Mechanisms of Oncogenic ADRs

Oncogenesis is a complex process involving genetic and epigenetic changes that result in an imbalance between cell division and apoptosis (programmed cell death).¹ Among the known factors implicated as potential "initiators" and/or "promoters" of cancer are tobacco, alcohol, solar radiation, ionizing radiation, occupational carcinogens, environmental pollutants, infectious agents, nutrients, and rarely, medications.

Primary oncogenic effects can be produced by drugs (initiators) that damage DNA or by drugs (promoters) that facilitate proliferation of cells carrying precancerous mutations.¹ Drugs that act as initiators are drugs that have been converted into reactive metabolites by polymorphic oxidation reactions. These reactive metabolites bind covalently to DNA in proto-oncogenes or tumor-suppressor genes, modify DNA, and lead to mutations.

Proto-oncogenes are normal genes that promote cell division. Oncogenes are proto-oncogenes, which through amplification or mutation became permanently activated allowing abnormal cells to survive and proliferate. Tumor suppressor genes are normal genes that slow down cell division, repair damaged DNA, or initiate apoptosis. Through mutations, tumor suppressor genes are inactivated leading to uncontrolled cell growth.

For example, activated oncogenes and inactivated tumor suppressor genes may alter the expression of cell-cycle regulatory proteins (e.g., cyclin-dependent kinases) that govern the initiation, progression, and completion of cell-cycle events, causing overexpression of cyclins and loss of expression of cyclin-dependent kinase inhibitors. Deregulated cyclin-dependent kinase activity provides malignant cells with a selective growth advantage.

Secondary oncogenic effects are related to therapeutic immunosuppression. Reactivated latent oncogenic viruses can induce mutations, gene amplifications, or chromosome rearrangements in host DNA.⁶ There are seven known human oncogenic viruses (Table 1). Human oncogenic DNA viruses include the Epstein-Barr virus, human papilloma viruses, hepatitis B virus, and herpes simplex virus-8, and Merkel cell polyomavirus. Human oncogenic RNA viruses include human T-lymphotropic virus type 1 and hepatitis C virus.