tetrathiomolybdate and Osteosarcoma

Since its domestication more than 10,000 years ago, the dog has been the animal that most intimately shares our work and homelife. Interestingly, the dog also shares many of our diseases including cancer such as osteosarcoma. Like the human, osteosarcoma is the most common bone malignancy of the dog and death from pulmonary metastasis is the most common outcome. The incidence of this spontaneous bone neoplasm occurs ten times more frequently that it does so in children with about 8,000-10,000 cases estimated to occur in dogs in the USA. Because there is no "standard of care" in veterinary medicine, the dog can also serve us by being a model for this disease in children. Although the most common therapy for the dog with osteosarcoma is amputation followed by chemotherapy, not all owners choose this route. Consequently, novel therapeutic interventions can be attempted in the dog with or without chemotherapy that could not be done in humans with osteosarcoma due to ethical concerns. This chapter will focus on the novel therapies in the dog that have been reported or are in veterinary clinical trials at the author's institution. It is hoped that collaboration between veterinary oncologists and pediatric oncologists will lead to the development of novel therapies for (micro- or macro-) metastatic osteosarcoma that improve survival and might ultimately lead to a cure in both species.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Aerosols; Animals; Antineoplastic Agents; Bone Neoplasms; Child; Deoxycytidine; Dog Diseases; Dogs; Gemcitabine; Humans; Interleukin-2; Lung Neoplasms; Molybdenum; Osteosarcoma; Phosphatidylethanolamines; Signal Transduction

Tetrathiomolybdate (TM) is a unique anticopper drug developed for the treatment of the neurologic presentation of Wilson's disease, for which it is excellent. Since it was known copper was required for angiogenesis, TM was tested on mouse cancer models to see if it would inhibit tumor growth based on an antiangiogenic effect. TM was extremely effective in these models, but all the tumors in the models started small in size - micrometastatic in size. Later, TM was tested in numerous human cancer trials, where it showed only modest effects. However, the mouse lesson of efficacy against micro disease was forgotten - all the trials were against bulky, advanced cancer. Now, the mouse evidence is coming back to life. Three groups are curing, or having major efficacy of TM, against advanced human cancers, heretofore virtually incurable, particularly if the cancer has been reduced to no evidence of disease (NED) status by conventional therapy. In that situation, where the remaining disease is micrometastatic, TM therapy appears to be curative. We have designed and initiated a study of TM in canine osteosarcoma at the micrometastatic phase to help put these findings on a firm scientific basis. TM also has major anti-inflammatory properties by inhibiting copper dependent cytokines involved in inflammation. This anti-inflammatory effect may be involved in TM's anticancer effect because cancers, as they advance, attract inflammatory cells that provide a plethora of additional proangiogenic agents.

Topics: Animals; Clinical Trials as Topic; Copper; Dogs; Humans; Inflammation; Molybdenum; Neoplasms; Osteosarcoma