Expression of Cytochrome P450 Enzymes in Pediatric Non-Rhabdomyosarcoma Soft Tissue Sarcomas: Possible Role in Carcinogenesis and Treatment Response.

The 5-year relative survival rate estimate of treated patients with non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) is ∼50% since they generally present with tumor progression, relapse, metastasis, and/or chemoresistance. The expression of cytochrome P450 (CYP) enzymes in malignancies can affect the pharmacology of drugs commonly used in chemotherapy or confer susceptibility to development of chemical carcinogenesis; in addition, their specific tumor expression can be used as a therapeutic target. Using qPCR and Western blot assays, the expression of CYP1B1, CYP2E1, CYP3A4, and CYP3A5 were analyzed in a cohort of tumor tissue paired with non-malignant adjacent tissue of patients with NRSTS. The mRNA and protein expression of CYP1B1, CYP2E1, and CYP3A4 were significantly increased in tumor tissue. We propose that the expression of these isoforms is related to carcinogenesis and chemoresistance frequently observed in these neoplasms.

MDR1 not CYP3A4 gene expression is the predominant mechanism of innate drug resistance in pediatric soft tissue sarcoma patients.

BACKGROUND: Intratumoral up-regulation of genes coding for drug transporters and metabolizing enzymes, such as MDR1 and CYP3A4, after chemotherapy are linked to cancer drug resistance. However their expression in primary soft tissue sarcomas (STS) prior to drug treatment and their role in innate resistance remain unclear. OBJECTIVE: The aim of this study was characterize MDR1 and CYP3A4 expression pattern before to chemotherapy and its clinical implication in pediatric STS. METHODS: In this prospective study we analyzed MDR1 and CYP3A4 mRNA expression in both normal and tumor tissues from 28 newly diagnosed STS pediatric and then compared with patients' clinical-pathological data, including chemotherapy response. RESULTS: Our data showed that the expression of the MDR1 gene was significantly higher in malignant tissue than in the normal tissues of patients with STS. In addition, high MDR1 expression was significantly associated with local advances, as well as poor response to treatment. In contrast, CYP3A4 expression level was negligible in both tumoral and non-tumoral tissues. CONCLUSIONS: These results suggest that a significant mRNA level of MDR1 gene was intrinsically present in STS before exposure to chemotherapeutic drugs, suggesting that MDR1 may be important contributors of innate chemoresistance of this tumor type.