Suppression by incadronate of invasion and growth of A-375 human melanoma in mandible in nude mice

Frequent invasion of oral cancers into the neighboring jaw bones is a major cause of increased mortality. Moreover, majority of patients with these oral cancers suffer from functional inconveniences and esthetic disadvantages during clinical course and after surgical treatments. Understanding of the mechanisms underlying oral cancer invasion into jaw bones is, therefore, critical to the better management of oral cancer patients. To study the pathophysiology of mandibular invasion of oral cancers, we established an animal model by inoculating the A-375 human melanoma cells onto mandible through masseter muscle in nude mice. Histological study showed that A-375 tumor cells aggressively destroyed the mandibular cortical bones and invaded into the bone marrow cavities. Histochemical examination revealed that there were numerous tartrate-resistant acid phosphatase-positive osteoclasts on the residual bone surfaces facing A-375 tumors. To examine the role of osteoclasts in mandibular bone invasion of A-375 tumors, we next studied the effects of the bisphosphonate incadronate (INC), a potent inhibitor of osteoclastic bone resorption, using this model. Daily subcutaneous injections of INC (1 mg/kg) markedly decreased A-375-increased osteoclasts, increased numbers of apoptotic osteoclasts and inhibited mandibular cortical bone destruction. Furthermore, INC significantly suppressed the growth of A-375 tumors, increased numbers of apoptotic A-375 cells and decreased the tumor-associated blood vessel density. These results suggest that invasion and growth of oral cancers in mandibular bone is dependent on osteoclastic bone resorption and that INC can inhibit the aggressive behavior of oral cancer through inhibiting osteoclastic bone resorption.