Pharmacology of Antineoplastic Agents (PP553 exam #2)

Replace hydrogen atoms with an alkyl radical causing covalent bonds with electron rich nucleic acids, proteins, amino acids, and glutathione leading to misreading of DNA code, cross-linking of DNA, single or double strand breaks, and inhibition of DNA, RNA, and protein synthesis

Subgroup of Alkylating agents with additional MOA of inhibiting DNA replication

Disrupt nucleic acid synthesis (work only on dividing cells in S phase) by either:
1. interfering with normal synthesis of nucleic acid by falsely substituting for purines or pyrimidines in the metabolic pathway
2. competitively binding for enzymes which process the purines and pyrimidines into DNA and therefore inhibit the synthesis of DNA

Bind to dihydrofolate reductase, resulting in depletion of reduced folates (tetrahydrofolate), which is necessary for thymidine and purine synthesis (thus inhibiting DNA synthesis) cell cycle specific

Metabolized to fluorodeoxyuridine monophosphate, (FdUMP), which, in the prescence of folates, binds tightly and interferes with thymidylate synthetase (enzyme required for synthesis of thymidine)

Phosphorylated to the active triphosphate form which competes with deoxycytidine for DNA polymerase, inhibiting DNA synthesis

Inhibits de novo nucleotide production

Covalent bond with topoisomerase I; binding allows uncoiling of double strand DNA which results in single-stranded DNA breaks

Intercalation of an area of the DNA double helix thus preventing DNA transcription and replication

Semi-synthetic podophyllotoxins that bind to tubulin; cell damage caused by DNA strand breaks through topoisomerase inhibition

Bind to microtubular proteins, which are essential contractile proteins of the mitotic spindle; arrest mitosis at the metaphase (cell-cycle specific)

Bind to tubulin, inducing the formation of aberrant, stabilized microtubules

Analogue of epitholene B, inhibits microtubules, arresting cell division in mitotic phase, causing cell death

Active metal complex causes single and double strand breaks via intercalation folowed by production of free radicals from oxygen (inhibits DNA replication)

Hydrolyzes the circultating aminoacid L-asparagine into aspartic acid, thus indirectly inhibiting protein synthesis.

Blocks DNA synthesis by inhibiting the enzyme ribonucleotide reductase

Initially stimulate release of gonadotropins, followed downregulation of pituitary receptors for LHRH (resulting in downregulation due to excessive stimulation). Pituitary stops producing FSH adn LH and eventually testes stop production of testoterone and ovaries stop production of estrogen.

Blocks estrogen receptors in most hormonal tissues. Stimulates production of transforming growth factor beta (inhibitory growth factor)

Non-steroidal inhibitors of corticosteroid synthesis; inhibits conversion of circulating androgens into estrogens

May slow DNA synthesis through inhibition of glucose transport or phosphorylation, leading to a decrease of cellular energy

Induces the enzyme, 17-hydrooxysteroid dehydrogenase, which oxidizes estradiol to the less potent form, estrone. Also activates estrogen sulfatransferase, which catalyzes the sulfation of estrogen to less active forms, thus antagonizing growth

Inhibits BCR-ABL tyrosine kinase (abnormal gene of the Ph chromosome in CML) specific inhibitor of the translocation-created enzyme, works by blocking the rapid growth of white blood cells

Inhibits the intracellular phophorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermals growth factor (EGFR-TK), (blocks growth stimulatory signals in cancer cells)

Human epidermal growth factor receptor Type 1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor

Targets the tyrosine kinase domains of HER-2 and EGFR-1, inhibiting growth of tumor cells and causing apoptosis.

Inhibits TK domains of VEGFR and other factors associated with metastasis and cell proliferation

Target receptors that are unique to or overexpressed in tumors

Reacts with CD20 (a B lymphocyte surface antigen) and depletes normal and malignant B cells; it also binds complement and increases antibody-dependent cell-mediated cytotoxicity

Antibody directed against HER/2 receptors on some breast cancer cells

Antibody to CD33 (expressed on leukemic blasts on > 80% in AML)

MOA: After binding, ozogamicin is released inside the myeloid cell, binding to DNA and causing double-stranded breaks

Binds to CD20, resulting in apoptosis

Radiolabeled monoclonal antibody for refractory non-Hodgkin's lymphoma

targets the EGFR and blocks the ability of EGF to initiate receptor activation and signaling to the tumor. Blockade results in an inhibition of tumor growth by interfering with the effects of EGFR activation including tumor invasion and metastases, cell repair and angiogenesis

binds to EGFR, resulting in interference of EGFR signaling, producing an anti-tumor effect.

Radiopharmaceutical for one type of non-Hodgkin's lymphoma, used with Rituxan

Diagnostic imagining agent

Anitiviral and antitumor effects of interferons are thought to be due to induction of enzymes that inhibit the synthesis of protein and DNA (block viral replication, suppress cell proliferation, enhances phagocytosis by macrophages)

Immunoregulatory protein produced by lymphocytes that exhibits a wide range of immunologic effects. It has no direct antitumor activity, but mediates its cytotoxicity through activation of effector cells including T-cells, natural killer cells, and lymphokine-activated killer cells

Fusion protein designed to direct the cytocidal action of diptheria toxin to cells which express the IL-2 receptor

Recombinant humanized monoclonal IgG1 antibody that binds to and inhibits a natural protein called human vascular endothelial growth factor (VEGF) which plays a role in the formation and maintenance of tumor blood vessels; works by targeting and inhibiting the function of a natural protein called "vascular endothelial growth factor" that stimulates new blood vessel formation.

Inhibits TNF-alpha, reduces phagocytosis by neutrophils, increases production of interleukin-10, alters adhesion molecule expression, and enhances cell-mediated immunity via interactions with T-cells

Angiogensis inhibitor

Proteasome inhibitors

Interacts with retinoic acid receptor to terminally differentiate leukemic promyeloblasts

Other MOA

Synthetic retinoid analogue that selectively activates a subclass of retinoid receptors called retinoid X receptors (RXR); once activated, they regulate cell differentiation, proliferation, and apoptosis

Chemoprotectants