|
The common mechanism underlying the cytotoxicity of most antitumor agents is cell cycle arrest. Antitumor agents primarily target neoplastic cells at the surface of the cancer tumor and smaller tumors with short mass-doubling time. Several antitumor agents work by inhibiting DNA replication and terminating cell division at S phase. Alkylating agents and platinum-containing compounds form intrastrand cross-links to prevent DNA replication. Anthracyclines and anthracenediones intercalate between G–C base pairs and prevent RNA transcription. Intercalation can also interfere with topoisomerase II-mediated strand reunion, resulting in double-strand breaks in DNA. Intercalated doxorubicin and bleomycin form complexes with ferric and ferrous ions that release reactive oxygen species (ROS), which can induce both single-strand and double-strand breaks to damage DNA.
Antimetabolites prevent the production of thymidine and purine bases required for DNA repair and synthesis. Other antitumor compounds interfere with cancer cell proliferation by directly preventing DNA synthesis or by inhibiting DNA repair enzymes such as topoisomerase II or telomerase. Microtubule inhibitors stop cell proliferation by blocking the assembly or the depolymeration of the mitotic spindle, terminating the cell cycle at metaphase.
The activity of other antitumor agents requires the expression of specific receptors or enzymes. For example, the selective estrogen response modifiers block the proliferation of estrogen-sensitive tumor cells by directly blocking estrogen receptor-induced gene transcription while aromatase inhibitors interfere with the synthesis and resulting availability of estrogen.
Additional mechanisms of action are under investigation, such as the use of retinoids or transforming growth factors to induce tumor cell differentiation, the use of antiangiogenic agents to block tumor vascularization and metastasis, and the application of cytokines and growth factors to enhance immune system function.
Antitumor Agents
|
