Orotate phosphoribosyltransferase is overexpressed in malignant pleural mesothelioma: Dramatically responds one case in high OPRT expression

Our plain-English summary of Orotate phosphoribosyltransferase is overexpressed in malignant pleural mesothelioma: Dramatically responds one case in high OPRT expression, by Y. Hamamoto, S. Takeoka, A. Mouri, et al (Rare Diseases, 2016).

The study

• Authors: Y. Hamamoto, S. Takeoka, A. Mouri, M. Fukusumi, K. Wakuda, T. Ibe, C. Honma, Y. Arimoto, K. Yamada, M. Wagatsuma, A. Tashiro, S. Kamoshida, M. Kamimura
• Journal: Rare Diseases
• Published: 2016;4(1):e1165909
• Type of article: Review
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Objective: Malignant pleural mesothelioma (MPM) is a rare and aggressive, treatment-resistant cancer. Pemetrexed, an inhibitor of thymidylate synthase (TS), is used worldwide for MPM as a first-line chemotherapy regimen. However, there is little consensus for a second-line chemotherapy. S-1, a highly effective dihydropyrimidine dehydrogenase (DPD)-inhibitory fluoropyrimidine, mainly acts via a TS inhibitory mechanism similar to pemetrexed. Orotate phosphoribosyltransferase (OPRT) is a key enzyme related to the first step activation of 5-fluorouracil (5-FU) for inhibiting RNA synthesis. We investigated 5-FU related-metabolism proteins, especially focusing on OPRT expression, in MPM Methods and Patients: Fifteen MPM patients who were diagnosed between July 2004 and December 2013 were enrolled. We examined the protein levels of 5-FU metabolism-related enzymes (TS, DPD, OPRT, and thymidine phosphorylase [TP]) in 14 cases

Results: High TS, DPD, OPRT, and TP expressions were seen in 28.6%, 71.4%, 85.7%, and 35.7% of patients, respectively. We found that OPRT expression was extremely high in MPM tissue. We experienced one remarkable case of highly effective S-1 combined therapy for pemetrexed refractory MPM. This case also showed high OPRT protein expression Conclusion: The present study suggests that OPRT expression is high in MPM tumors. Although pemetrexed is mainly used for MPM chemotherapy as a TS inhibitor, S-1 has potential as an anticancer drug not only as a TS inhibitor but also inhibiting RNA synthesis through the OPRT pathway. This is the first report investigating OPRT protein expressions in MPM.

In plain English

This retrospective study from the National Hospital Organization Disaster Medical Center in Tokyo, Japan, examined tumor samples from patients diagnosed with malignant pleural mesothelioma between July 2004 and December 2013. A table listed patients' asbestos histories, but the study did not analyze asbestos exposure. Of 15 patients, 14 had tissue stained for four enzymes linked to how fluorouracil-type drugs such as S-1 work: TS, DPD, OPRT and TP. High expression, meaning more than 25% of tumor cells stained, was seen for TS in 28.6% (4/14), DPD in 71.4% (10/14), OPRT in 85.7% (12/14) and TP in 35.7% (5/14) of tumors. Among 12 patients given pemetrexed-based chemotherapy, the authors reported a statistically significant association between TS and DPD levels and survival time. The article also described one 66-year-old man with high tumor OPRT. After three earlier treatments, he received S-1 plus carboplatin. His pleural thickening shrank markedly; he remained in partial response at 5 months but developed grade 4 anemia needing transfusion. The authors concluded that OPRT expression is high in these tumors and that S-1 needs further study.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective single-hospital study of tumor enzyme levels (immunohistochemistry), with one case report of a patient treated with S-1 plus carboplatin. The journal labels the article a mini-review, but it reports original data.
• Who was studied: 15 patients diagnosed with malignant pleural mesothelioma at the National Hospital Organization Disaster Medical Center, Tokyo, Japan, between July 2004 and December 2013. Ages ranged from 41 to 87 years (median 68). Tissue was available for 14 patients. Table 1 lists 14 male patients and 1 female patient.
• Exposure: Table 1 has an 'Asbestos history' column for each patient, but its entries are garbled ('—', 'C', 'unknown'), and the study did not analyze asbestos exposure. The study measured tumor levels of four enzymes (TS, DPD, OPRT, TP) and looked at chemotherapy, mainly pemetrexed-based regimens. One patient received S-1 plus carboplatin.
• Main results:
  • Average staining scores (on a 1 to 5 scale) in the 14 tumors were 1.9 for TS (standard error 0.3), 3.5 for DPD (0.5), 4.2 for OPRT (0.3) and 2.6 for TP (0.5).
  • High expression (more than 25% of cells stained) was found in 28.6% (4/14) of tumors for TS, 71.4% (10/14) for DPD, 85.7% (12/14) for OPRT and 35.7% (5/14) for TP.
  • All 10 patients with low TS expression had high OPRT expression.
  • Among the 12 patients treated with pemetrexed-based chemotherapy, the authors reported a significant association between high versus low TS expression and survival time (P = 0.029) and between high versus low DPD expression and survival time (P = 0.0067). No other significant associations were found. The direction of the associations is not stated.
  • Case report: a 66-year-old man with stage IV disease had earlier received three regimens: cisplatin plus pemetrexed; carboplatin plus pemetrexed, followed by pemetrexed maintenance; and carboplatin plus gemcitabine. He then received carboplatin plus S-1, and his pleural thickening shrank markedly. His tumor scored 1 for TS, 5 for OPRT, 5 for DPD and 1 for TP.
  • The same patient developed grade 4 anemia requiring transfusion. At 5 months after starting treatment, he remained well with a partial response.
• The authors' conclusion: The authors concluded that OPRT expression was high (12 of 14 cases) compared with the other enzymes in malignant pleural mesothelioma. They stated that, theoretically, high OPRT could make S-1 more effective, and that further clinical studies of S-1 in this disease are needed.
• Limitations the authors state:
  • Small sample size, a single institution, and a retrospective design.
  • Only one patient responded to S-1. That patient also received carboplatin, so the effect of S-1 alone could not be determined.
  • The authors noted that two other studies reported TS expression might not be a marker of pemetrexed efficacy, which tempers their own TS survival finding.
  • S-1 caused side effects in this patient (grade 4 anemia). The authors added that such rare treatments are hard to generalize and that prospective studies are needed.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Pemetrexed (Alimta), Chemotherapy, Fluorouracil (5-FU).

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