Block 2 Drugs

Front 1

Alkylating agent

Back 1

Become reactive in aqueous solution and react with DNA to add bulky alkyl groups to N7 of guanine. Results in base pair errors, interstrand and intrastrand cross-links, and damaged DNA recognition. Ex. cyclophosphamide

Front 2

Platinum

Back 2

Inside the cell, Cl, cyclohexane and oxalate ligands are displaced by H2O, leaving the platinum (+) charged and highly reactive. Pt then bind to nucleophilic sites on DNA, adding bulky adducts (esp. to N7guanine) interfering w/ base pairing and DNA replication, and can cause single and double strand breaks and apoptosis.
Ex. cisplatin is a radiation sensitizer used in head and neck, lung, esophageal cancers and is esp. powerful in germ cell carcinomas.

Front 3

Antimetabolite

Back 3

Purine or pyrimidine analogs that interfere w/ normal cell function, esp. w/ DNA and RNA synthesis. Most inhibit formation of nucleosides, DNA replication, or are incorporated into DNA, leading to strand termination or base mismatches.

Ex. 5-fluorouracil disrupts pyrimidine synthesis by inhibiting thymidylate synthase, thereby reducing number available for DNA repair. It also incorporates into DNA and RNA (may result in strand breakage as a result of DNA repair).

Front 4

Microtubule-inhibitor/stabilizers

Back 4

Vinca bind to beta tubulin and block polymerization w/ alpha tubulin into microtubules, leading to apoptosis. Ex. vincristine

Taxanes bind to tubulin and stabilize microtubule conformations leading to apoptosis. Ex. paclitaxel

Front 5

5alpha-reductase inhibitor

Back 5

Inhibits conversion of testosterone to DHT (a potent stimulator of prostate cell proliferation).
Ex. finasteride

Front 6

Selective estrogen response modifiers (SERMS)

Back 6

Bind to ER and induce conformational change, as well as recruit coregulatory proteins w/ + or - effects on transcription. Effect depends on levels of ERalpha and beta in tissues (all are antagonists to beta).
Ex. tamoxifen is an ER antagonist in breast tissue and hypothalamus (inhibiting proliferation), but agonist in endometrium and bone.
Ex.2 raloxifene is like tamoxifen but has a neutral effect on endometrium.
Both only work on ER+ or PR+ breast cancer.

Front 7

Aromatase Inhibitors

Back 7

Inhibit conversion of androstenedione and testosterone to estradiol in post-menopausal women. Not indicated for pre-menopausal women, b/c lowered E2 levels feedback to the pituitary causing the ovaries to produce more androgens, countering AIs' effect and causing ovarian cysts. Ex. anastrazole

Front 8

Imatinib (Gleevac)

Back 8

Small molecule used in CML treatment. Blocks binding of ATP to BCR-ABL tyrosine kinase, inhibiting its activity. Prone to resistance possibly due to point mutations in BCR-ABL gene leading to altered drug binding or amplification of BCR-ABL gene. Can achieve a complete cytogenic response w/ FISH, but most pts will have detectable leukemia thru RT-PCR - indicates drug acts by inhibiting proliferation rather than inducing apoptosis of immature leukocytes.

Nilotinib and Dasatinib are options if resistance to imatinib develops.

Front 9

Poly (ADP-Ribose) Polymerase (PARP) Inhibitors

Back 9

PARP is a nuclear protein activated when DNA is damaged that works primarily to repair ssDNA breaks thru BER. Inhibiting PARP results in ssDNA breaks turning into dsDNA breaks, leading to apoptosis in homologous recombination (HR) deficient cells. Since BRCA1/2 are HR repair genes, breast cancer cells lacking these are esp. sensitive to loss of PARP.

Front 10

GnRH agonists

Back 10

Continuous GnRH exposure eventually causes downregulation of GnRH receptors on pituitary gonadotrophs leading to inhibition of LH/FSH release and inhibition of estrogen release. Ex. Goserelin.

Front 11

Trastuzumab

Back 11

Monoclonal antibody targeted against the EC domain of the HER2 receptor. Binding to HER2 prevents activation of HER2's IC tyrosine kinase via several proposed mechanisms: inhibition of receptor dimerization, inhibition of shedding of the EC domain, increased endocytotic degradation of the receptor, or recruitment of immune cells.

Front 12

Erlotinib

Back 12

Small molecule tyrosine kinase inhibitor of EGFR1 (overexpressed in lung cancer); inhibits receptor phosphorylation via binding to ATP binding pocket of receptor. Ex. Tarceva

Front 13

Cetuximab

Back 13

Monocolonial antibody to EGFR1 given intravenously

Front 14

Bevacizumab

Back 14

Monoclonal antibody that binds to VEGF (the ligand) to prevent vascularization of tumors. Different from other cancer drugs b/c it targets genetically stable endothelial cells, which are less likely to mutate to resistance.

Front 15

Biguanides

Back 15

Metformin - works thru AMPK pathway to increase cellular AMP levels -> works in liver to reduce gluconeogenesis.
Insulin sensitizer.

Front 16

Sulfonylurea/Miglinitide

Back 16

Binds ATP-sensitive K+ channels on surface of pancreatic cells -> stimulates exocytosis of insulin vesicles.

Front 17

Alpha-glucosidase inhibitors

Back 17

Blocks breakdown of complex carbs into glucose
Ex. acarbose, miglitol

Front 18

Incretins

Back 18

Gut hormones that amplify insulin secretion and suppress glucagon after meals.

Ex. Sitagliptin, exenatide

Front 19

Beta-blockers

Back 19

Reduce symptoms of hyperthyroidism by reducing the thyroid hormones effects on beta-adrenergic receptors.

Front 20

Thionamides

Back 20

Treatment for hyperthyroidism that inhibit the activity of thyroid peroxidase at its three rxns in synthesis of T3/T4

Front 21

Lapatinib

Back 21

Small molecule Her2/neu inhibitor that binds the intracellular portion of receptor. Less resistance to this drug.

Front 22

Thiazolidinediones

Back 22

TZD - PPAR-gamma agonist that results in increased GLUT4 expression, decreased FFA levels, and increased adiponectin release from adipocytes.
Ex. Rosiglitazone