Med Chem Midterm

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Chemotherapy

Back 1

use of chemical agents to control and disease

has become synonymous with the treatment of cancer

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Neoplasm

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New growth

"cancer"

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Proto-oncogene

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a normal gene that can become an oncogene due to mutations or increased expression

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Tumor Suppressor Gene

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a normal gene that protects the cell from cancer

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Metastasis

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when cancer has spread from its primary site to other regions

cause of 90% of cancer deaths

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Apoptosis

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programmed cell death

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Cytotoxic Chemotherapy

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"toxic to cells"

quantitative rather than qualitative

most effective in rapidly dividing cells

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4 most common cancers

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Lung
Breast
Colorectal
Prostate

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Cancers that cause the most deaths

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Lung
Stomach
Liver
Colon
Breast
Cervical

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Causes of cancer

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1) Hereditary (5%) - passed down genetic material
2) Damage to genes during ones' life (95%) - inherited mutations, chemical exposures, infectious agents

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Properties of a cancer cell

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1) limitless potential of replication
2) Longer survival (evade apoptosis)
3) Genetic instability
4) Sustained angiogenesis
5) metastasis

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Role of apoptosis in cancer

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pathway can be altered

Characterized by: DNA fragmentation, chromatin condensation, membrane blebbing, fragmentation of the nucleus and cell

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Cell cycle in cancer chemotherapy

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many of most effective cancer treatments target it

virtually every step of cell growth/division has been targeted

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Combo of chemotherapy drugs for cancer

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various drugs work through different cytotoxic mechanisms and allow:
1) several molecular targets to be targeted at same time
2) decrease chance of tumor resistance
3) improves survival
4) can use at lower doses reducing toxic effects

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Alkylating agents

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1) nitrogen mustards
2) nitrosureas
3) Alkyl sulfonates
4) Triazenes
5) Platinum compounds

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Nitrogen mustard

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Cyclophosphamide

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Nitrosureas

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Carmustine

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Platinum Compound

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Cisplatin

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Target of Alkylating agents

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Nuclear DNA

agents are not cell cycle dependent

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Resistance to alkylating agents

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1) Increased DNA repair
2) Decreased drug permeability
3) Production of trapping agents

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Alkylating mainly react with what

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ring nitrogens and extracyclic oxygen

**N7 of guanine**

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Common ADRs of all alkylating agets

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1) myelosuppression
2) nausea and vomiting
3) Teratogenic
4) carcinogenesis

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Common ADR of Cyclophosphamide

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Nephrotoxicity

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Common ADR of Carmustine

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Myelosuppression
Acute pulmonary toxicity (high doses)

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Common ADRs of Cisplatin

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Nephrotoxicity (DLT)
Ototoxicity

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MOA and structure of Cyclophosphamide

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**2 chlorine atoms decrease basic strength of amino nitrogen

MOA:
1)first undergoes cyclization forming unstable aziridinium ion
2) unstable cation release Cl, tertiary amine transformed to quaternary ammonium
3) Aziridinium ring highly electrophilic and targeted by nucleophiles in DNA - react with N7 of quanine

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Metabolism of Cyclophosphamide

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Oxidized to 4-hydroxycyclophosphamide to Aldophosphamide (active) then to phosphoramide mustard and acrolein and lastly to active quarternary aziridinium ion

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Toxic metabolites of Cyclophosphamide

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Acrolein
Chloroacetaldehyde

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Structure and MOA of Carmustine

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**Very lipophilic, crosses BBB

MOA:
1) Lose protein
2) form vinyl diazotic acid and isocyanate
3) form vinyl carbocation and acetaldehyde

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Agents of Carmustine that alkylate DNA

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1) Vinyl carbocation
2) Acetaldehyde
3) 2-chloro-ethylamine

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Structure and MOA of Cisplatin

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**central Pt, 2 Cl and 2 ammonia in cis configuration

MOA:
1)high chloride prevents hydrolysis
2) enters cells, low chloride prompts cell to give positively charged species
3) attracted to negatively charged DNA
4) causes replication arrest, transcription inhibition, etc

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Groups of Antimetabolites

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1) Purine analogs
2) Pyrimidine analogs
3) Folate analogs

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Purine Analogs

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1) 6-Mercaptopurine (6-MP)
2) 6-Thioguanine (6-TG)
3) Cladribine

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Pyrimidine Analogs

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1) Capacetibine
2) 5-FU

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Folate Analogs

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1) Methotrexate
2) Pemetrexed
3) Pralatrexate

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Role of Cell Cycle for Antimetabolites

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Cell Cycle Dependent - kills in S-phase

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Structure and Admin of 6-Mercaptopurine

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1) analog of hypoxanthine
2) orally available as prodrug

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Structure and Admin of 6-Thioguanine

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1) Analog of Guanine
2) Orally available as prodrug

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Metabolism of a) 6-MP and b) 6-TG

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a) Extensive metabolism to 6-TGN (lethal in DNA)
b) metabolized directly to 6-TGN

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Full metabolism of 6-MP and 6-TG

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salvaged by HPRT and converted to monophosphate (TIMP or TGMP), diphosphate, then triphosphate

Kinases/Reductases generate GTP and thio-deoxy-GTP which are incorporated into RNA and DNA

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Pharmacogenomics of 6-MP and 6-TG

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Reduced TPMT activity (heterozygous)
(reduce dose 30-70%)

Deficient TPMT activity (homozygous)
(alternate agent)

**active drug accumulates (TOXIC) - severe bone marrow toxicity and myelosuppression**

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structure and advantages of Chlofarabine

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Analog of deoxyadenosine
2' chloroadenine base of cladribine
Fluoro group replacing 2'-hydroxyl grp

Advantages:
1) higher affinity for dCK (rate limiting)
2) decreased phosphorolytic cleavage
3) enhanced resistance to acid hydrolysis

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MOA of clofarabine

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1) incorporation into DNA and inhibit DNA polymerases
2) inhibit ribonucleotide reductase
3) induce apoptosis

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MOA of Nelarabine

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1) rapidly dealkylated to ara-G (active)
2) ara-G phosphorylated (mono-di-tri)
3) ara-GMP (mono) - ara-GTP (tri)
4) competes with dGT for incorporation into DNA
5) inhibits DNA synthesis and repair actions = chain termination

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Routes of administration of 5-FU

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1) Bolus injection = favors RNA damage (myelosuppresion)

2) Continuous Infusion = favors DNA damage (hand-foot syndrome)

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MOA of 5-FU

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*cell cycle specific*

1) prodrug - carried into cell and converted to f-dUMP
2) FdUTP mimics uracil and inhibits RNA replication and synthesis
3) FdUTP incorporates into DNA - incorrect base pairing
4) FdUMP competes for thymidylate synthetase (TS)

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Thymidylate Synthetase

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enzyme providing only means of adding a methyl group to a 5-position of the pyrimidine ring

inhibited by fdUMP

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Leucovorin and 5-FU

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increases formation of TS/5-FU complex
**promotes 5-FU inhibition of TS**

Helps 5-FU work better

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Capecitebine

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Prodrug of F-dUMP

Taken ORALLY

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Pharmacogenomics of 5-FU and Capecitabine

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Dihydropyrimidine Dehydorgenase (DPD) deficiency
**serious toxicity**
Partial DPD deficiency
**life threatening complications**

Genetic testing for DPD activity before use

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Methotrexate

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1) IMMUNOSUPPRESSIVE
2) cell cycle specific - kills in S phase
3) reversibly binds t dihydrofolate reductase (higher affinity than FH2) = depletion of FH4 (cell death)

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Pemetrexed

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1) multi-targeted antifolate (inhibits TS, DHFR,GARFT,AICARFT, C1-TSF synthase)
2) cell-cycle dependent
3) receive B12 and folic acid

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Pralatrexate

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1) has propargyl group substitution at C10
2) same target as MTX but with enhanced properties (higher affinity for RFC)

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Resistance for antimetabolites

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1) alteration of antifolate transport into cell
2) decreased intracellular polyglutamation
3) increased expression of intracellular catabolic enzyme gamma-glutamyl hydrolase
4) alterations in over expression of DHFR and mutated DHFR
5) ABC/MRP - efflux of drug out of cell