title: Pilot studies of the effect of zoledronic acid (Zometa) on tumor-derived cells ex vivo in the ATP-based tumor chemosensitivity assay.
abstract: There is debate regarding the direct effect of bisphosphonates against visceral metastases from solid tumors, despite their proven efficacy against the skeletal complications of metastasis. The aim of this study was to determine whether zoledronic acid showed direct activity against five ovarian cell lines and tumor-derived cells, and whether addition of zoledronic acid to cytotoxic agents increased their cytotoxicity. In this study we used a standardized ATP-based tumor chemosensitivity assay (ATP-TCA) to measure the activity of alendronate, clodronate and zoledronic acid in five ovarian carcinoma cell lines and human solid tumors (breast, lung, ovarian, unknown primary carcinoma, and cutaneous and uveal melanoma) (n=34). We also tested the combination of zoledronic acid with paclitaxel and cisplatin in tumor-derived cells. All five cell lines exhibited greater sensitivity to bisphosphonates than the tumor-derived cells and in all five the IC50 for zoledronic acid was less than 4 muM. In the tumor-derived cells, zoledronic acid showed concentration-dependent inhibition with a median IC50 for all tumors tested of 17 muM and evidence of apoptosis (caspase activation). Simultaneous addition of zoledronic acid to cisplatin or paclitaxel showed no major increase in cytotoxicity. We conclude that the activity of bisphosphonates was greater in cell lines than in tumor-derived cells. However, the pattern of activity of bisphosphonates was the same in cell lines and tumor derived cells. This study suggests a direct, or possibly an indirect, effect of zoledronic acid and other nitrogen-containing bisphosphonates against neoplastic cells, but simultaneous addition with cisplatin or paclitaxel does not substantially increase the activity of the cytotoxic agent.
authors.affiliation: Translational Oncology Research Centre, Department of Histopathology, Queen Alexandra Hospital, Portsmouth, UK. Louise.knight@porthosp.nhs.uk
authors.forename: Louise A
authors.initials: LA
authors.lastname: Knight
authors.forename: Mark
authors.initials: M
authors.lastname: Conroy
authors.forename: Augusta
authors.initials: A
authors.lastname: Fernando
authors.forename: Marta
authors.initials: M
authors.lastname: Polak
authors.forename: Christian M
authors.initials: CM
authors.lastname: Kurbacher
authors.forename: Ian A
authors.initials: IA
authors.lastname: Cree
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019386:Alendronate / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004002:Clodronic Acid / Q000494:pharmacology; D004164:Diphosphonates / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D009382:Neoplasms, Unknown Primary / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D004002:Clodronic Acid; D000077211:Zoledronic Acid; D000255:Adenosine Triphosphate; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases; D017239:Paclitaxel; D002945:Cisplatin; D019386:Alendronate