.forename: Sertac
authors.initials: S
authors.lastname: Yazici
authors.forename: Junqin
authors.initials: J
authors.lastname: He
authors.forename: Robert R
authors.initials: RR
authors.lastname: Langley
authors.forename: Paul
authors.initials: P
authors.lastname: Mathew
authors.forename: Dominic
authors.initials: D
authors.lastname: Fan
authors.forename: Isaiah J
authors.initials: IJ
authors.lastname: Fidler
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D001859:Bone Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D000068877:Imatinib Mesylate; D007093:Imidazoles / Q000008:administration & dosage; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology; D017239:Paclitaxel / Q000008:administration & dosage; D010879:Piperazines; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D011743:Pyrimidines / Q000008:administration & dosage; D000077211:Zoledronic Acid
chemical_list: D001549:Benzamides; D004164:Diphosphonates; D007093:Imidazoles; D010879:Piperazines; D011743:Pyrimidines; D000077211:Zoledronic Acid; D000068877:Imatinib Mesylate; D017239:Paclitaxel