Important clinical considerations emerge from the principles presented in the foregoing discussion of the hallmarks of cancer: These hallmarks provide a road map for the development of new therapeutic agents for the treatment of cancer (
Fig. 6.31
ETIOLOGYOFCANCER:CARCINOGENICAGENTS
Carcinogenic agents inflict genetic damage, which lies at the heart of carcinogenesis. Three classes of carcinogenic agents have been identified: (1) chemicals, (2) radiant energy, and (3) microbial products. Chemicals and radiant energy are documented causes of cancer in humans, and oncogenic viruses are involved in the pathogenesis of tumors in several animal models and some human tumors. In the following discussion, each class of agents is considered separately; of note, however, several may act in concert or sequentially to produce the multiple genetic abnormalities characteristic of neoplastic cells.
More than 200 years ago, the London surgeon Sir Percival Pott correctly attributed scrotal skin cancer in chimney sweeps to chronic exposure to soot. On the basis of this observation, the Danish Chimney Sweeps Guild ruled that its members must bathe daily. No public health measure since that time has achieved so much in the control of a form of cancer. Subsequently, hundreds of chemicals have been shown to be carcinogenic in animals.
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EGFR inhibitors Aerobic glycolysis inhibitors Telomerase inhibitors Proapoptotic BH3 mimetics Selective anti-inflammatory drugs Sustaining proliferative signaling Inducing angiogenesis Activating invasion and metastasis Deregulating cellular energetics Resisting cell death Enabling replicative immortality Tumor-promoting inflammation Cyclin-dependent kinase inhibitors Immune activating anti-CTLA4 mAb Inhibitors of VEGF signaling MDM2 inhibitors Inhibitors of HGF/c-Met Evading growth suppressors Avoiding immune destruction Genome instability and mutation
Fig. 6.31 Therapeutictargetingofthehallmarksofcancer.(From Hanahan D,Weiberg RA:The hallmarks of cancer: the next generation. Cell144:646, 2011.)
Some of the major agents are presented in
Table 6.5.
A few comments on a handful of these are offered next.
Direct-acting agents require no metabolic conversion to become carcinogenic. They are typically weak carcinogens but are important because some of them are cancer chemotherapy drugs (e.g., alkylating agents) used in regimens that may cure certain types of cancer (e.g., Hodgkin lymphoma), only to evoke a subsequent, second form of cancer, usually leukemia. This situation is even more tragic when the initial use of such agents has been for non-neoplastic disorders, such as rheumatoid arthritis or granulomatosis with polyangiitis. The associated risk for induced cancer is low, but its existence dictates judicious use of such agents.
The designation indirect-acting refers to chemicals that require metabolic conversion to an ultimate carcinogen.
Some of the most potent indirect chemical carcinogens are polycyclic hydrocarbons that are created with burning of fossil fuels, plant, and animal material. For example, benzo[a]pyrene and other carcinogens formed during the combustion of tobacco are implicated in the causation of lung cancer, and in olden days, benzo[a]pyrene created during the burning of coal was likely responsible for the high incidence of scrotal cancer in chimney sweeps. Polycyclic hydrocarbons also may be produced from animal fats during the process of broiling meats and are present in smoked meats and fish. In the body, benzo[a]pyrene is
Table 6.5 Major Chemical Carcinogens
Anti-cancerdrugs(cyclophosphamide,chlorambucil,nitrosoureas,andothers)