Medchem Exam 1 part 2

• Loss of cell growth
• decreased cell differentiation
• ability to invade surrounding tissue
• ability to establish new growth at ectopic sites (metastasis)

prevent cancer cells from multiplying, invading and metastasizing

• <100 different tumor types
• cancer cells similar to normal cells
• Tumor eradication elicits an immune response
• Cancer drug toxicity

• cell proliferation
• cell death

gene overexpressed in cancer cells

• RB binds cyclin D and is phosphorylated by CDK4
• Structure opens and releases Cyclin D

• Drives cell cycle much faster
• 20-30% of cancer cases
• 2nd major mutation
• high [CDK4]
• high [cyclin D]
• low [P16]

• transcription factor that functions as a "tumor suppressor"
• senses DNA problems and stops cell cycle
• -50% of cancer patients have mutated p53
• -causes resistance to some types of chemotherapy

• Cancer drugs work by damaging DNA to induce p53 mediated apoptosis
• -mutated p53 = drug may not work

Inhibits specific proteins or enzymes required for specific phases of the cell cycle

Only a fraction of cells are in the specific phase for the drug to act

• Altered metabolism
• Decreased uptake of drug into cell
• increased target
• defective apoptosis

• no receptors present
• poor perfusion of large solid tumors

• Decreased uptake mediated by P-glycoprotein
• Increased glutathions which neutralize alkylating agents, platinum compounds and antibiotics
• Decreased DNA topoisomerase II

• Normal tissues undergo damage from anti-cancer drug
• supplementary drugs allviate toxic effects or stimulate normal cells

• Do not use 2 phase specific drugs targeting the same phase
• Combination therapy is more effective than monotherapy

• decrease resistance
• decrease toxicity
• target different cell cycle phases

• Alkylating Agents
• Antimetabolites
• Natural Products
• Miscellaneous Agents
• Hormones and Antagonists

• Nitrogen Mustards
• Ethyleneimines
• Alkyl sulfonates
• Nitrosoureas
• triazenes

• platinum complex
• methylhydrazine

• Produce cytotoxic, mutagenic and carcinogenic effects by reacting with cellular DNA
• -N7 bond of guanine is susceptible to forming bonds with alkylating agents
• -Alkylated guanine mispairs with thymine
• Consequences trigger p53 mediated apoptosis

nitrogen mustards

prodrug which is activated by cytochrome p450 enzyme

• Platinum coordination complex
• Very effective in testicular and ovarian cancer
• Toxic to kidney and GI tract

• Enters cell via diffusion or active Cu²⁺ transporter
• Covalently binds to nucleophilic sites on DNA

• Prevent biosynthesis or use of normal cellular metabolites
• Drug closely related to structure of metabolite it antagonizes
• S-phase specific

• Folic Acid analogs
• Pyrimidine analogs
• Purine analogs

• Methrotrexate inhibits dihydrofolate reductases (DHFR)
• Undergoes conversion of polyglutamates which inhibit thymidylate synthesis

• Drug analogs of A,C and T must countain sugar group
• -cannot be synthesized in the cell
• Halogenated Pyrimidines
• -Flourine
• -Prevents methylation of 5 position by thymidylate synthase (TS)

• Loss or decreased activity of enzymes necessary for activation of 5-FU
• Amplification of TS
• Mutation of TS that is not inhibited (most common)
• Insufficient concentrations of cofactor required to lock TS in inactive state
• -5,10-methylene tetrahydrofolate

• Analog of 2'-deoxycytidine
• Hinders rotation of pyrimidine base around nucleosidic bond and interferes with base stacking
• Potent inhibitor of DNA polymerase

• Antiviral and anticancer
• Substitution of S for O creates compounds that are readily converted to nucleotides and incorporated into DNA

mitotane

bind to the glucocoricoid receptor and activate gene expression that leads to apoptosis

used for acute leukemia in children and malignant lymphoma in children and adults

• glucocorticoid
• suppress mitosis in lymphocytes

• competitive inhibitors of androgen receptor
• - AR blocker or Anti-androgens
• -Steroidal or non-steroidal

• Cause surge in LH and FSH leading to negative feedback of gonadotropin release
• complete androgen blockage

Blocks androgens from adrenals and gonads

• Selective estrogen-receptor modulators (SERMs)
• Selective estrogen-receptor downregulators(SERDs)
• Aromatase Inhibitors (AIs)

• Tamoxifen
• partially inactivated transcription of estrogen genes

• "Pure anti-estrogens"
• Binds 100x stronger than tamoxifen to ER
• -inhibits dimerization
• -increases degredation
• No transcription of estrogen genes will occur

• Aromatase is responsible for conversion of androstenedion and testosterone to estrogens
• 1st, 2nd and 3rd Generations
• 3rd Gen has 2 types
• -Type 1=binds irreversibly "suicide substrate"
• -Type 2=binds reversibly