Abstract
Drug interaction in cancer chemotherapy is one of the most common phenomena in cancer treatment. Cancer patients often take several medications at the same time, not only for treating their cancer but also for side effects and other secondary illnesses. The number of comedications increases with age, and drug interactions are critical for elderly patients. Because of this, they can be at high risk for adverse drug interactions and duplicate medications. Consequences of these interactions can range from inactivation of cancer-fighting medications to severe injury or death of the patient. Pharmacogenetics studies the relationship between genetic polymorphisms and individual responses to drugs. In recent years, there has been great progress in our knowledge of the effects of drug-metabolizing enzymes and molecular target genetic polymorphisms on cancer chemotherapy. Pharmacogenetics focuses on the prediction of drug efficacy and toxicity based on a patient’s genetic profile with routinely applicable genetic tests to select the most appropriate medication at optimal doses for each individual patient.
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1.1 Introduction
Drug interactions and pharmacogenetics seem to present two different problems for the side effects of cancer chemotherapy. In fact, we will see later in this chapter that these two approaches are not so different.
Drug interaction in cancer chemotherapy is one of the most common phenomena in cancer treatment. Drug interactions in oncology are of particular importance owing to the narrow therapeutic index and the inherent toxicity of anticancer agents. Interactions with other medications can cause small changes in the pharmacokinetics or pharmacodynamics of a chemotherapy agent that could significantly alter its efficacy or toxicity. Evaluation of drug potential interactions should not be limited solely to the anticancer group. A drug interaction occurs whenever the effects of one drug are modified by the prior or concurrent administration of another pharmacologically active substance. Such interactions may result in an antagonistic, synergistic, or unexpected response [1].
A drug interaction is defined as the pharmacologic or clinical response to the administration or co-exposure of a drug with another substance that modifies the patient’s response to the drug. It is reported that more than 20% of all adverse reactions to drugs are caused by interactions between drugs [2]. This incidence increases among the elderly and patients who take two or more medications. Patients with cancer are particularly at risk for drug interactions because they could be taking many different medications as part of their cancer treatment or for the management of other illnesses [3].
Drug interactions can occur throughout the process of drug disposition as a result of endogenous and exogenous factors. Drug interactions can be the result of pharmacokinetic or pharmacodynamic factors or a combination of mechanisms. Pharmacokinetic interactions involve one drug or substance altering the absorption, distribution, metabolism, or elimination of another drug or substance. A common example of a pharmacokinetic interaction occurs when two drugs compete for the same metabolic pathway. When the pathway becomes saturated, neither drug can be metabolized fully, which results in higher serum concentrations of the agents and can lead to clinically unfavorable consequences. Pharmacodynamic interactions occur when two drugs or substances have similar molecular targets but do not affect the pharmacokinetic parameters of each other. When two or more drugs that have similar pharmacodynamic activity are coadministered, the additive effects might result in an excessive response or toxicity. Pharmacodynamic interactions between drugs with opposing effects can reduce the response to one or both drugs [4,5,6].
In this section, we have intentionally focused on the unexpected drug interactions that have been well documented in cancer patients. A special section describes interactions between anticancer drugs and resistance-modifying agents because although pharmacodynamic interactions are the aim of this kind of association, pharmacokinetic interactions can be the chief explanation for resistance reversal.
1.2 Principles of Drug Interactions
1.2.1 Physical Interactions or Chemical Incompatibilities
Cancer patients usually receive intravenous (IV) anticancer drugs plus other supportive treatment, such as antiemetics, antibiotics, and others. Special attention should be paid to the physical and chemical interactions that can occur when the drugs are given simultaneously [7].
Cancer patients usually require multiple-drug therapy. In fact, the cancer chemotherapy regimen alone often consists of three or four agents. Supportive therapy adds more drugs to the overall regimen, resulting in the (perceived) need to administer several drugs simultaneously. Also, having a steep dose–response curve, low therapeutic index, and significant toxicity, anticancer agents are particularly critical drugs. Any deviation from the dose or concentration that produces optimum activity is bound to cause problems one way or another, either through increased toxicity or loss of response. Either way the outcome may be fatal for the patient. Furthermore, one should keep in mind that chemical inactivation of anticancer drugs by the admixture of other drugs is not usually visible in terms of evident product degradation. In other words, even if an added drug does not cause clouding, precipitation, or a color change in the cytotoxic drug solution, you can never be sure that there will be no chemical inactivation. So make it a rule to always administer cytotoxic drugs alone [8].
Selected examples are presented in the following sections.
1.2.1.1 pH Effects
Some cytotoxic drugs (e.g., fluorouracil) dissolve only at extreme pH values. Adding other drugs may cause such a shift in pH that fluorouracil will flocculate.
1.2.1.2 Solubilizers
Other cytotoxic agents can be kept in solution only with the aid of solubilizers, which tend to be effective only within specific concentration ranges. Outside these ranges, the drugs may crystallize (e.g., etoposide, teniposide, paclitaxel).
1.2.1.3 Plasticizers
Solubilizers may leach plasticizers from plastics, thus producing toxic effects (this is why PVC-free transfusion-giving sets must be used for paclitaxel infusions). Conversely, lipophilic cytotoxic drugs may be extracted by plasticizers from an aqueous solution.
1.2.1.4 Sorption
Protein sorption to glass surfaces has been described in the literature. This phenomenon may cause loss of activity of biologically potent drugs, which tend to be administered in minute amounts.
1.2.2 Chemical Reactions
Of the broad spectrum of possible chemical reactions, here are a few examples:
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Hydrolysis (e.g., etoposide lactone ring cleavage in basic pH range)
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Redox reactions (e.g., platinum coordination complexes and sulfite, thiols)
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Photolysis (e.g., carmustine [nitrosourea] or dacarbazine [triazene])
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Racemization (e.g., etoposide as CH-acid compound in alkaline solution)
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Formation of coordination complexes (e.g., platinum derivatives)
1.2.3 Denaturation
Many proteins are stable only at specific pH values and ionic strengths (filgrastim, for instance, is unstable in normal saline). Deviations may lead to denaturation, which will not necessarily be visible as flocculation in the case of biologically potent drugs (growth factors, interferon). Loss of biologic activity will then not be macroscopically evident.
1.2.4 Pharmacokinetic Interactions
Very few cytotoxic agents are administered by the oral route, but now with the tyrosine kinase inhibitor family, everything has changed; all the “small molecules” are orally administered. We should, therefore, take the pharmacokinetic interactions into consideration, including the absorption, distribution, metabolism, and elimination of anticancer drugs.
1.2.4.1 Absorption
Many factors are able to reduce the digestive absorption of a drug. These include the degree of ionization of the drug, its contact with the digestive mucous (transit problems, defective digestive secretion), the gastric emptying, and gastrointestinal motility. Food delays gastric emptying, raises intestinal pH, increases hepatic blood flow, and slows gastrointestinal transit, so it can significantly affect the pharmacokinetic profile of some orally administered medications. Food–drug interactions can have four pharmacokinetic effects on the bioavailability of the orally administered anticancer agent: delayed, decreased, increased, or unaffected absorption.
Some orally administered anticancer agents are prodrugs, which require metabolic activation for cytotoxic activity through first-pass effects in the gastrointestinal tract and/or liver before they reach the systemic circulation. Capecitabine , altretamine, etoposide phosphate, and estramustine phosphate sodium are anticancer agents that are used in the treatment of various solid tumors (including breast, colorectal, ovarian, lung, prostate, and testicular cancer) and require such activation. Therefore, factors that alter the absorption of these medications can have profound effects on their pharmacokinetics. A decrease in the rate and extent of absorption is noted when estramustine phosphate sodium is given with food or milk, and bioavailability has been reported to decrease by 36 and 63%, respectively [9]. Therefore, it is recommended that estramustine phosphate sodium be taken with water 1 h before or 2 h after a meal. By contrast, food has been shown to have only a minor effect on the pharmacokinetics of fluorouracil (5-FU). The rate of absorption of capecitabine (a 5-FU prodrug) is decreased in a fed state, which results in an increase in hepatic first-pass metabolism, which in turn reduces the extent of systemic absorption of the prodrug [10]. However, a greater effect is seen on the area under the concentration–time curve (AUC) of capecitabine as compared with 5′-deoxy-5′ fluorouridine (5′-DFUR), the precursor to the pharmacologically active compound 5-FU. So, the change in AUC of capecitabine is probably not clinically significant, as capecitabine itself is not the active compound.
The absorption of orally administered anticancer agents that are not prodrugs can also be altered by metabolism within the gastrointestinal tract [11]. Evidence indicates that the activity of cytochrome P450 enzymes (CYP enzymes) in the gut wall is a significant factor that alters the bioavailability of orally administered anticancer agents that are CYP3A substrates [12]. Drug–food, drug–herb, or drug–drug interactions can occur when an orally administered CYP3A substrate is given concomitantly with an inhibitor or inducer of intestinal CYP activity. One of the best described examples of a food that alters intestinal CYP3A activity is grapefruit juice. Grapefruit juice is known to be a potent inhibitor of intestinal CYP3A4 and therefore increases the bioavailability of various drugs, such as the anti-inflammatory and immunosuppressive agent cyclosporine and the calcium-channel blocker nifedipine [13,14,15,16].
1.2.4.2 Ionization
Digestive absorption is complete when it is achieved by passive diffusion (e.g., in a non-ionized form). Most of the substances that are capable of ionizing a drug decrease its digestive absorption. Substances such as alkalinizing agents decrease the absorption of acid drugs, and acidifying drugs (citric and tartaric acid) decrease the alkaline drug absorption.
1.2.5 Complexation
This type of interaction occurs during the digestive process, when the drug forms (with another drug or any other substance) a nonresorbable complex (e.g., aluminum colloids combined with acid drugs).
1.2.5.1 Contact with the Digestive Mucosa
This kind of antagonism includes different physiopathologic circumstances, such as food attendance and lack of digestive secretion.
1.2.5.2 Gastrointestinal Motility
Drugs are mainly absorbed at the intestinal level, where a wide mucous surface exists. Absorption at this level is affected all the more when gastric emptying is faster. Any substance that modifies the gastric emptying acts on the kinetics of the intestinal absorption of anticancer drugs. The anticholinergic substances slow down gastric emptying and delay the absorption of the drugs. On the other hand, metoclopramide accelerates gastric emptying and accelerates the absorption of associated drugs.
1.2.5.2.1 Modifications in Drug Diffusion
These modifications become apparent in either an increase in the concentration of the free active form of the drug or a decrease in this concentration.
1.2.6 Binding to Plasma Proteins
The competition of drugs for plasma proteins is one of the most common reasons for the occurrence of toxic side effects (methotrexate–aspirin [17, 18], methotrexate–indomethacin [19], methotrexate–trimethoprim–sulfamethoxazole [20, 21], etc.). Clinicians should be very careful with the association of drugs that are highly bound to proteins (usually albumin) because the binding sites are the same and limited in number.
1.2.6.1 Modification of the Tissue Binding
This modification is the result of competition between two drugs for the same binding sites in a tissue. This kind of interaction is similar to the protein plasma binding but directly into the tissues.
1.2.6.1.1 Metabolic Interactions
The metabolic interactions mainly occur with drugs with hepatic metabolism. The anticancer drugs involved in metabolic interactions with other drugs are those metabolized by liver enzymes, which are induced or inhibited by the associated substances. The main metabolic inducers are rifampicin, spironolactone, and phenobarbital [22, 23]; the main metabolic inhibitors are monoamine oxidase inhibitors, tricyclic antidepressants, phenothiazine neuroleptics, and allopurinol [24, 25].
1.2.6.1.2 Modifications in the Elimination
Drug interactions leading to changes in the elimination of anticancer drugs mainly concern urinary drug elimination. Modifications in urinary elimination are principally due to changes of the urine pH expressing a modification in the ionization of the substances filtered by the glomerulus and secreted at the proximal tubule level. An increase in the degree of ionization of the drug corresponds to an increase in the urinary elimination of the drug. On the other hand, a decrease in drug ionization leads to a decrease in its renal elimination.
1.2.6.1.3 Miscellaneous
We should always take into account the possibility that the patient is suffering from another disorder that could, by itself, interact with the pharmacokinetic behavior of the anticancer drug. For example, thyroid dysfunction may influence drug pharmacokinetics, just as the cardiovascular and respiratory systems can.
1.2.7 Pharmacodynamic Interactions
Pharmacodynamic interactions involve the therapeutic power of the anticancer drug. They can enhance or decrease antineoplastic efficacy and modify the importance of the drug’s toxic side effects. Pharmacodynamic interactions mainly concern the hematologic system, the liver, and the kidney.
1.2.7.1 Terminology
The anticancer drug alone is considered as reference for the therapeutic activity. The pharmacologic consequences of drug interactions are always quantitative modifications of one or more effects of the associated drugs. Either the intensity of an effect, its duration, or both can be affected. If it is a global increase of the effect, the interaction is either synergy or enhancement. If it is a decrease of the effect, the interaction is antagonism.
1.2.7.2 Synergy and Antagonism
Usually, we use the term “synergy” when two drugs have effects going in the same direction. The effect is additive when the observed effect is the sum of both effects. Synergy’s main characteristic is that it affects only the common effects of the drugs. According to the extent of the modifications that occur, it can be described as partial, additive (the most frequent), and synergistic. Conversely, antagonisms can be observed when the effects of drug association produce a milder effect than the most active drug alone. The antagonism can be total or partial.
1.2.7.3 Enhancement and Antagonism
Enhancement is characterized by a special phenomenon in which the increased effects all belong to the same drug. Other substances in the association do not have these effects but are capable of increasing their intensity when associated with the drug. Antagonism also exists in such situations.
It is important to note that the term “antagonism” is used to describe two phenomena, which are the contrary of synergy and the contrary of enhancement. Usually, interaction between two drugs is not defined by its mechanism but rather by its pharmacologic consequences. The interaction supervention supposes that the interaction is sufficiently intense to have a clinical translation.
It is relatively common to detect drug interactions in pharmacokinetic terms with no pharmacodynamic repercussions.
1.3 Interactions Between Anticancer Drugs and Other Active Substances
Very little study has been devoted to interactions between anticancer drugs and other active substances, which is quite surprising because cancer patients usually receive a large number of pharmaceuticals and the therapeutic margin for anticancer drugs is always narrow. Mostly, the drug interactions have been reported case by case (Tables 1.1 and 1.2).
1.3.1 Antiemetics
Many anticancer drugs induce nausea and vomiting in cancer patients. For these reasons, antiemetics are usually used in combination with cancer treatments. The antiemetic drugs usually act at the level of the central nervous system through the dopamine or serotonin receptors. Among the antiemetics, chlorpromazine and metoclopramide seem to be the most involved in drug interactions.
1.3.1.1 Chlorpromazine
Chlorpromazine combined with caffeine enhances cytotoxicity of alkylating agents in some rodent transplantation tumors and in the human melanoma xenograft system in mice [43]. The mechanism of its action may be related to increased retention within the tumor cells, to fixation of DNA damage, or to a nonspecific cytotoxicity. On the other hand, when chlorpromazine and caffeine have been used in patients with disseminated malignant carcinoma, no tumor cytotoxicity was enhanced [44].
1.3.1.2 Metoclopramide
Metoclopramide might enhance antitumor activity of anticancer drugs because structurally related compounds (nicotinamide, benzamide, etc.) inhibit the chromatin-bound enzyme adenosine diphosphate ribosyl transferase [26]. This enzyme is activated by DNA-damaging agents and may play a role in DNA repair. This hypothesis was tested against a squamous cell carcinoma of the head and neck in xenografted nude mice. Metoclopramide was given at the same time as cisplatin and again 24 and 48 h later. Compared with mice not given metoclopramide, cisplatin antitumor activity was doubled, with no other increase in cisplatin toxicity. In another study with metoclopramide and chlorpromazine, epirubicin cytotoxic activity was enhanced when tested against Chinese hamster fibroblasts without any intrinsic cytotoxic activity [27].
1.3.1.3 Granisetron and Ondansetron
Development of serotonin receptor antagonists gives a therapeutic class without the classic adverse reactions associated with dopamine receptor blockade, such as severe sedation or extrapyramidal side effects. Finally, of the selective 5HT3 receptor antagonists, both granisetron and ondansetron have been tested for their potential to affect drug cytotoxicity. No evidence was found that these two compounds antagonize or enhance the antitumor properties of anticancer drugs such as cisplatinum [45, 46].
1.3.2 Antiulcer Drugs
Cimetidine and ranitidine are histamine H2 antagonists used for the treatment of diseases caused by gastric hyperacidity. Evidence has accumulated that cimetidine can alter drug metabolism through the ability to inhibit the hepatic microsomal cytochrome P450 enzyme system [47]. Ranitidine binds less avidly to microsomal enzymes and, in clinical dosage, does not appear to significantly alter microsomal metabolism [47]. Ranitidine when associated with cyclophosphamide does not change the pattern or degree of cyclophosphamide-induced leukopenia or granulocytopenia. Ranitidine administration has no significant effect on the area under the curve values for the two major oncolytic cyclophosphamide metabolites 4-hydroxycyclophosphamide and phosphoramide mustard; nevertheless, ranitidine administration is associated with significantly prolonged plasma terminal half-life and increases area under the curve for the parent drug that is not active [48].
Several anticancer drugs, including cyclophosphamide, the nitrosoureas, doxorubicin, procarbazine , and hexamethylmelamine, undergo metabolism through the hepatic oxidative microsomal enzyme system [28,29,30].
The result of the interaction between cimetidine and the former anticancer agents is a decrease of the antineoplastic agent clearance, leading to an increase in their activities and toxicities by typical pharmacokinetic interaction [49,50,51].
1.3.3 Analgesics (Nonsteroidal Anti-inflammatory Drugs)
Many cases of drug interactions between nonsteroidal anti-inflammatory drugs (NSAIDs) and anticancer drugs have been reported. There have been fatal interactions between methotrexate and naproxen [52] as well as clinical and pharmacokinetic evidence of life-threatening interactions between methotrexate and ketoprofen [31]. In the latter chapter, no abnormalities in methotrexate kinetics or toxicity were noticed when ketoprofen was given at least 12 h after completion of high-dose methotrexate. The kidney was suggested to be the site of drug interaction.
A probable interaction between methotrexate and/or 5-FU and indomethacin has been reported [32]. This NSAID is known to enhance cell killing by methotrexate in vitro. Other mechanisms than renal damage are of importance in the explanation of indomethacin–methotrexate interaction such as displacement and increased transport into malignant cells [33]. Inhibition of prostaglandin synthesis seems to participate in the effect of indomethacin on methotrexate cytotoxicity.
Pharmacokinetic interaction between cisplatinum and indomethacin has been reported in vitro and in vivo [34]. The result of this interaction was an increase in free cisplatinum concentrations due to the fact that both indomethacin and cisplatinum are highly protein-bound.
Morphine, cocaine, and atropine stimulated transport of choline and nitrogen mustard into L5178Y lymphoblasts [53] and into leukemic white blood cells [54], which is interesting since the accumulation of alkylating agents is of importance for their cytotoxicity.
1.3.4 Antimicrobial Agents
Antimicrobial therapy is quite common for patients treated for hematologic malignancies or solid tumors. For this reason, extensive studies have been published on the effects of anticancer agents on the antibacterial activity of antibiotics [55]. However, the effects of antibiotics on the antineoplastic activity of anticancer drugs have been considerably less discussed.
Nevertheless, there are some reports on the effects of antibiotics on the toxicity of anticancer drugs. Penicillin in combination with furosemide impaired methotrexate renal secretion and caused increased toxicity [41]. Penicillin also inhibits accumulation of methotrexate in renal slices of rabbit and monkeys and delayed the elimination of methotrexate [35]. Decreased methotrexate antitumor effect has been reported with kanamycin, neomycin, and penicillin due to a decrease of the cellular uptake of methotrexate [42]. The nephrotoxic antibiotics aminoglycoside gentamicin can enhance the toxic renal effects of methotrexate on the tubule [56].
Trimethoprim–sulfamethoxazole and netilmicin enhance the epirubicin oxygen radical formation.
Antifungal drugs such as amphotericin B potentialize the cytotoxicity of many anticancer agents (doxorubicin, vincristine , CCNU ) on leukemia cells of mice [57]. Amphotericin B has also been suggested to potentialize the effect of doxorubicin, cyclophosphamide, and carmustine in human neoplasia [58].
1.3.5 Miscellaneous
Anticoagulants such as dicumarol increase the enzymatic activation of mitomycin C to reactive alkylating metabolites and cause a subsequent increased cytotoxicity [59]. Warfarin, another anticoagulant, retards the growth of Lewis lung carcinoma in mice and small cell carcinoma of the lung in humans [60]. A synergistic action between 5-FU and warfarin has been also reported [36].
Psychiatric drugs are quite widely used in elderly patients being treated for cancer. The use of these psychopharmaceuticals has an influence on the activity of the antineoplastic agents. Diazepam blocks the cells in pre-S-phase and induces mitotic arrests at prometaphase by inhibiting centriolar separation [37, 38]. Diazepam also causes an enhancement of doxorubicin and mitoxantrone cytotoxicity [39]. Amitriptyline, a tricyclic antidepressive, modifies the blood–brain barrier and enhances the penetration of drugs into the central nervous system [40].
Bronchodilators are often indicted in patients with airway obstruction or prominent wheezing. The main classes of bronchodilators, (beta)β-adrenoceptor agonists, and methylxanthines raise the level of 3′ 5′ cyclic AMP in mast cells and bronchial smooth muscles, thereby inhibiting mediator production and reducing muscle contractility.
As cyclic AMP is a second messenger in other cellular events, it is evident that bronchodilators might influence tumor cells and interact with cancer treatment [61]. The interaction of cyclic AMP on the cytotoxic effect of doxorubicin has been suggested [62].
1.4 Anticancer Drug–Anticancer Drug Interactions
The interactions among anticancer drugs are of importance because the chemotherapeutic protocols include at least three different antineoplastic drugs. This is why the possibility of drug interactions should be known and taken into account. Two aspects of drug interactions are concerned. Drug interaction may be desired for clinical modulation of an anticancer agent or undesired.
1.4.1 Modulation
The modulation of an anticancer agent is accomplished by a compound that modifies some aspect of the biochemical pharmacology of the anticancer drug to improve its therapeutic index. The best example of clinical anticancer drug modulation is that of 5-FU modulation by leucovorin, which is discussed in another chapter of this book.
Another example of 5-FU modulation is the combination of methotrexate (MTX) and 5-FU [63]. The interaction of MTX and 5-FU is complex, and theoretical models for both antagonism and synergy have been postulated. By altering reduced folate pools involved in ternary complex formation, MTX may be expected to hinder 5-FU inhibition of thymidylate synthase [64, 65]. By inhibiting de novo purine synthesis, there is also less nucleic acid synthesis available for fluoropyrimidine nucleotide incorporation. However, the net balance of potential negative and positive effects appears to favor synergy. The most plausible mechanism of MTX/5-FU interaction appears to be through increased levels of phosphoribosylpyrophosphate, an intermediate needed in de novo purine synthesis, resulting from inhibition of purine synthesis [66].
1.4.2 Undesired Drug Interactions
The undesired anticancer drug–anticancer drug interactions are probably fairly frequent because more than 800 polychemotherapeutic protocols have been recorded (hematologic malignancies plus solid tumors). In theory, it would seem to be an impossible task in a limited space to develop the subject of drug interactions when anticancer drugs are combined, but this is not the case in practice. In fact, very few interactions among the anticancer drug group have been reported in the literature. For this reason, it is more important to give the philosophical criteria for planning a polychemotherapeutic protocol.
In order to obtain a better antitumor response with drug association than with each drug alone, an association should discriminate between tumor sensitivity and toxic side effects. In other words, a drug association should combine the antineoplastic properties of each drug without adding their toxic side effects. One of the fundamental principles of drug combination is to combine drugs that do not have the same toxic effects.
Some impossible associations due to the same toxic effects, such as methotrexate with cisplatinum for renal toxicity, have led to second-generation drugs that do not have the same toxicities. For example, carboplatin and trimetrexate are free of the renal toxic effect of their corresponding first-generation drugs, due to the fact that the association of cisplatin with trimetrexate [67] and carboplatin with methotrexate [68] is possible and safer.
1.5 Drug Interactions Between Anticancer Drugs and Resistance-Modifying Agents
Several systems exist by which tumor cells resist cancer chemotherapy. Numerous resistance-modifying agents are used in clinics in order to circumvent multidrug resistance (MDR), which is one of the most frequent reasons for chemotherapy failure. To reverse MDR, the combination between anticancer agents and resistance-modifying agents leads to pharmacologic interactions [69].
Pharmacodynamic interactions could be defined as desirable interactions, but the question is as follows: Are the pharmacodynamic direct interactions in target organs or are they due to pharmacokinetic modifications of the anticancer agent? In other words, the maximum tolerated dose of the antineoplastic agents when administered without the modulator is usually well established, but this is not the case for the maximum tolerated dose of the anticancer drugs when associated with the MDR-modulating drug. Clinicians should be very careful when they initiate a protocol that associates anticancer chemotherapy and MDR modulators.
1.6 Pharmacogenetics
Pharmacogenetics relates variation in gene structure to variation in phenotypes associated with therapeutic or toxic responses to drugs and other foreign chemicals in human populations [70]. Methods of study in pharmacogenetics include the correlation of observed variation in drug pharmacokinetics or pharmacodynamics with allelic variation in individual genes encoding proteins that act as targets of drug action or mediators of drug elimination, the elucidation of biochemical and molecular mechanisms that produce variable protein function, the development of probe drug-testing procedures and predictive animal models to more precisely define the role of genetics in producing variable drug response in human populations, and the development of simple genetic tests to predict unexpected drug responses and thus to guide the clinician in the selection of appropriate drugs and drug doses [71,72,73].
Personalized medication management, including DNA testing, is extremely important for the proper treatment of cancer because finding the right drug and dose is so vitally important. This is not surprising to people that study genetics. Research shows that of all the clinical factors that alter a patient’s response to drugs, such as age, sex, weight, general health, and liver function, genetic factors account for a significant proportion [74,75,76].
Early in the development of irinotecan , researchers observed that the active metabolite of the drug, SN-38, was cleared from the body through a process called glucuronidation [77]. A gene called UGT1A1 was responsible for sticking that glucuronide group onto the drug [78, 79]. Once glucuronide was on a compound, it was easily excreted by the bile. So, for example, bilirubin and a number of estrogen molecules in the body are glucuronidated. Irinotecan is one of several anticancer drugs that also undergo this process. Researchers found that a subset of the population, about 10%, has a genetic change in the UGT1A1 gene that hinders their ability to perform this glucuronidation process [80]. This change does not have an apparent phenotype; it is something that could be detected by the usual bilirubin test or by some outward manifestation of the patient. When patients with the genetic change in UGT1A1, called UGT1A1*28, receive a standard dose of irinotecan , they have a very high risk of severe or even fatal neutropenia, a condition that drastically lowers the ability of the body to fight off infection. This UGT1A1*28 genetic change is responsible for Gilbert’s syndrome, which is a lack of bilirubin glucuronidation [81, 82]. In 2004, the FDA reviewed the data on UGT1A1*28 and decided that this genetic change should be included in the insert for irinotecan as a risk factor for severe toxicity. (TA)6/(TA)6 is the normal genotype; generally, there is no change in the administered dose of irinotecan provided that no other agents known to interact with irinotecan are also administered. Patients with the (TA)6/(TA)7 heterozygous genotype have intermediate UGT1A1 activity and may be at increased risk for neutropenia; however, clinical results have been variable, and such patients have been shown to tolerate normal starting doses. Patients with the (TA)7/(TA)7 homozygous genotype should have their starting dose reduced by at least one level of irinotecan [83]. However, the precise dose reduction is not known, and subsequent dose modifications should be considered based on the individual patient’s tolerance to treatment.
Recent research has shown that up to 35% of women with estrogen receptor (ER)-positive breast cancer may fail tamoxifen treatment because of drug interactions and their genetic makeup [84]. The ability of these women to convert tamoxifen to the active compound endoxifen is compromised, resulting in a greatly increased risk of relapse [85]. DNA testing and careful analysis of overall drug regimens in these patients provide evidence that can be used to improve their chances of survival. With more than 500,000 women currently taking tamoxifen, this research has wide-reaching implications.
Tamoxifen is a prodrug widely used to treat, and as prophylaxis for, ER-positive breast cancer. Out of the approximately 120,000 new ER-positive breast cancer patients per year in the IS, 41,000 of whom will die; 42,000 are predicted to fail tamoxifen treatment because of 2D6 poor metabolizer phenotype. “Hot flashes,” a common side effect, are typically treated with selective serotonin reuptake inhibitors (SSRIs), many of which are potent inhibitors of CYP2D6, phenol-converting intermediate metabolizer patients into 2D6 poor metabolizers, now demonstrated as crucial to the activation of tamoxifen to endoxifen. Endoxifen has a 100 times greater receptor affinity than tamoxifen and is 30–100 times more effective. CYP2D6 genetically normal metabolizers also taking an inhibitor had 58% lower endoxifen levels and are likely to be in the group of ∼35% of patients who do not respond to tamoxifen. CYP2D6 frank poor metabolizers, homozygous for *3, *4, *5, and *6, had endoxifen levels 26% of WT. CYP2D6*4/*4 poor metabolizers had a 3.12 hazard ratio for breast cancer relapse. Two-year relapse-free survival is 68% in patients with the 2D6 PM phenotype and 98% in normal metabolizers [85, 86]. This suggests that widespread genotyping and therapeutic drug monitoring could result in successful outcomes for many of the 35% of ER-positive breast cancer patients who currently fail tamoxifen treatment [87].
Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the degradation of pyrimidine bases like thymidine and uracil [88]. DPD is also the main enzyme involved in the degradation of structurally related compounds like 5-fluorouracil (5-FU), a widely used anticancer drug [89, 90]. In 5-FU-based cancer chemotherapy, severe toxicities are observed at higher rates in patients who are heterozygous for a mutant DPYD allele, compared with toxicities in patients who are homozygous for the wild DPYD allele. The adverse effects of 5-FU are often lethal for patients homozygous for the mutant DPYD allele [91, 92].
On the basis of catalytic activity and on the basis of the mutation frequency, a 3% frequency for heterozygotes (−/+) to DPD was predicted, projecting a 1:1000 homozygote (+/+) for this mutation across racial lines.
The DPD test for 5-FU is considered appropriate for any person who is taking or considering 5-FU-based chemotherapy. It is recommended that this screening be accompanied by direct measurement of DPD activity prior to 5-FU treatment in cancer patients. Although this test looks for the most frequent genetic variation that causes DPD enzyme deficiency, this does not rule out the possibility of a decrease in DPD activity due to other factors or genetic variations [93, 94].
1.7 Summary
Drug–drug interactions with the pharmacologic results are a really important factor. More oncologists are usually aware of antineoplastic drug associations because they know the toxic side effects of each of the associated components, but they are much less aware of the pharmacologic effects of anticancer drugs and other medical treatments.
The availability of potent and reliable genetic techniques can change the way patients will receive chemotherapy in the near future. With this perspective in mind, oncologists and clinical pharmacologists should prompt the inclusion of pharmacogenetic investigation and DNA collection into early phases of clinical drug development. Recurrent, even after dose reduction, or unexplainable toxicity can be induced by genetically reduced drug inactivation/elimination. When polymorphic genes involved in the systemic disposition of a new agent are identified, prospective phenotype/genotype correlation analysis should be performed in phase I–II clinical trials, following the example of two recent phase I and pharmacogenetic studies. Pharmacogenetics has emerged as a novel and challenging area of interest in oncology.
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Lokiec, F. (2018). Drug Interactions and Pharmacogenetics. In: Dicato, M., Van Cutsem, E. (eds) Side Effects of Medical Cancer Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-70253-7_1
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