Cancer Therapeutics

Molecular Basis of the Therapeutic Index

Therapeutic index is defined as follows: LD ₅₀ , or median lethal dose, is the dose of drug that causes death in 50% of experimental animals, and ED ₅₀ , or median effective dose, is the dose that produces a specified effect (“response”) in 50% of the population under study. The therapeutic index in the clinic compares the dose of a drug that causes untoward toxicities to the dose that produces the desired therapeutic effect.

All drugs have targets, but it is the unique relationship of the target to the disease that can ultimately affect a drug’s therapeutic index. Traditional drug targets included DNA (nucleotide bases, enzymes of DNA synthesis, degradation, and repair), microtubules, and growth factor receptors. New targets include mutated, overexpressed, or fused growth factor/oncogene products (EGFR [Her-1], Her-2/neu, ras, bRaf, bcr:abl), immune checkpoint modulators (CTLA4, PD-1), cell surface antigens (CD33, CD22, CD20), anti-apoptotic proteins (bcl-2), cell-cycle regulators (cyclin-dependent kinases), epigenetic targets (histone deacetylases and methyltransferases), metabolic pathways (mTOR, PI3K, AKT) , stem-cell pathways (notch, wnt), and the machinery of protein synthesis ( l -asparaginase) and degradation (proteasome). Drugs that affect these newer targets are often referred to as targeted therapies , creating the false impression that classic chemotherapeutics do not have targets.

The specificity/selectivity of a drug for a particular target is, in general, proportional to the affinity constant, K _a , more accurately defined for competitive drug target interactions as the K _i , which is the reciprocal of the concentration of drug required to inhibit 50% of the target’s activity when controlled for all possible ligand or substrate concentrations. The activity of a drug refers to its effectiveness independent of dose or concentration.

There are several factors that help explain why cancer cells are more sensitive to cancer therapeutic drugs than normal tissues. For any drug, the therapeutic index is related to absorption, uptake, distribution, and metabolism. Differences in tumor vasculature, intratumoral pressure, and drug binding may alter drug uptake in a favorable or unfavorable way. Classically, the therapeutic index of intravenously administered cancer chemotherapy has been thought to be due primarily to cell-cycle kinetics. Many chemotherapeutic agents are more effective against cycling than noncycling cells and are tested under cell culture conditions where cancer cells rapidly proliferate (“log phase”); this a posteriori conclusion was derived from these observations. However, many solid tumors have a relatively long doubling time, yet a therapeutic index remains. Therefore, alternative explanations must exist. One includes differences in energy requirements between normal and malignant cells. For example, whereas normal tissues use oxidative phosphorylation to metabolize glucose, malignant tissues are often dependent on aerobic glycolysis. This is thought to reflect the selection pressure placed on tumor cells to cope with relatively hypoxic and nutrient-deprived conditions. Rather than using the electron transfer chain within the mitochondria to yield 36 mol ATP per mol glucose, cancer cells metabolize glucose via glycolysis, generating a net 2 mol ATP per mol glucose metabolized (the Warburg effect). As a result, cancer cells are metabolically fragile and are unable to cope as readily with cellular damage. This may be particularly relevant for drugs that block the effects of growth factors, because growth factor depletion produces rapid downregulation of nutrient transporters, which would lead to metabolic crisis in cancer cells more rapidly than in normal cellular counterparts.

Another concept is that tumor cells exhibit “oncogene addiction” and that inhibition of one or more of these oncogene products rapidly results in apoptotic cell death in “addicted” cancer cells but not in normal counterparts. Thus, tumor cells that depend on their survival by overexpression of a growth factor receptor (e.g., EGFR) would be more susceptible to inhibitors than are normal cells.

Drugs Affecting Growth Factors and Growth Factor Receptors

Cancer cells usurp the mechanisms of normal cell division, which results from the interaction of growth factors with specific receptors (plasma membrane, cytoplasmic, or nuclear). This initiates a signal transduction cascade culminating in activation of nuclear transcription factors that produce cell-proliferation and cell-viability molecules. Thus, it stands to reason that some of our most effective drugs target growth factors or their receptors (see Table 46-1 ) and the downstream consequences of this interaction that include activation of protein kinases, replication of DNA, transcription of mRNA, synthesis of new proteins, formation of the mitotic spindle through microtubule polymerization, and creation of interphase daughter cells via microtubule depolymerization (see Table 46-2 ). In addition, the nutrient requirements of cancer cells create an increased dependence on the uptake of glucose (the basis for positron emission tomography or PET scan) and the ability to sustain energy requirements through frequent alterations in the PI3K/AKT/mTOR pathway and activation of autophagic cell survival ( Figure 46-2 ).