nitrogen mustards: mustard gas used first during wwi. leukopenia and gi ulceration noted in...

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