The variability of drug response in patients is one the most important issue in clinical practice. The individual response to drug is very variable: reduced or absent therapeutic effects or adverse reactions may be observed in patients, although the same drug and the same dosage has been dispensed. This variability between individuals was ascribed to the influence of environmental factors, as age, sex, nutritional state, hepatic and renal functional state, life habits as diet, smoke and alcohol, the concomitant administration of other drugs or comorbidities. Now it is assumed that, beyond factors above mentioned, inherited factors play an important role in the individual response to drugs. Studies on homo and dizygotic twins suggest, for some drugs subject to high metabolism, genetic factors play an important role in pharmacokinetics and pharmacodynamics. The clinical result of interindividual drug response heterogeneity can be therapeutic failure, severe or fatal adverse reactions. Pharmacogenetics rises in the Fifties when researchers began to think about drug response adjusted, at least in part, by genes. Pharmacogenetics studies the interindividual variations of DNA sequence related to drug response. The practical application of pharmacogenetic knowledge is the availability to predict the response of a patient to a drug based on a routine genetic test in order to achieve to a tailored therapy, “ the right drug to the right patient”. DNA tests, based on these genetic variation, can predict the response of a patient to a drug. Clinicians can use this information to decide the right therapy and the tailored dosage. Benefits will be a decrease of adverse reactions in better clinical outcome and reduced costs.
DNA sequence variations present in at least 1% of population are called polymorphisms. These genetic polymorphisms give rise to enzymes with different levels of metabolic activity or to receptors with different drug affinity, changing the individual drug response. The genetics variation often involves a single nucleotide and are termed single nucleotide polymorphism (SNP), but can affect also more than a single nucleotide or wide DNA sequences: substitutions, deletions, insertions, amplifications and translocations.
The individual drug response variability is significant mainly in oncologic therapy because here drugs are characterized by a narrow therapeutic index, with a minimum variation between effective dose and toxic dose. Changes in antitumoral drug metabolism due to genetic variations can produce important alterations in toxic and effectiveness of drug effect. Unfortunately this occurs frequently as the dose of antineoplastic agents is determined by the oncologist in a standardized manner on the basis of the patient's body surface (obviously taking into account other non-genetic factors of variability). As for other pathologies, the variations in the DNA sequence may relate to the structure of genes that coding for enzymes of the metabolism and transport of drugs or proteins involved in the action of drugs, influencing the destiny of the organism, toxicity as well as more recently shown, effectiveness. In this regard, importantly, not only the polymorphisms of the host genome, but also those of the cancer genome can influence tumor response to anticancer drugs. Polymorphisms of the host and tumor genome regulate both the transport, retention and efflux of drugs cancer, determining the degree of penetration into the tumor tissue; the genome of the tumor has the majority of polymorphisms that influence tumor aggression and its drug-sensitivity or resistance; polymorphisms of the host genome are the major determinants of the risk of toxicity for the patient, to which however do not contribute in a substantial way the polymorphisms of the tumor genome.
As for other pathologies, the variations in the DNA sequence may relate to the structure of genes that coding for enzymes of the metabolism and transport of drugs or proteins involved in the action of drugs, influencing the destiny of the organism, toxicity as well as more recently shown, effectiveness. In this regard, importantly, not only the polymorphisms of the host genome, but also those of the cancer genome can influence tumor response to anticancer drugs. Polymorphisms of the host and tumor genome regulate both the transport, retention and efflux of drugs cancer, determining the degree of penetration into the tumor tissue; the genome of the tumor has the majority of polymorphisms that influence tumor aggression and its drug-sensitivity or resistance; polymorphisms of the host genome are the major determinants of the risk of toxicity for the patient, to which however do not contribute in a substantial way the polymorphisms of the tumor genome.
