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Updated: Mar 23, 2026
Implantation and Monitoring by PET/CT of an Orthotopic Model of Human Pleural Mesothelioma in Athymic Mice
Published on: December 21, 2019
An intrapleural administration of zoledronic acid for inoperable malignant mesothelioma patients: a phase I clinical
Yuji Tada1, Kenzo Hiroshima2, Hideaki Shimada3
1Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Background:
The third generation of bisphosphonates is clinically in use for patients of osteoporosis or malignancy-linked hypercalcemia. The agents can also produce anti-tumor effects on bone metastasis of several types of tumors. We recently found that one of the agents achieved cytotoxicity to mesothelioma in vitro and in an orthotopic animal model. Mesothelioma is resistant to a number of chemotherapeutic agents, and suppression of local tumor growth is beneficial to the patients since metastasis to extra-thoracic organs is relatively infrequent until a late stage.
Methods/Design:
We demonstrated in an orthotopic mouse model that an intrapleural but not intravenous injection of zoledronic acid, one of the third generation bisphosphonates, at a clinically equivalent dose suppressed the tumor growth. Nevertheless, a high concentration of zoledronic acid administrated in the pleural cavity produced pleural adhesion. We also showed that zoledronic acid produced synergistic cytotoxic effects with cisplatin, the first-line chemotherapeutic agent for mesothelioma. We then planned to conduct a phase I clinical study to investigate any adverse effects and a possible clinical benefits produced by an intrapleural administration of zoledronic acid to mesothelioma patients who became resistant to the first-line chemotherapeutic agents. The clinical trial is a dose escalation study starting with 0.4, 1, 4, 8 and 16 mg per person since safety of administration of zoledronic acid into the pleural cavity remains unknown. Each dose group consists of three persons and the protocol allows to repeat administration of the same dose into the pleural cavity at a 4-weeks interval.
Discussion:
We will conduct a possible combinatory study of intrapleural administration of zoledronic acid and systemic administration of the first-line agent to a chemotherapy-naïve patient based on the maximum tolerance dose of zoledronic acid determined by the present clinical trial. We propose that administration of bisphosphonates in a closed cavity is a treatment strategy for tumors developed in the cavity probably through the direct cytotoxic activity.
Trial Registration:
UMIN clinical trials registry, Japan. Register ID: UMIN8093.
