Pharmacogenetic testing in oncology: a Brazilian perspective

Pharmacogenetics, a major component of individualized or precision medicine, relies on human genetic diversity. The remarkable developments in sequencing technologies have revealed that the number of genetic variants modulating drug action is much higher than previously thought and that a true personalized prediction of drug response requires attention to rare mutations (minor allele frequency, MAF<1%) in addition to polymorphisms (MAF>1%) in pharmacogenes. This has major implications for the conceptual development and clinical implementation of pharmacogenetics. Drugs used in cancer treatment have been major targets of pharmacogenetics studies, encompassing both germline polymorphisms and somatic variants in the tumor genome. The present overview, however, has a narrower scope and is focused on germline cancer pharmacogenetics, more specifically, on drug/gene pairs for which pharmacogenetics-informed prescription guidelines have been published by the Clinical Pharmacogenetics Implementation Consortium and/or the Dutch Pharmacogenetic Working Group, namely, thiopurines/TPMT, fluoropyrimidines/UGT1A1, irinotecan/UGT1A1 and tamoxifen/CYP2D6. I begin by reviewing the general principles of pharmacogenetics-informed prescription, pharmacogenetics testing and the perceived barriers to the adoption of routine pharmacogenetics testing in clinical practice. Then, I highlight aspects of the pharmacogenetics testing of the selected drug-gene pairs and finally present pharmacogenetics data from Brazilian studies pertinent to these drug-gene pairs. I conclude with the notion that pharmacogenetics testing has the potential to greatly benefit patients by enabling precision medicine applied to drug therapy, ensuring better efficacy and reducing the risk of adverse effects.

Mechanisms of the UTP-induced tension in mammalian skeletal muscles

The mechanisms of UTP-induced tension in human and rat skinned fibers were investigated using isometric tension recordings, electrophysiological techniques and biochemical methods. In fast-type fibers from rat extensor digitorum longus (EDL) the UTP-induced tension: a) required previous loading of CA2+ into the sarcoplasmic reticulum (SR); b) was inhibited by previous exposure to caffeine; c) was abolished by functional disruption of the SR; d) was not affected by blockade of the SR Ca2+-release channels by ruthenium red or heparin; e) was prevented by spermidine. These data point to the SR as the target of UTP action and suggest a pathway of UTP-induced Ca2+-release independent of the ryanodine- or the IP3-sensitive Ca2+-release channels. Accordingly, UTP failed to stimulate the electrophysiological activity of ryanodine-sensitive channels, incorporated into lipid bilayers. We suggest that UTP-induced Ca2+-release might occur via the channel form of the SR Ca2+-ATPase. The UTP-induced tension in human slow-type fibers was not affected by the SR Ca2+ content or by disruption of the SR, but was accompanied by changes in the tension-pCa relationship, namely increase in maximum Ca2+-activated tension, and in apparent Ca2+-affinity of troponin. The UTP-induced tension in slow-type fibers from rat soleus was partially inhibited by Ca2+-depletion from, or by disruption of the SR, and was accompanied by changes in tension/pCa relationship, similar to those observed in human fibers. Both in skinned fibers and in isolated SR vesicles, UTP was less effective than ATP as a substrate for the SR Ca2+-ATPase. This effect might contribute to UTP-induced tension.