nitrogen mustards: mustard gas used first during wwi. leukopenia and gi ulceration noted in...
DESCRIPTION
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 PresentationTRANSCRIPT
![Page 1: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/1.jpg)
Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors
Bondage: crosslinking agentsBondage: crosslinking agents
![Page 2: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/2.jpg)
Spontaneous activation of mechlorethamineSpontaneous activation of mechlorethamine
![Page 3: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/3.jpg)
Bifunctional crosslinking Bifunctional crosslinking between G residues in the between G residues in the
DNADNA
![Page 4: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/4.jpg)
Other alkylating agents and intermediatesOther alkylating agents and intermediates
mechlorethaminemechlorethamine
cyclophosphamidecyclophosphamide
procarbazineprocarbazine
carmustinecarmustine
parent compound reactive parent compound reactive intermediateintermediate
![Page 5: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/5.jpg)
Cyclophosphamide (Cytoxan) Cyclophosphamide (Cytoxan) requires P450 activation in liverrequires P450 activation in liver
![Page 6: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/6.jpg)
Cisplatin: chloro to hydroxyl conversion in cellCisplatin: chloro to hydroxyl conversion in cell
G residuein DNA
G
H2O
![Page 7: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/7.jpg)
Vaporization: Bleomycin, radiationVaporization: Bleomycin, radiation
![Page 8: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/8.jpg)
Bleomycin chelates iron/catalyzes Bleomycin chelates iron/catalyzes formation of hydroxyl radicalsformation of hydroxyl radicals
![Page 9: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/9.jpg)
ConfusionConfusion
Actinomycin DActinomycin D
![Page 10: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/10.jpg)
Actinomycin D: Actinomycin D: -intercalates into the-intercalates into theDNA duplex DNA duplex -blocks RNA synthesis-blocks RNA synthesisand DNA replicationand DNA replication
![Page 11: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/11.jpg)
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
![Page 12: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/12.jpg)
PharmacogeneticsPharmacogenetics
![Page 13: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/13.jpg)
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
![Page 14: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/14.jpg)
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
![Page 15: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/15.jpg)
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
![Page 16: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/16.jpg)
RegulationRegulation Hormone therapy:Hormone therapy:
breast cancerbreast cancer prostate cancerprostate cancer ovarian, endometrial cancerovarian, endometrial cancer
![Page 17: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/17.jpg)
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
![Page 18: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/18.jpg)
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
![Page 19: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/19.jpg)
Position of mutation in BRCA determines Position of mutation in BRCA determines risk for breast versus ovarian cancerrisk for breast versus ovarian cancer
![Page 20: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/20.jpg)
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
![Page 21: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/21.jpg)
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
![Page 22: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/22.jpg)
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
![Page 23: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/23.jpg)
Clinical trial of herceptinClinical trial of herceptin
![Page 24: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/24.jpg)
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
![Page 25: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/25.jpg)
![Page 26: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/26.jpg)
Tumor vasculature regrowth after Tumor vasculature regrowth after anti-VEGF therapy stopped?anti-VEGF therapy stopped?
![Page 27: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/27.jpg)
Avastin (bevacizumab) Avastin (bevacizumab) benefits may not persistbenefits may not persist
![Page 28: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/28.jpg)
![Page 29: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/29.jpg)
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.
![Page 30: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/30.jpg)
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.
![Page 31: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/31.jpg)
Gleevec (imatinib) is a specific inhibitor
![Page 32: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/32.jpg)
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
![Page 33: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/33.jpg)
Protein kinase inhibitors on the Protein kinase inhibitors on the market and in developmentmarket and in development
![Page 34: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/34.jpg)
Many new drugs targeted to the Many new drugs targeted to the EGF and VEGFR pathwaysEGF and VEGFR pathways
FDA
Tarceva
Avastin
![Page 35: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/35.jpg)
Tarceva (erlotinib) is an EGFR tyrosine kinase inhibitor that also promotes regeneration
![Page 36: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/36.jpg)
HDAC inhibitors:promisingHDAC inhibitors:promising
![Page 37: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/37.jpg)
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
![Page 38: Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors](https://reader034.vdocuments.site/reader034/viewer/2022052702/5681682f550346895dddd2a7/html5/thumbnails/38.jpg)