Jisha K, Venkateswaramurthy N*, Sambathkumar R
Department of Pharmacy Practice, J.K.K. Nattraja College of Pharmacy, Kumarapalayam 638183,
Tamil Nadu, India
Pharmacogenomics is an upcoming field that focusing on the genetic variations related to drug action. The cellular abnormalities arise from the inter individual genetic modifications, through the variation in genetic sequences or due to the modification in gene activation or DNA-related proteins. The pharmacogenomics study deals with the variation that provides the therapy more effective and safer by determining selection and dosing of drugs for an inter individuals and the medication demonstrates unpredictable efficacy and toxicity linked to the medication in the individual patients. Genetic polymorphisms in phase I and phase II enzymes may explain part of the inter-individual variation observed in anticancer drug pharmacokinetics and pharmacodynamics. There are numerous therapy choices for many kinds of cancer. The selection of the most suitable treatment would benefit from guidelines to enable the initiation of effective treatment as soon as possible. Failed therapy or unacceptable toxicity can considerably decrease the ideal therapeutic window resulting in a change in medication or dose. Consequently, it will be crucial to elucidate the role of pharmacogenomics in individualizing treatment in the near future research including genotype-driven clinical trials. Furthermore, trials involving gene/SNP detection approaches will be crucial for chemotherapy where there are no known validated markers to identify fresh prospective markers.
Genetic variations within the individual gene provide the mechanistic foundation for pharmacogenetics and the variation has the ability to make treatment safer and more efficient by determining drug selection and dosage for a patient.1 Cancer pharmacogenetics has begun because of the potential for cancer therapy individualization, minimizing toxicity and maximizing efficacy.2
Drug-related toxicity depends on the genotype of non-tumor tissues, so hereditary polymorphisms will play an important part in toxicity and key dose-limiting factor in most chemotherapy regimens. Clinical reaction to drugs has an effect on tumor development, survival and magnitude of negative occurrences and quality of life modifications.3,4
Pharmacogenetics for the therapy of cancer is very important, as cancer therapies show serious systemic toxicity and unpredictable effectiveness. Genetic polymorphisms are present in the genes that code for metabolic enzymes and cellular objectives for most chemotherapy agents5 such as Dihydropyrimidine dehydrogenase protein (DPD, encoded by the DPYD gene) plays a main role in fluoropyrimidine metabolism and Irinotecan is metabolized by uridine diphosphate glucuronosyl transferase (UGT1A1). The risk of developing serious toxicity was correlated with UGT1A1*28 allele.6,7 There are significant differences between cancer and other disease pharmacogenomics. Individualized cancer therapy can be accomplished for most patients with cancer by identifying patients at danger of serious toxicity or those likely to benefit from a specific treatment.8 Most cytotoxic agents have a small therapeutic index and patients can respond differently to an equivalent dose, calculated on the body surface, in terms of toxicity and antitumor efficacy.9,10
Response of Predictive markers:
The most effective therapy reaction forecast was the clinical implementation of pharmacogenetic markers. For therapy reaction, there are at least 16 FDA-approved anti-cancer drugs with validated predictive markers. These predictive markers are all tumor or somatic genomic modifications frequently defined by DNA-based mutations, changes in gene copy numbers, rearrangement of chromosomes, and epigenetic changes. Dramatic clinical responses may be seen when these tumors are treated with drugs targeting oncogenes to which tumors are dependent on for their growth, survival and metastatic potential.11,12 One of the examples most studied is the relationship between activity and outcome of CYP2D6. CYP2D6 is liable to its active metabolite, endoxifen, for the biotransformation of tamoxifen. CYP2D6 polymorphisms have been shown to correlate the systemic exposure of endoxifen.13
Previously, decreased activity of CYP2D6 was believed to be associated with poorer clinical results when tamoxifen was handled in the adjuvant environment for breast cancer patients. Recent retrospective analyzes of two major adjuvant studies of breast cancer, however, failed to identify a connection between CYP2D6 polymorphisms and the therapy outcome of tamoxifen-treated patients.14 There is still no known variation in the dose of tamoxifen that would influence the result. Hormonal therapy adherence rates can affect tamoxifen's efficacy in complicating matters.
In a research of 8769 members, 43 percent of whom took tamoxifen, 26 percent took aromatase inhibitors, and the rest took both, only 49 percent took hormonal adjuvant therapy in the ideal timetable for the complete period.15 Younger females were at the greatest danger of non-adherence, whereas Asian women were more likely to adhere to the prescribed therapy. In a prospective observational trial, there were greater discontinuation rates at 4 months for CYP2D6 comprehensive metabolizers. Paradoxically, the comprehensive metabolizers that might profit more from tamoxifen were also more likely to stop the medicine early.16 patients who are on tamoxifen avoid potent CYP2D6 inhibitors (e.g., antidepressants, such as paroxetine and fluoxetine).17 Although the US FDA endorsed the AmpliChip CYP450 test to test the CYP2D6 metabolizer status,18 Studies on the importance of CYP2D6 polymorphisms on clinical impacts of tamoxifen and on the escalation of the dose of tamoxifen in patients with CYP2D6 impairment are underway.17
The aim of this review is to discuss the polymorphisms resulting in a change of activity of certain proteins, such as metabolizing enzymes, cellular receptors or selective drug target proteins, causing an altered pharmacological effect in cancer therapy.
EFFECT OF DRUG WITH ENZYME ACTION:
Genomic studies have promoted efficient use of anticancer drugs and many anticancer reagents have gradually become useless for patients with a favorable tumor marker mutation p53.19
Trastuzumab, a monoclonal antibody which is effective for the management of HER-2 positive breast cancer but it is only responsive for 25-30% patients. Trastuzumab has anti-proliferative and proapoptic consequences, but other than trastuzumab includes antiangiogenic action and immune mechanisms including complementary cytotoxicity (CMC) and ADCC dependent on antibodies.20,21
The IgG fragment C receptors (FcRs) are expressed on leukocytes which classified as FcRI, FcRII and FcRIII. FcRs also split in individuals as FcRIIa, FcRIIb, FcRIIIa, FcRIIIb. The genetic polymorphism linked to valine (V) or phenylalanine (F) phenotype expression in amino acid 158 on FcRIIIa significantly affects the affinity of IgG1 to the Fc receptor. In particular, immune effector cells with the FcRIIIa V allle mediate ADCC of anti-HER-2 IgG1 variants are better than cells with the F allle. Higher response rate (RR) to trastuzumab was found in patients with homozygous 158 V / V FcRIIa and/or homozygous 131 H / H FcRIIa alleles. Trastuzumab in Her-2 positive operative breast cancer drives the therapeutic effect by ADCC. Trastuzumab's effectiveness may also rely on its capacity to induce an immune response.22,23
The US FDA approves tamoxifen for breast cancer therapy and prevention.24,25 Administration of tamoxifen in estrogen receptor (ER)-positive breast cancer patients as adjuvant therapy for 5 years following anthracycline based chemotherapy reduces the recurrence rate by nearly 50% and the mortality rate by a third after 15 years of follow-up.26 When tamoxifen is administered as monotherapy, the genotype of the germline CYP2D6 is significantly associated with the outcome of the disease. Tamoxifen therapeutic failure in breast cancer has been associated with reduced CYP2D6 activity due to inefficient activation of tamoxifen. Tamoxifen is considered to be a prodrug that requires extensive metabolism by cytochrome enzymes P450 (CYP450) to generate its anti-tumor effects arising from disturbance of the receptor action of estrogen.27
5-Fluorouracil (5-FU) is an uracil analog which is commonly used in the treatment of solid tumors such as colorectal and breast cancer and requires 5-Fluoro-2-deoxyuridine monophosphate (5-FdUMP) activation. Dihydropyrimidine dehydrogenase (DPD) inactivates at least 85% of 5-FU to dihydrofluorouracil in the liver.28 5-FdUMP functions by inhibiting the replication of tumor cells by inhibiting thymidylate synthase (TS), an enzyme necessary for synthesis of pyrimidine. DPD inactivates 5-FU in the liver and has huge differences in activity between individuals resulting in excessive 5-FdUMP in patients with low activity causing gastrointestinal, hematopoietic and neurological toxicity.29-32
6‑mercaptopurine is an antimetabolite that has been commonly used to treat leukemia and lymphoma via inhibiting new DNA synthesis. TPMT, an enzyme capable of transferring a methyl group into purine and inactivating 6-mercaptopurine. TPMT's functional deficiency would boost the amount of 6 in vivo mercaptopurine and has been discovered to cause severe side effects.33
Due to the high polymorphism frequency in its coding sequence, TPMT's enzyme activity varies considerably in a population. The variable activity of TPMT was correlated with 6 efficacy and side effects of mercaptopurine, with decreased TPMT activity corresponding to enhanced therapeutic efficacy and enhanced clinical toxicity. TPMT enzymes activity will be reduced, resulting in comparatively elevated concentrations of 6 mercaptopurine and serious toxicity.34,35
Capecitabine is a 5 FU prodrug prescribed for metastatic breast and colon cancer treatment. In vivo, capecitabine is actively transformed into 5 FU through a sequence of catalytic transformations, which eventually undergoes anabolic and catabolic biotransformation in order to attain anticancer function. DPD is one of the enzymes that catalyzes uracil and thymine ring decrease and regulates the rate-limiting step in 5 FU liver inactivation. 5 FU therapy results and germline differences in DPD with decreased DPD activity correspond to 5 FU half-life longer and enhanced toxicity risk.36,37
These drugs are two monoclonal antibodies that were designed to inhibit the proliferation of the tumor cells with over-expressed EGFR in various cancers. However, in some patients, although they had the mutated EGFR, these drugs were discovered to be inefficient. The connection between the resistance of cetuximab/panitumumab and KRAS mutations was revealed by several study teams later.38 KRAS is a GTPase membrane that in EGFR signaling pathways can activate many proteins, such as c Raf and PI3K. Typically, aberrant activation of these proteins would lead to the development of cancer independent of upstream EGFR signals. It is not surprising that if KRAS is actively mutated, cetuximab or panitumumab inactivation of EGFR will not have a beneficial effect on the treatment of KRAS-caused cancers.39
Irinotecan is typically used in combination with 5-fluorouracil or oxaliplatin to treat colorectal cancer and other strong tumors. A member of the family UDP-glucuronosyltransferase, UGT1A1, by glucuronidation inactivates the active irinotecan form, SN38. The UGT1A1 enzyme is accountable for hepatic bilirubin glucuronidation and is the major UGT1A enzyme engaged in SN38 glucuronidation. Under UGT1A1 expression, surplus SN38 in the cell causes serious, life-threatening diarrhea and/or neutropenia.40
Gefitinib is an oral agent used to target the tyrosine kinase receptor of the epidermal growth factor and has some effect on non-small cell lung cancer. It has been shown that EGFR-TKIs, gefitinib-IRESSA inhibit cell proliferation that over-expresses EGFR, including certain ER-negative cell lines.41 Studies of Gemcitabine in vitro and Phase I have shown activity against many tumor types, particularly NSCLC. This drug is extremely cytotoxic, however, and the development of innate or acquired drug resistance was a significant challenge in gemcitabine treatment and resulted in a decrease in patients with cancer survival. It is used in conjunction with other drugs to treat non-small cell lung cancer, bladder cancer, and ovarian cancer locally developed or metastatic.42
Paclitaxel is used as a first-line chemotherapy treatment for non-small cell lung cancer (NSCLC), but patients acquired resistance becomes a critical problem. Tubulin is the "building block" of microtubules, and agents that bind to tubulin are believed to block cell division by interfering with the function of the mitotic spindle, blocking the cells at the metaphase-anaphase junction of mitosis. Microtubules are complicated structures that perform many cellular tasks, including cell shape maintenance, intracellular transport, secretion, and neurotransmission. In addition, microtubules are extremely vibrant and unstable structures that constantly incorporate free dimers into the soluble tubulin pool and release dimers.43 Docetaxel shows higher affinity to ί-tubulin, targeting centrosomal organization and acting on cells during three stages of the cell cycle (S / G2/M), whereas paclitaxel creates cell damage by influencing the mitotic spindle in the G2 and M stages of the cell cycle, and peak resistance to paclitaxel is early in the S phase.44 Chemotherapy agents known as taxanes have appeared as one of the most strong classes of cancer-fighting compounds with a broad spectrum of activity. It has been demonstrated that the tubulin/microtubule complex is a clinically helpful antitumor target. Paclitaxel, docetaxel, vinblastine, and discodermolide are examples of chemotherapeutics that operate through tubulin polymerization disturbance. First, docetaxel is a paclitaxel semi-synthetic derivative. Unlike the other three compounds, vinblastine stabilizes all microtubules, adds tubulin and leads to depolymerization of microtubules.45
FUTURE AND PHARMACOGENETICS:
Future developments in some significant areas will play a critical part in determining the overall effect of pharmacogenetic data on therapeutic decisions. Improvements are needed in genome-wide methods such as gene expression arrays, high-throughput methods, SNP chips, genome-wide scans that could identify candidate genes and SNPs that were previously unknown and functionally important. Many stumbling blocks face the current approach to pharmacogenetics. Candidate gene-based techniques do not provide a reliable prediction of tumor drug reaction and normal tissue toxicity due to the absence of understanding of the precise position of all factors concerned.46
Genetic variations in genes have described a lot of inter-individual variation in anticancer drug reaction and toxicity. Treatment for cancer uses various therapeutic agents that have a broad range of toxicity, often with limited therapeutic indicators. Development of drug resistance and serious side effects are the main issues of cancer chemotherapy. Pharmacogenetics research in anticancer drugs is an active area of research for its capacity to reduce life-threatening toxicity and improve therapeutic effectiveness prior to administration of chemotherapy. Tumor genomic heterogeneity inevitably generates differences between unrelated patients in reaction to the same treatment. Thus, there is a need to define the marker for the treatment to be given, to clarify the role of pharmacogenomics in individualizing treatment.
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Received on 16.11.2019 Modified on 23.12.2019
Accepted on 19.01.2020 ©A&V Publications All right reserved