Bisphosphonates can be devastatingly harmful to some women with osteoporosis, but researchers in Japan think one of the ingredients in the latest generation of that drug can be helpful in treating mesothelioma.
The ingredient they are looking at is zoledronic acid. The researchers say they are opening a Phase I study of zoledronic acid that will test their theories about it on a small group of mesothelioma patients at Chiba University Hospital in the city of Chiba, Japan.
During this study, the investigators will be evaluating the safety and efficacy of zoledronic acid delivered by intrapleural injection.
Mesothelioma patients who wish to participate in this initial clinical trial will be deemed eligible for enrollment if surgical resection isn’t an option and they have seen dismal results from first-line chemotherapy.
The researchers plan to inject the enrolled mesothelioma patients with 100 ml of zoledronic acid at regular intervals, until the safe dose limit is established and the antitumor effects become evident.
The researchers outlined all this in a recent issue of SpringerPlus, an online open journal. They expressed hope that success will lead to a Phase II study using the maximum tolerance dose right from the beginning.
Zoledronic Acid Triggers Immune Response to Mesothelioma
Earlier, preclinical trial data on zoledronic acid suggest that its antitumor effects stem from activated immune responses.
According to the Chiba University researchers, zoledronic acid inhibits farnesyl pyrophosphate synthase in the mevalonate pathway.
This, in turn, increases concentrations of isopentenyl pyrophosphate and triphosphoric acid I-adenosine-50-yl ester 3-(3-methylbut-3-enyl) ester in mesothelioma tumor cells.
Certain T cells produced via the immune system are activated by these molecules. They also are attracted to the binding receptors present on these same molecules.
When the attracted T cells bind to those receptors, the T cells then secrete molecules of interferon-γ into the mesothelioma tumor cells. The mesothelioma tumor cells begin shutting down as a result.
The mechanism by which this occurs is not clearly understood. However, that provides another reason why the Chiba University researchers want to proceed with clinical trials of zoledronic acid.
The researchers said their interest in exploring the potential of zoledronic acid against mesothelioma was sparked by earlier trials using it against breast cancer, prostate cancer and bone cancer.
Controversy Surrounds Bisphosphonates
Zoledronic acid is the key ingredient of drugs used to treat osteoporosis and hypercalcemia. Those drugs are called bisphosphonates. Bisphosphonates have been the subject of considerable controversy, as well as lawsuits, over the years.
The best known commercial bisphosphonate is Fosamax, manufactured by pharmaceutical giant Merck & Co. Fosamax was once routinely prescribed to women at risk for bone fractures or bone thinning due to advanced age.
However, as it turned out for some women, taking Fosamax longer than three years weakened bones rather than strengthened them.
The Chiba University researchers evidently do not believe this risk of bone weakening will be an issue for the mesothelioma patients who receive zoledronic acid.
The title of the SpringerPlus article about the forthcoming Phase 1 clinical trial is “An Intrapleural Administration of Zoledronic Acid for Inoperable Malignant Mesothelioma Patients: A Phase I Clinical Study Protocol.”
