Resistance to chemotherapy in a childhood cancer

By Mary Beth Genter

Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) make up about 8% of all childhood cancers. The cause(s) of these tumors is not known. Despite treatments, including surgery and chemotherapy, the tumors frequently return and spread to other sites in the body. Unfortunately, the five-year survival rate for children with NRSTS that have spread or recurred is only about 50%.

Carmen Torres-Zárate and collaborators at the Instituto Nacional de Pediatria and Universidad Autónoma de México, in Mexico City, Mexico, studied the possible reason for the recurrence of NRSTS, with a focus on the enzymes that perform drug metabolism in many tissues in the body. The Cytochrome P450 (CYP) enzymes are a large family of proteins that are called “drug metabolizing enzymes”. These enzymes are found in many tissues in the body, including liver, lung, skin, and muscle. CYPs can degrade drugs, environmental contaminants, naturally-occurring toxins, and even toxic molecules that are normally produced by our bodies, such as ammonia. On the other hand, these enzymes can make some chemicals, such as acrylamide, which is found in some fried foods, more toxic.

In the Torres-Zárate study, tissue from NRSTS that were removed from children, as well as small pieces of adjacent tissue that appeared to be tumor-free, were obtained. The tissues were processed so that the level of several important CYP enzymes could be evaluated. The investigators found that three CYP enzymes were, on average, expressed at higher levels in tumor tissue, compared to adjacent non-tumor tissue. This is important for several reasons. First, these CYPs all have the ability to degrade drugs. So, it follows that if a drug, such as a chemotherapy drug, is degraded very rapidly in a tumor, the drug will not be present for sufficient time to destroy the tumor. A second benefit of this knowledge is that it may be useful in designing a personalized treatment regimen for a specific patient. A clinician often knows of several drugs that may be appropriate for treating specific types of tumors. We, as scientists, also which CYP enzyme degrades particular drug(s). So, with knowledge that a patient’s tumor expresses high levels of a certain CYP, the clinician may be able to prescribe a drug that would not be rapidly degraded in the tumor cells, and thereby, hopefully succeed in destroying the tumor. Other studies have demonstrated that patients with other tumors that express high levels of CYP enzymes are, unfortunately, associated with poor clinical outcomes. An example of a tumor stained to show a protein of interest is shown in the accompanying cover photograph.

The authors hope to validate these findings in a larger study population and also to continue their quest to optimize patient treatment based on knowledge of CYP expression levels, as well as expression of other genes related to cancer development and prognosis, in NRSTS.

Article Details
Expression of Cytochrome P450 Enzymes in Pediatric Non-Rhabdomyosarcoma Soft Tissue Sarcomas: Possible Role in Carcinogenesis and Treatment Response
Carmen Torres-Zárate, Araceli Vences-Mejía, Jesús Javier Espinosa-Aguirre, Eduardo Díaz-Díaz, José Martín Palacios-Acosta, Rocío Cárdenas-Cardós, Daniel Hernández-Arrazola, Jaime Shalkow-Klincovstein, Rodolfo R. Jurado, Rebeca Santes-Palacios, Dora Molina-Ortiz
First Published April 19, 2022
International Journal of Toxicology

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