Important discoveries have revealed the molecular basis for the transformation, proliferation, and survival of cancer cells. These advances have revealed new targets for cancer drug design, and have produced agents that inhibit the signaling molecules and pathways responsible for cancer (Figure 10-1) (1). These inhibitors of cancer-associated targets include monoclonal antibodies (mAbs) either alone or coupled with cytotoxic agents or radioisotopes; modified proteins and peptidomimetic molecules; and small-molecular-weight drugs. Still in the development stage are small interfering RNAs (siRNA), antisense oligonucleotides, gene therapy approaches, and ribozymes or DNAzymes. In this chapter we will consider the small molecules that have been approved for clinical use. Monoclonal antibodies and their conjugates will be considered elsewhere (Chapter 15) (see Table 10-1) (2,3,4,5,6,7,8,9).
Schematic of growth factor receptor signaling in tumor cells.
TABLE 10-1 |Favorite Table|Download (.pdf) TABLE 10-1
|Agent ||Target of Inhibition ||Plasma T 1/2 ||Pharmacokinetics ||Dose Adjustment (% Reduction of Recommended Dose if Available) ||Drug Interactions |
|Liver Dysfunction2 ||Renal Dysfunction (CrCl in mL/min) ||Severe Toxicities (BBW in Bold) ||CYP Inh.* ||CYP Ind.# ||Inh. CYP** ||Others |
|Monoclonal antibodies |
|Trastuzumab ||HER2 ||5.8 d ||Likely eliminated via RES ||None ||None ||Cardiotoxicity, reduced LVEF, serious infusion reactions, pulmonary toxicities, nephrotic syndrome (rare) ||No ||No ||No ||Anthracyclines, paclitaxel and cyclophosphamide—increased cardiotoxicity. Paclitaxel—increased levels |
|Pertuzumab ||HER2 ||18 d || ||None (not studied) || |
CrCl > 30: none
CrCl < 30: none (not studied)
|Cardiotoxicity, reduced LVEF, serious infusion reactions, embryo-fetal toxicity ||No ||No ||No ||None reported |
|Ibritumomab Tiuxetan Y-90 ||CD20. Tiuxetan links the antibody and Y-90, a high-energy beta emission ||27–30 h ||6–11% renal excretion, 7.2% parent compound ||None ||None ||Serious infusion reactions, severve cytopenias, cut. and mucocut. reactions, radiation injury ||No ||No ||No ||Several medications (including, but not limited to, aspirin, clopidogrel, warfarin, heparin, enoxaparin, dalteparin, fondaparinux)—bleeding |
|Tositumomab I131 ||CD20. Binding of the I131 loaded antibody and beta emission ||8 d || ||None ||None ||Infusion-related reactions, prolonged and severe cytopenias, anaphylactic reactions ||No ||No ||No ||None reported |
|Rituximab ||CD20 ||5–78 d || ||None ||None ||Serious infusion reactions, TLS, severe mucocut. Reactions, PML ||No ||No ||No ||Cisplatin—renal failure. Infection by live vaccines. Inadequate immunologic response to influenza and pneumococcal vaccine |
|Alemtuzumab ||CD52 on several immune cells ||12 d || ||None ||None ||Cardiotoxicity, serious infusion reactions, infections, cytopenias ||No ||No ||No ||Increased risk of infection by live vaccines |
|Ofatumumab ||CD20 ||12–14 d || ||None ||None ||Infusion-related reactions ||No ||No ||No ||None reported |
|Brentuximab Vedotin ||CD30. Internalization and disruption of microtubules by MMAE inhibiting cancer cell growth ||4–6 d ||Metabolizaed by CYP3A4/5. 24% renal excretion ||None (not determined for MMAE) ||None (not determined for MMAE) ||Neutropenia, PNP, PML ||Yes ||No ||No ||Bleomycin— increased lung toxicity |
|Ipilimumab ||CTLA4 ||14.7 d || ||None ||None...|
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