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Bondage: crosslinking agents. Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors. Spontaneous activation of mechlorethamine. Bifunctional crosslinking between G residues in the DNA. Other alkylating agents and intermediates. - PowerPoint PPT Presentation
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Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors
Bondage: crosslinking agentsBondage: crosslinking agents
Spontaneous activation of mechlorethamineSpontaneous activation of mechlorethamine
Bifunctional crosslinking Bifunctional crosslinking between G residues in the between G residues in the
DNADNA
Other alkylating agents and intermediatesOther alkylating agents and intermediates
mechlorethaminemechlorethamine
cyclophosphamidecyclophosphamide
procarbazineprocarbazine
carmustinecarmustine
parent compound reactive parent compound reactive intermediateintermediate
Cyclophosphamide (Cytoxan) Cyclophosphamide (Cytoxan) requires P450 activation in liverrequires P450 activation in liver
Cisplatin: chloro to hydroxyl conversion in cellCisplatin: chloro to hydroxyl conversion in cell
G residuein DNA
G
H2O
Vaporization: Bleomycin, radiationVaporization: Bleomycin, radiation
Bleomycin chelates iron/catalyzes Bleomycin chelates iron/catalyzes formation of hydroxyl radicalsformation of hydroxyl radicals
ConfusionConfusion
Actinomycin DActinomycin D
Actinomycin D: Actinomycin D: -intercalates into the-intercalates into theDNA duplex DNA duplex -blocks RNA synthesis-blocks RNA synthesisand DNA replicationand DNA replication
Topoisomerase inhibitorsTopoisomerase inhibitors Topo II inhibitorsTopo II inhibitors
doxorubicindoxorubicin (daunorubicin, idarubicin, (daunorubicin, idarubicin, etoposideetoposide) ) bind to DNA/topo II complex and prevents re-bind to DNA/topo II complex and prevents re-sealing of DNA breaks made by topo II sealing of DNA breaks made by topo II • also act to inhibit DNA and RNA synthesisalso act to inhibit DNA and RNA synthesis• etoposide (similar to above) causes DNA strand etoposide (similar to above) causes DNA strand
breaks and cell deathbreaks and cell death Topo I inhibitorsTopo I inhibitors
camptothecins (camptothecins (irinotecanirinotecan, topotecan) bind the , topotecan) bind the Topo I/DNA complex and prevent religationTopo I/DNA complex and prevent religation
PharmacogeneticsPharmacogenetics
Starvation for substratesStarvation for substrates MethotrexateMethotrexate: :
inhibitor of human DHFRinhibitor of human DHFR 5-fluorouracil5-fluorouracil: :
inhibits thymidylate synthetase and inhibits thymidylate synthetase and misincorporated into RNAmisincorporated into RNA
5-FU first--> then MTX = antagonism5-FU first--> then MTX = antagonismMTX first--> (hrs) then 5-FU = synergismMTX first--> (hrs) then 5-FU = synergism
dUMPdUMP
dTMPdTMP
5-FdUMP5-FdUMP thymidinethymidinesynthetasesynthetase
FH2FH2
FH4FH4
DHFRDHFR
MTXMTX
5-FU5-FU
purines/aminopurines/aminoacidsacids
purinespurines
Methotrexate and 5-fluorouracil
Starvation for substratesStarvation for substrates MethotrexateMethotrexate: :
inhibitor of human DHFRinhibitor of human DHFR 5-fluorouracil5-fluorouracil: :
inhibits thymidylate synthetase and misincorporated into RNAinhibits thymidylate synthetase and misincorporated into RNA 6 thioguanine6 thioguanine: :
inhibits purine biosynthesisinhibits purine biosynthesis cytosine arabinosidecytosine arabinoside, difluorodeoxycytidine , difluorodeoxycytidine
(gemcitabine): (gemcitabine): inhibits DNA polymerase and gets misincorporatedinhibits DNA polymerase and gets misincorporated
hydroxyureahydroxyurea: : inhibits ribonucleotide reductase and therefore DNA synthesisinhibits ribonucleotide reductase and therefore DNA synthesis
RegulationRegulation Hormone therapy:Hormone therapy:
breast cancerbreast cancer prostate cancerprostate cancer ovarian, endometrial cancerovarian, endometrial cancer
Risk of breast CA Risk of breast CA in BRCA1/2 in BRCA1/2
carrierscarriers BRCA mutations in about 7% of BRCA mutations in about 7% of
Caucasian breast CA pts.Caucasian breast CA pts. BRCAs are tumor suppressor BRCAs are tumor suppressor
proteinsproteins loss of heterozygosity leads to loss of heterozygosity leads to
tumor formationtumor formation exercise, normal weight, and exercise, normal weight, and
child bearing delays onsetchild bearing delays onset other variables (environment?) other variables (environment?)
seem to be speeding onsetseem to be speeding onset
BRCA protein function? BRCA protein function? BRCA proteins have unique BRCA proteins have unique
domain structures that bind domain structures that bind phosphorylated regulatory phosphorylated regulatory proteinsproteins
BRCA1 is an E3 ubiquitin BRCA1 is an E3 ubiquitin ligase that participates in ligase that participates in DNA repair and BRCA2 DNA repair and BRCA2 seems to be involved in seems to be involved in homologous recombination. homologous recombination. Both are required for Both are required for genomic stabilitygenomic stability
Position of mutation in BRCA determines Position of mutation in BRCA determines risk for breast versus ovarian cancerrisk for breast versus ovarian cancer
Tamoxifen antagonizes estrogen action Tamoxifen antagonizes estrogen action in breast cancer cells and affects growth in breast cancer cells and affects growth
factor synthesisfactor synthesis TamoxifenTamoxifen
IGF-1IGF-1 TGFTGF plasminogen plasminogen
activatoractivator laminin laminin
receptorsreceptors TGFTGF
Emergence of Immunotherapy• Paul Ehrlich (1904) hypothesized that antibodies could be
used as ‘magic bullets’ to treat cancer• Köhler and Milstein (1979) described a method to develop
antibodies with defined specificity• Rituximab is approved by FDA in 1997 for the treatment of
B-cell non-Hodgkin’s lymphoma• Addition of rituximab to standard CHOP chemotherapy
provided the first improvement in survival in diffuse large cell lymphoma (2002) in 25 years
Antibodies in Cancer Antibodies in Cancer ChemotherapyChemotherapy
Herceptin (trastuzumab)Herceptin (trastuzumab) humanized monoclonal antibody against humanized monoclonal antibody against
HER2 (human epidermal growth factor HER2 (human epidermal growth factor receptor 2)receptor 2)
Avastin (bevacizumab)Avastin (bevacizumab) humanized monoclonal against VEGF humanized monoclonal against VEGF
(vascular endothelial growth factor)(vascular endothelial growth factor) CetuximabCetuximab
antibody against the EGF receptorantibody against the EGF receptor
Clinical trial of herceptinClinical trial of herceptin
Induction of VEGF and angiogenesisInduction of VEGF and angiogenesis
HIF = hypoxia inducible HIF = hypoxia inducible factorfactor
oxygen dependent oxygen dependent proline hydroxylation proline hydroxylation regulates degradation of regulates degradation of HIF-HIF- by proteasome by proteasome
low oxygen leads to low oxygen leads to increased HIF and increased HIF and induction of VEGF and induction of VEGF and other genesother genes
Tumor vasculature regrowth after Tumor vasculature regrowth after anti-VEGF therapy stopped?anti-VEGF therapy stopped?
Avastin (bevacizumab) Avastin (bevacizumab) benefits may not persistbenefits may not persist
Assembly of tubulinAssembly of tubulininto microtubulesinto microtubules
Vinca alkaloids (vincristine,Vinca alkaloids (vincristine,vinblastine, vindesine)vinblastine, vindesine)inhibit polymerizationinhibit polymerization
Taxol: binds microtubules andTaxol: binds microtubules andprevents depolymer-prevents depolymer-ization.ization.
Microtubules do more than just help segregate chromosomesMicrotubules do more than just help segregate chromosomesat mitosis: for example, they are involved in vesicleat mitosis: for example, they are involved in vesicle
transport in neurons.transport in neurons.
Gleevec (imatinib) is a specific inhibitor
Imatinib (Gleevec) highly effective in Imatinib (Gleevec) highly effective in treatment of CMLtreatment of CML
5000 pts develop CML each year in US
2.1 billion $ for Novartis
Protein kinase inhibitors on the Protein kinase inhibitors on the market and in developmentmarket and in development
Many new drugs targeted to the Many new drugs targeted to the EGF and VEGFR pathwaysEGF and VEGFR pathways
FDA
Tarceva
Avastin
Tarceva (erlotinib) is an EGFR tyrosine kinase inhibitor that also promotes regeneration
HDAC inhibitors:promisingHDAC inhibitors:promising
Proteasome inhibitor: Proteasome inhibitor: BortezomibBortezomib
small molecule inhibitor of small molecule inhibitor of the 26S proteasomethe 26S proteasome
approved by FDA for approved by FDA for relapsed multiple myelomarelapsed multiple myeloma
one-year survival rate was one-year survival rate was 80 percent among patients 80 percent among patients taking bortezomib and 66 taking bortezomib and 66 percent among patients percent among patients taking dexamethasonetaking dexamethasone