Pharmacogenetics Of Drug Targets Theoretical Background

From a theoretical point of view, the chemosensitivity of a tumor may be influenced by the genetic background of a disease in three different ways. First, if the drug target plays an important role in the process of tumor progression (i.e., HER2/neu) and its expression in tumor tissue is low at the time of drug treatment, despite efficient target saturation by the drug, the therapeutic effect is likely to be unsatisfactory. On the contrary, high expression may indicate a critical dependence of the cancer cell on the specific function of the target, and thus drug treatment is likely to result in effective cell killing (Fig. 3).

Second, if the drug target is not involved in neoplastic transformation and/or progression, being an enzyme of nucleotide synthesis, and its expression is low at the time of drug treatment, it will be saturated, and a high cytotoxic effect will be obtained. On the contrary, high expression will result in the residual drug target being available for cell survival with the treatment producing low cell killing. Typical examples of such targets are thymidylate synthase [TS (7)] and ribonucleotide reductase (RR) (Fig. 4).

Third, mutations may reduce the affinity of the drug for the target, thus resulting in unbound target and drug resistance (i.e., mutations affecting the kinase domain of c-kit). Less frequently, mutations affecting the coding sequence may increase the drug affinity of the target resulting in effective target saturation, high cytotoxicity, and optimal tumor sensitivity (Fig. 5).

Finally, genetic variation in the drug-metabolizing enzymes may be associated with a poor- or extensive-metabolizer phenotype. Examples of well-characterized polymorphic

Drug target involved in tumor progression (i.e., EGFR, HER2/neu)

Low expression Modest biological role

Target saturation

Low cytotoxic effect

Target saturation

Drug x

High expression Relevant biological role

High expression Relevant biological role

Critical impairment of target function

High cytotoxic effect

Figure 3 Relationship between chemosensitivity and the expression of drug targets involved in neoplastic transformation and/or progression. If the expression is low at the time of drug treatment, this reflects a secondary role played by the drug target, and, despite efficient saturation, the therapeutic effect is likely to be low. In contrast, high expression indicates critical dependence of the cancer cell on the specific function of the target, and drug treatment is likely to result in effective cytotoxicity. A typical example of such a target in solid tumors is HER2/neu. Abbreviations: EGFR, epidermal growth factor receptor; HER2/neu, human epidermal receptor 2/neu.

Drug target NOT involved in tumor progression (i.e., TS, RR)

Low expression

Target saturation

Target saturation

High cytotoxic effect

High expression

Target

Residual target function 1

Low cytotoxic effect

Figure 4 The relationship between chemosensitivity and expression of the drug target not involved in neoplastic transformation and/or progression. If the expression is low at the time of drug treatment, the drug target will be saturated, and a high cytotoxic effect will be obtained. In contrast, high expression will result in the residual drug target being available for the cell to survive and treatment will produce low cytotoxicity. Typical examples of such targets are: TS and RR. Abbreviations: TS, thymidylate synthase; RR, ribonucleotide reductase.

Drug target involved

n tumor progression

Mutation (i.e., c-kitAsP816Val) Reduced affinity i ^

Unbound target

Drug resistance

Mutation (c-kitVal560Gly) Increased affinity

Target

Target saturation 1

High cytotoxic effect

Figure 5 Relationship between chemosensitivity and the genotype of the drug target. Mutations may reduce drug affinity with the target (i.e., thus resulting in unbound target and drug resistance. Conversely, drug-target affinity may be increased (i.e., c-kitVal560Gly) with effective target saturation, high cytotoxic effect, and optimal tumor sensitivity.

Time

Figure 6 Poor-metabolizer, wild-type, and fast-metabolizer phenotypes and drug pharmacodynamics. Progressive increment in drug area under the concentration-time curve (area under the curve, shaded areas on the left graph) results in the increase in both drug exposure of peripheral tissues and drug effect (i.e., ANC decrease, right graph). Abbreviation: ANC, absolute neutrophil count.

Poor-metabolizer

Time

Pharmacokinetic parameter

Figure 6 Poor-metabolizer, wild-type, and fast-metabolizer phenotypes and drug pharmacodynamics. Progressive increment in drug area under the concentration-time curve (area under the curve, shaded areas on the left graph) results in the increase in both drug exposure of peripheral tissues and drug effect (i.e., ANC decrease, right graph). Abbreviation: ANC, absolute neutrophil count.

variants are cytochrome P-450 enzymes (CYP450), folyl-polyglutamate synthase, thiopurine S-methyltransferase, UDP-glucuronosyl-transferase, dihydropyrimidine dehydrogenase, and glutathione S-transferase. The drugs affected are epipodophyllo-toxins, antifolates, thiopurines, camptothecins and anthracyclines, fluoropyrimidines, and cisplatin analogs, respectively. The extensive-metabolizer phenotype, with respect to enzymes of drug inactivation, is associated with reduced drug exposure of cancer cells and normal tissues, high tolerability, but impaired activity, whereas high activity of the enzymes involved in prodrug activation (i.e., CYP450 and cyclophosphamide) is likely to result in poor tolerability but high anticancer activity (Fig. 6).

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