Evaluation of liposomal clodronate for treatment of malignant histiocytosis in dogs
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Malignant histiocytosis (MH) is an aggressive cancer derived from myeloid lineage cells in both dogs and humans. In dogs, the tumor is characterized by the rapid development of metastatic tumors in multiple sites, including especially the lungs and lymph nodes. Humans develop an analogous disease known as Langerhans cell histiocytosis, which primarily affects children and young adults. Because these tumors are often resistant to conventional chemotherapy, there is a need for newer therapeutic approaches. Systemic administration of liposomal clodronate (LC) has been shown to effectively deplete phagocytic cells (e.g., macrophages and dendritic cells) in mice. We investigated therefore whether LC could also be used to treat naturally occurring MH in dogs. First, the susceptibility of canine MH cells to LC-mediated killing was assessed in vitro. Then the clinical safety and effectiveness of LC as a treatment for MH was assessed in a pilot study in five pet dogs with spontaneous MH. We found that canine MH cells were very susceptible to LC-induced apoptotic cell death, whereas other tumor cell lines were resistant to killing by LC. Studies using labeled liposomes demonstrated that susceptibility to LC killing was directly related to the efficiency of liposome uptake. In pet dogs with spontaneous MH, we found that a short course of LC treatment elicited significant tumor regression in two of five treated animals. These findings suggest that liposomal delivery of clodronate and possibly other bisphosphonates may offer an effective new approach to treatment of histiocytic neoplasms in dogs and humans.
KeywordsCancer Immune Bisphosphonate Macrophage Dendritic cell
The authors wish to acknowledge the assistance of Dr. Amanda Guth with flow cytometry. This work was supported by grants from the Canine Health Foundation and by an NIH Training Grant (T32 RR00707).
- 9.Frith JC, Monkkonen J, Auriola S, Monkkonen H, Rogers MJ (2001) The molecular mechanism of action of the antiresorptive and antiinflammatory drug clodronate: evidence for the formation in vivo of a metabolite that inhibits bone resorption and causes osteoclast and macrophage apoptosis. Arthritis Rheum 44:2201–2210CrossRefPubMedGoogle Scholar
- 11.Gazzaniga S, Bravo AI, Guglielmotti A, van Rooijen N, Maschi F, Vecchi A, Mantovani A, Mordoh J, Wainstok R (2007) Targeting tumor-associated macrophages and inhibition of MCP-1 reduce angiogenesis and tumor growth in a human melanoma xenograft. J Invest Dermatol 127:2031–2041CrossRefPubMedGoogle Scholar
- 17.Lehenkari PP, Kellinsalmi M, Napankangas JP, Ylitalo KV, Monkkonen J, Rogers MJ, Azhayev A, Vaananen HK, Hassinen IE (2002) Further insight into mechanism of action of clodronate: inhibition of mitochondrial ADP/ATP translocase by a nonhydrolyzable, adenine-containing metabolite. Mol Pharmacol 61:1255–1262CrossRefPubMedGoogle Scholar
- 20.MacEwen EG, Withrow SJ (1996) Small animal clinical oncology. Saunders Co, Philadelphia, PAGoogle Scholar