Mesothelioma Chemo Using S-1 May Be More Effective for Certain Patients

This was unexpected. Researchers in Japan were investigating the body’s response to the thymidylate synthase inhibitor drug S-1 as a gauge of mesothelioma survival.

In the course of that investigation they unexpectedly came upon evidence indicating that S-1 may slow or stop mesothelioma progression in patients who express high levels of orotate phosphoribosyltransferase.

Orotate phosphoribosyltransferase is an enzyme. It participates in the process of inhibiting thymidylate synthase.

The researchers, from the National Hospital Organization Disaster Medical Center in Tokyo, wanted to expand the current understanding of that process.

The drug S-1 is an oral fluoropyrimidine chemotherapy agent. It consist of tegafur, 5-chloro-2, 4-dihydroxypyridine, and potassium oxonate. S-1 is made in Japan and is approved for use in that country.

The researchers were investigating S-1’s mechanisms of operation as a thymidylate synthase inhibitor. Inhibition of thymidylate synthase is important in the fight against mesothelioma.

The researchers reported that there appears to be a link between thymidylate synthase production and mesothelioma survival time. Basically, the more thymidylate synthase your cells express, the shorter your expected survival.

Mesothelioma Affected by Chemo Combo of Carboplatin and S-1

But the real surprise was the discovery of a patient who responded unusually favorably to the administration of S-1 as part of his mesothelioma chemotherapy regimen.

The patient was 66 years old. Chemotherapy had been unsuccessful for him each of the previous three times it was tried. It had worked for a while the first time he received it. But then the mesothelioma grew back.

The same thing happened the second time. On both those occasions, the chemotherapy agent used was pemetrexed.

Doctors switched the patient to carboplatin and gemcitabine on the third try. He was helped by it for just three months before the mesothelioma started up again.

His care team decided to try one last thing. They gave him carboplatin again, but this time paired it with S-1. Both were administered to him daily for two weeks. After that he received doses at three-week intervals.

To the patient’s delight — and to his doctors’ amazement — the mesothelioma tumor responded to this fourth-line chemotherapy. According to the researchers, his thickened pleura “dramatically shrank in size.”

The researchers also noted that the mesothelioma showed no sign of resurgence after five months of this treatment.

Chemo with S-1 May Be More Effective for Mesothelioma Patients with High Orotate Phosphoribosyltransferase Expression

The patient was one of 15 mesothelioma sufferers whose medical records the researchers had pulled together for a retrospective study.

“The aim of this…study was to assess the orotate phosphoribosyltransferase expression which is a potential prognostic indicator of S-1 treatment for MPM,” they explained.

“We found that orotate phosphoribosyltransferase protein in mesothelioma tumor tissue was significantly higher compared to other 5-fluorouracil metabolic-related enzymes,” they added.

To conduct this study, the researchers examined the records of patients who were diagnosed with malignant pleural mesothelioma between July 2004 and December 2013 by doctors at the medical center

Five of the patients had the epithelioid form of mesothelioma, four had the sarcomatoid type and three had the biphasic form. The type that the remaining patients had could not be clearly established.

Nearly all had been treated with just chemotherapy. A few had received chemotherapy preceded by surgery.

The researchers found high orotate phosphoribosyltransferase expression in 12 out of 14 cases they were able to evaluate.

From all of this, they ultimately concluded that chemotherapy with S-1 might be more effective in mesothelioma patients with high orotate phosphoribosyltransferase expression. However, the researchers said more studies are needed to confirm that theory.

The researcher’s article is titled “Orotate Phosphoribosyltransferase is Overexpressed in Malignant Pleural Mesothelioma: Dramatically Responds One Case In High OPRT Expression.” Their findings appear in the journal Rare Diseases.