Chemical carcinogens.Carcinogenesis is a multistep process involving a sequence ofinitiation (mutation) followed by promotion (proliferation). Initiators can be either direct-acting chemical carcinogens (mutagens which cause cancer directly by modi-fying DNA) or indirect-acting chemical carcinogens (procarcinogens which require metabolic conversion to form active carcinogens). Promotors cause cellular prolif-eration of mutated (initiated) cells, which may lead to accumulation of additional mutations.
· Clinically important chemical carcinogens are numerous, and include nitro-samines (gastric cancer), cigarette smoke (multiple malignancies), polycyclic aromatic hydrocarbons (bronchogenic carcinoma), asbestos (bronchogenic carcinoma, mesothelioma), chromium and nickel (bronchogenic carcinoma), arsenic (squamous cell carcinomas of skin and lung, angiosarcoma of liver), vinyl chloride (angiosarcoma of liver), aromatic amines and azo dyes (hepa-tocellular carcinoma), alkylating agents (leukemia, lymphoma, other cancers), benzene (leukemia), and naphthylamine (bladder cancer). Potential carcino-gens are screened by the Ames test, which detects any mutagenic effects of potential carcinogens on bacterial cells in culture; mutagenicity in vitro cor-relates well with carcinogenicity in vivo.
Radiation.Ultraviolet B sunlight is the most carcinogenic because it produces pyrim-idine dimers in DNA, leading to transcriptional errors and mutations of oncogenes and tumor suppressor genes, thereby increasing the risk of skin cancer. Xeroderma pigmentosum is an autosomal recessive inherited defect in DNA repair, in which the pyrimidine dimers formed with ultraviolet B sunlight cannot be repaired; this defect predisposes to skin cancer. Ionizing radiation includes x-rays and gamma rays, alpha and beta particles, protons, and neutrons. Cells in mitosis or the G2 phase of the cell cycle are most sensitive to radiation. Radiation causes cross-linking and chain breaks in nucleic acids. Atomic bomb survivors experienced an increased incidence of leukemias, thyroid cancer, and other cancers. Uranium miners historically had increased lung cancer, related to inhalation of radioactive radon, which is a decay product of uranium.
RNA oncogenic viruses.Human T-cell leukemia virus (HTLV-1) causes adult T-cellleukemia/lymphoma.
DNA oncogenic viruses include the following:
· Hepatitis B virus (hepatocellular carcinoma)
· Epstein-Barr virus (EBV), which has been implicated in Burkitt lymphoma, B-cell lymphomas in immunosuppressed patients, nasopharyngeal carcinoma
· Human papilloma virus (HPV), which causes benign squamous papillomas (warts-condyloma acuminatum) and a variety of carcinomas (cervical, vulvar, vaginal, penile, and anal)
· Kaposi-sarcoma-associated herpesvirus (HHV8) which causes Kaposi sarcoma
Loss of immune regulation.Immunosurveillance normally destroys neoplastic cellsvia recognition of “non-self” antigens, and both humoral and cell-mediated immune responses play a role. Patients with immune system dysfunction have an increased number of neoplasms, especially malignant lymphomas.