Drug-based systemic therapy is used primarily as (1) the major treatment modality for a few types of curable malignancies, such as Hodgkin disease and other hematopoietic cancers, acute leukemia in children, and testicular cancer in men; (2) palliative treatment for many types of advanced cancers; and (3) adjuvant treatment before, during, or after local treatment (surgery and/or radiotherapy) with the dual aims of both eradicating occult micrometastases and of improving local control of the primary tumor. Such treatments usually involve a combination of drugs. The most important factors underlying the successful use of drugs in combination are (1) the ability to combine drugs at close to full tolerated doses with additive effects against tumors and less than additive toxicities to normal tissues and (2) the expectation that drug combinations will include at least 1 drug to which the tumor is sensitive. Since the first documented clinical use of chemotherapy in 1942, when the alkylating agent nitrogen mustard was used to obtain a brief clinical remission in a patient with lymphoma, there have been continuous efforts to develop new, effective anticancer therapies. Initially focused on cytotoxic chemotherapies (the pharmacology of which are described in Chap. 18), the number and range of cancer drugs has expanded, with more than 200 drugs or biologic agents licensed for use in North America, and many more undergoing clinical trials. New types of anticancer agents that have emerged include monoclonal antibodies (such as trastuzumab, cetuximab, bevacizumab, and blinatumomab) that target cell surface receptors, and small molecules that interact with various cell signaling or survival pathways (eg, imatinib, erlotinib, afatinib, venetoclax). These newer “targeted” agents (reviewed in Chap. 19) represent a substantial shift in emphasis in anticancer drug therapy. In contrast to conventional cytotoxic agents, which usually target proliferating cells and interact with DNA, these target specific pathways that interfere with various functions of the cell including those that promote cell division (trastuzumab, imatinib), cell survival, and apoptosis (venetoclax) or contribute to immune-mediated cellular damage (blinatumomab). Other agents, such as those that inhibit angiogenesis (eg, bevacizumab; see Chap. 11) act indirectly to inhibit tumor growth.
This chapter deals with the scientific basis of cancer drug discovery. It introduces the concepts of how cancer drug targets are identified and some of the approaches used to discover and design new drugs. The chapter also discusses the biologic properties of important anticancer drugs, experimental methods used to determine their activity, their toxicity to normal tissues, the concept of therapeutic index, and the biologic basis of using drugs in combination and with radiotherapy. The many causes of drug resistance are addressed in Chapters 18 and 19.
17.2 STRATEGIES TO DEVELOP ANTICANCER DRUGS
17.2.1 High Throughput DNA Sequencing
Although many chemotherapy drugs were developed by observing effects of compounds on cancer cells in culture and in experimental animals without knowledge of a ...