Carcinogenic Agents

2021-02-24 12:00 AM

Chemical carcinogens. Carcinogenesis is a multistep process involving a sequence of initiation (mutation) followed by promotion.

CARCINOGENIC AGENTS

Chemical carcinogens. Carcinogenesis is a multistep process involving a sequence of initiation (mutation) followed by promotion (proliferation). Initiators can be either direct-acting chemical carcinogens (mutagens that cause cancer directly by modifying DNA) or indirect-acting chemical carcinogens (procarcinogens that require metabolic conversion to form active carcinogens). Promotors cause cellular proliferation of mutated (initiated) cells, which may lead to the accumulation of additional mutations.

  • Clinically important chemical carcinogens are numerous and include nitrosamines (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 the liver), vinyl chloride (angiosarcoma of the liver), aromatic amines and azo dyes (hepatocellular carcinoma), alkylating agents (leukaemia, lymphoma, other cancers), benzene (leukaemia), and naphthylamine (bladder cancer). Potential carcinogens are screened by the Ames test, which detects any mutagenic effects of potential carcinogens on bacterial cells in culture; mutagenicity in vitro correlates well with carcinogenicity in vivo.

 Radiation. Ultraviolet B sunlight is the most carcinogenic because it produces pyrimidine dimers in DNA, leading to transcriptional errors and mutations of oncogenes and tumour 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 leukaemias, 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.

Oncogenic viruses.

RNA oncogenic viruses. The Human T-cell leukaemia virus (HTLV-1) causes adult T-cell leukaemia/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 papillomavirus (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 cells via 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.