Jae Kyung Roh

Alkylating Anticancer Drugs

Alkylating agents are the first chemotherapeutic anticancer agents developed, and account for the largest drug group among conventional cytotoxic chemotherapeutics. This class is largely divided into three subgroups: classical alkylating agents, nonclassical alkylating agents, and alkylating-like agents. Classical alkylating agents include nitrogen mustards, nitroso ureas, aziridines, and alkyl sulfonates. Nonclassical alkylating agents include hydrazine, triazene, and altretamines. In addition, the alkylating-like agent group, which functions by crosslinking with DNA similarly to alkylating agents, includes platinum compounds (Fig. 4.1).

Advancements in Bioscience and New Cancer Drugs

The parallel development of life science and cancer treatment after the introduction of the cell theory in 1838 can be briefly summarized as shown in Fig. 11.1. In the mid-1850s, cancer entered the field of science after being designated as neoplasm, which is defined as a new mass of cells created from the division of tumor cells.

Advancement of the Science and History of Cancer and Anticancer Drugs

Schleiden and Schwann first reported the Cell Theory in 1838, and Remak and R. C. Virchow advocated this theory for cancer in the mid-1850s. They named cancer “neoplasm,” which was defined as a new mass of cells that emerges from abnormal proliferation of cells (Fig. 2.1). Thus, cancer was introduced into the field of science, was scientifically defined, and became an object of study.

Hormonal Anticancer Drugs

Paul Ehrlich, a pioneer in chemotherapy, experienced many failures while developing anticancer chemotherapy due to the indiscriminate toxicity of chemotherapy drugs. In 1915, based on his experience, he stressed on the importance of understanding the biological difference between normal cells and cancer cells for the development of a cancer-specific magic bullet. This suggestion was realized with the invention of targeted anticancer agents after decades of basic research in the field of cancer biology. Another example of an anticancer drug that was successfully developed after understanding the biological characteristics of a specific cancer is the hormonal anticancer drug.

Natural Product Anticancer Drugs

Natural product anticancer drugs that are used clinically include compounds isolated from plants such as the vinca alkaloids, taxane/taxane analogues, podophyllotoxin derivatives, and camptothecin derivatives, as well as anticancer antibiotics isolated from various Streptomyces species such as anthracycline/anthracenedione, bleomycin, and actinomycin (Fig. 6.1). Vinca alkaloids and taxane/taxane analogues exhibit anticancer effects by inhibiting the microtubule function of spindle fibers, which is related to chromosome segregation, while podophyllotoxin derivatives, camptothecin derivatives, and other antibiotics cleave DNA bases, causing DNA damage through the suppression of topoisomerase I or II and the production of free radicals.

Immunotherapeutic Anticancer Drugs and Other Miscellaneous Anticancer Drugs

Immunotherapeutic anticancer agents eliminate cancer cells by acting on the immune system and activating the immune response against cancer cells. This class of drugs includes cytokines such as INFγ and IL2, nonspecific immune stimulants BCG and levamisole, and recently developed anti-CTLA-4 monoclonal antibody ipilumumab.

Molecular Targeted Anticancer Drugs

From the middle of the 1960s, combination chemotherapy was at the center of chemotherapy for cancer. Following successful treatment of various hematologic malignancies through combination chemotherapy, significant effort was aimed at utilizing such treatments in patients with solid cancers. Research into solid cancer treatment using combination chemotherapy was a core component of anticancer research programs from 1970s, but in spite of long-term, large-scale clinical trials, revolutionary results did not emerge, and the progression of anticancer chemotherapy has gradually slowed since 1980. Ultimately, in 2003, it was determined that mega-dose combination chemotherapy combined with bone marrow transplant was not superior than conventional combination chemotherapy in advanced breast cancer, and it was widely believed that cytotoxic chemotherapy had reached its limit as a treatment for solid cancer. The failure of mega-dose cytotoxic chemotherapy as a treatment for solid cancers showed researchers that a deep biological understanding of the complexity and diversity of individual types of cancer was essential for more effective cancer treatment.

Chronology of Anticancer Drug Development

Cancer was not recognized as a major cause of death in western industrialized countries until the nineteenth century, but the cancer-related mortality increased rapidly after the decrease in lethal infectious diseases, such as tuberculosis and typhoid, following national efforts to improve hygiene and public health. The decrease in these diseases also rapidly increased the average life span, and since the twentieth century, cancer has become one of the leading causes of death, demonstrating that it is highly age-dependent. In the United States, life expectancy increased from 47 to 68 years in the first 50 years of the twentieth century, and cancer had been the second most common cause of death since 1933 [1]. Following this, cancer therapy has emerged as a matter of the national concern, and the F.D. Roosevelt administration enacted the worlds first National Cancer Act in 1937, which sought the ways to overcome cancer at a national level by establishing the National Cancer Institute (NCI) that specialized in cancer research [2]. Later, European countries started making efforts to stop the spread of cancer, based on their national research institutions.

Antimetabolic Anticancer Drugs

Antimetabolic drugs bind to a specific enzyme and prevent normal metabolites from interacting with the enzymes, leading to inhibition of a specific metabolic pathway. Especially, the antimetabolic anticancer drugs interfere with DNA synthesis at multiple levels by inhibiting enzymes that utilize folic acid or synthesize the precursors of pyrimidine and purine, which are necessary for cell growth. In addition, some antimetabolites are directly incorporated into DNA, which inhibits DNA synthesis (Fig. 5.1). Therefore, these drugs are largely classified into folic acid derivatives that inhibit enzymes of folate pathway such as dihydrofolate reductase (DHFR), pyrimidine or purine derivatives that inhibit pyrimidine or purine synthesis, and direct inhibitors of DNA synthesis (Fig. 5.2).

Complications of Anticancer Drugs and Their Management

Anticancer therapy targets actively growing and dividing cells. Because of this characteristic, anticancer drugs assaults not only cancer cells but also normally proliferating cells such as blood cells, mucosal epithelial cells, and skin epithelial cells. Therefore, they inevitably have various side effects. Most of such side effects are mild and transient, but some can become severe and irreversible. To increase compliance with anticancer therapy and to maintain the quality of life of cancer patients, the complications of anticancer therapy must be well understood and properly managed.