title: Bisphosphonates significantly increase the activity of doxorubicin or vincristine against canine malignant histiocytosis cells.
abstract: Canine malignant histiocytosis (MH) is an aggressive neoplasm of macrophages and dendritic cells. It carries a poor prognosis because of the development of widespread metastasis and poor sensitivity to chemotherapy. Thus, there is a large need for new treatments for MH. We hypothesized that bisphosphonates might be useful to increase the effectiveness of cytotoxic chemotherapy against MH. To address this question, we conducted in vitro screening studies using MH cell lines and a panel of 6 chemotherapy and 5 bisphosphonate drugs. The combination of clodronate with vincristine was found to elicit synergistic killing which was associated with a significant increase in cell cycle arrest. Second, zoledronate combined with doxorubicin also significantly increased cell killing. Zoledronate significantly increased the uptake of doxorubicin by MH cells. On the basis of these findings, we conclude that certain bisphosphonate drugs may increase the overall effectiveness of chemotherapy for MH in dogs.
authors.affiliation: Department of Clinical Sciences, Animal Cancer Center, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Hafeman
authors.forename: D
authors.initials: D
authors.lastname: Varland
authors.forename: S W
authors.initials: SW
authors.lastname: Dow
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000008:administration & dosage* / Q000627:therapeutic use; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use; D054747:Histiocytic Sarcoma / Q000188:drug therapy / Q000662:veterinary*; D014750:Vincristine / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D004164:Diphosphonates; D014750:Vincristine; D004317:Doxorubicin