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© The Author 2007. Published by Oxford University Press.
ARTICLES |
Antitumor Effects of Clinical Dosing Regimens of Bisphosphonates in Experimental Breast Cancer Bone Metastasis
Affiliations of authors: INSERM, Research Unit U.664; Université Claude Bernard Lyon 1; and Faculté de Médecine Laennec, Lyon, France (FD, CLG, PC); Novartis Institutes for Biomedical Research, WKL-125.901, Basle, Switzerland (J. Gasser, J. Green)
Correspondence to: Philippe Clézardin, PhD, DSc, INSERM Research Unit U.664, Faculté de Médecine Laennec, Rue Guillaume Paradin, 69372 Lyon cedex 08, France (e-mail: clezardin{at}lyon.inserm.fr).
Background: Bisphosphonates exhibit direct antitumor activity in animal models, but only at high doses that are incompatible with the clinical dosing regimens approved for the treatment of cancer patients with skeletal metastases. We compared the antitumor effects of clinical dosing regimens of the bisphosphonates zoledronic acid and clodronate in a mouse model of bone metastasis.
Methods: Mice (n = 6–10 per group) were treated with zoledronic acid, clodronate, or vehicle starting before (preventive protocols) or after (treatment protocols) intravenous injection with human B02/GFP.2 breast cancer cells, which express green fluorescent protein (GFP) and luciferase and metastasize to bone. Zoledronic acid was given as daily, weekly, or single doses at a cumulative dose of 98–100 µg/kg body weight, equivalent to the 4-mg intravenous dose given to patients. Clodronate was given as a daily dose (530 µg/kg/day), equivalent to the daily 1600-mg oral clinical dose given to patients. Bone destruction was measured by radiography, x-ray absorptiometry or tomography, and histomorphometry (as the ratio of bone volume to tissue volume). Skeletal tumor burden was measured by histomorphometry (as the ratio of tumor burden to soft tissue volume [TB/STV]) and luciferase activity. All statistical tests were two-sided.
Results: In treatment protocols, daily clodronate was less effective at decreasing the TB/STV ratio than daily (53% versus 87%, difference = 34%, 95% confidence interval [CI] = 16% to 44%, P<.001) or weekly (53% versus 90%, difference = 37%, 95% CI = 19% to 46%, P<.001) zoledronic acid–dosing regimens. Compared with vehicle, a single dose of zoledronic acid decreased tumor burden by only 16% (95% CI = 9% to 22%, P<.001). In preventive protocols, daily clodronate and daily or weekly zoledronic acid decreased the TB/STV ratio by 49% (95% CI = 40% to 57%, P = .006), 83% (95% CI = 68% to 98%, P<.001), and 66% (95% CI = 47% to 84%, P<.001), respectively, compared with vehicle, whereas a single dose of zoledronic acid decreased tumor burden by only 13% (95% CI = –2% to 28%, P = .84). Mice treated with a daily preventive regimen of clodronate or with a daily or weekly preventive regimen of zoledronic acid showed a decreased B02/GFP.2 cell tumor burden compared with vehicle, whereas a single preventive dose of zoledronic acid had no effect.
Conclusion: Daily or repeated intermittent therapy with clinical doses of bisphosphonates inhibits skeletal tumor growth in a mouse model.
| Context and Caveats Prior knowledge At high doses, bisphosphonates exhibit antitumor properties in animal models. However, the high doses of bisphosphonates used in animals are incompatible with approved treatment regimens for patients, and the bisphosphonate doses that are approved for patients do not have convincing antitumor effects. Study design In vivo study of clinical dosing regimens of bisphosphonates in a mouse model of breast cancer cell metastasis to bone. Contribution Bisphosphonates administered at low dosages on a daily or weekly dosing schedule were shown to inhibit skeletal tumor growth in a mouse model of bone metastasis. Implications Continuous or frequent intermittent low-dose therapy with bisphosphonates may facilitate the prolonged exposure of bone marrow to these drugs, thus enabling a direct effect on tumor cells that reside in bone. Limitations The mouse model does not recapitulate all steps required for spontaneous metastasis of breast cancer cells to bone and does not take into account the role of the immune system.
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Manuscript received May 16, 2006; revised November 21, 2006; accepted December 22, 2006.
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J Natl Cancer Inst 2007 99: 257.
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