Journal of the National Cancer Institute Advance Access originally published online on August 11, 2008
JNCI Journal of the National Cancer Institute 2008 100(16):1167-1178; doi:10.1093/jnci/djn240
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© The Author 2008. Published by Oxford University Press.
ARTICLES |
Antitumor Effects of Doxorubicin Followed by Zoledronic Acid in a Mouse Model of Breast Cancer
Affiliations of authors: Academic Unit of Clinical Oncology, School of Medicine and Biomedical Sciences (PDO, HM, DVL, REC, IH); Centre for Stem Cell Biology, Department of Biomedical Sciences, University of Sheffield, UK (MJ); Department of Pharmaceutics, University of Kuopio, Finland (HM)
Correspondence to: Ingunn Holen, PhD, Academic Unit of Clinical Oncology, School of Medicine and Biomedical Sciences, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK (e-mail: i.holen{at}sheffield.ac.uk).
Background: The potent antiresorptive drug zoledronic acid (Zol) enhances the antitumor effects of chemotherapy agents in vitro. We investigated the effects of clinically achievable doses of doxorubicin (Dox) and Zol, given alone, in sequence, and in combination, on the growth of established breast tumors in vivo.
Methods: Female MF1 nude mice were inoculated subcutaneously with 5 x 105 human breast cancer MDA-MB-436 cells that stably expressed green fluorescent protein (ie, MDA-G8 cells). Beginning on day 7 after tumor cell injection, the mice were injected weekly for 6 weeks with saline, Dox (2 mg/kg body weight via intravenous injection), Zol (100 µg/kg body weight via intraperitoneal injection), Dox plus Zol, Zol followed 24 hours later by Dox, or Dox followed 24 hours later by Zol (n = 8–9 mice per group). The effects of treatment on tumor growth were determined by measuring tumor volume; on tumor cell apoptosis and proliferation by immunohistochemistry using antibodies for caspase-3 and Ki-67, respectively; and on bone by microcomputed tomography and bone histomorphometry. All P values are two-sided.
Results: Treatment with Dox or Zol alone or Zol followed 24 hours later by Dox did not statistically significantly decrease final tumor volume compared with saline. Mice treated with Dox plus Zol had statistically significantly smaller final tumor volumes than those treated with Dox alone (mean = 122 mm3 vs 328 mm3, difference = 206 mm3, 95% confidence interval [CI] = 78 to 335 mm3, P < .001), with Zol alone (122 mm3 vs 447 mm3, difference = 325 mm3, 95% CI = 197 to 454 mm3, P < .001), or with Zol followed 24 hours later by Dox (122 mm3 vs 418 mm3, difference = 296 mm3, 95% CI = 168 to 426 mm3, P < .001). Treatment with Dox followed 24 hours later by Zol almost completely abolished tumor growth. Tumors from mice that were treated with Dox followed by Zol had more caspase-3–positive cells than tumors from mice treated with saline (mean number of caspase-3–positive cells per square millimeter: 605.0 vs 82.19, difference = 522.8, 95% CI = 488.2 to 557.4, P < .001), with Zol alone (605.0 vs 98.44, difference = 506.6, 95% CI = 472.0 to 541.2, P < .001), or with Zol followed by Dox (605.0 vs 103.1, difference = 501.9, 95% CI = 467.3 to 536.5, P < .001). The treatment-induced increase in the number of caspase-3–positive cells was mirrored by a decrease in the number of tumor cells positive for the proliferation marker Ki-67. No evidence of bone disease was detected in any of the treatment groups following microcomputed tomography and histological analysis of bone.
Conclusion: Sequential treatment with Dox followed by Zol elicited substantial antitumor effects in subcutaneous breast tumors in vivo, in the absence of bone disease.
| CONTEXT AND CAVEATS Prior knowledge Zoledronic acid is a potent inhibitor of osteoclastic bone resorption that also enhances the antitumor effects of chemotherapy agents both in vitro and in in vivo models with a high degree of tumor-induced bone disease. Study design An examination of the effects of clinically achievable doses of doxorubicin and zoledronic acid, given alone, in sequence, and in combination, on the growth of tumors derived from a human breast cell line that does not metastasize readily to bone in a mouse model. Contribution Sequential treatment with doxorubicin followed by zoledronic acid inhibited the growth of subcutaneous breast tumors in vivo, in the absence of bone disease. Implications There may be benefits of combining zoledronic acid with cytotoxic agents for the treatment of patients with early-stage breast cancer. Limitations Mice were treated with higher total doses of the drugs than those that breast cancer patients receive. The relevance of the mouse model to humans is not certain. From the Editors
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Manuscript received December 17, 2008; revised June 2, 2008; accepted June 16, 2008.
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J Natl Cancer Inst 2008 100: 1119.