Nitrogen mustards: mustard gas used first during WWI. Leukopenia and GI ulceration noted in survivors Bondage: crosslinking agents
Spontaneous activation of mechlorethamine
Bifunctional crosslinking between G residues in the DNA
Other alkylating agents and intermediates mechlorethamine cyclophosphamide procarbazine carmustine parent compound reactive intermediate
Cyclophosphamide (Cytoxan) requires P450 activation in liver
Cisplatin: chloro to hydroxyl conversion in cell G residue in DNA G H2OH2O
Vaporization: Bleomycin, radiation
Bleomycin chelates iron/catalyzes formation of hydroxyl radicals
Confusion Actinomycin D
Actinomycin D: -intercalates into the DNA duplex -blocks RNA synthesis and DNA replication
Topoisomerase inhibitors Topo II inhibitors doxorubicin (daunorubicin, idarubicin, etoposide) bind to DNA/topo II complex and prevents re- sealing of DNA breaks made by topo II doxorubicin (daunorubicin, idarubicin, etoposide) bind to DNA/topo II complex and prevents re- 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 breaks and cell deathetoposide (similar to above) causes DNA strand breaks and cell death Topo I inhibitors camptothecins (irinotecan, topotecan) bind the Topo I/DNA complex and prevent religation camptothecins (irinotecan, topotecan) bind the Topo I/DNA complex and prevent religation
Pharmacogenetics
Starvation for substrates Methotrexate: inhibitor of human DHFR inhibitor of human DHFR 5-fluorouracil: inhibits thymidylate synthetase and misincorporated into RNA inhibits thymidylate synthetase and misincorporated into RNA
5-FU first--> then MTX = antagonism MTX first--> (hrs) then 5-FU = synergism dUMP dTMP 5-FdUMP thymidinesynthetase FH2 FH4 DHFRMTX5-FU purines/aminoacids purines Methotrexate and 5-fluorouracil
Starvation for substrates Methotrexate: inhibitor of human DHFR inhibitor of human DHFR 5-fluorouracil: inhibits thymidylate synthetase and misincorporated into RNA inhibits thymidylate synthetase and misincorporated into RNA 6 thioguanine: inhibits purine biosynthesis inhibits purine biosynthesis cytosine arabinoside, difluorodeoxycytidine (gemcitabine): inhibits DNA polymerase and gets misincorporated inhibits DNA polymerase and gets misincorporated hydroxyurea: inhibits ribonucleotide reductase and therefore DNA synthesis inhibits ribonucleotide reductase and therefore DNA synthesis
Regulation Hormone therapy: breast cancer breast cancer prostate cancer prostate cancer ovarian, endometrial cancer ovarian, endometrial cancer
Risk of breast CA in BRCA1/2 carriers BRCA mutations in about 7% of Caucasian breast CA pts. BRCAs are tumor suppressor proteins loss of heterozygosity leads to tumor formation exercise, normal weight, and child bearing delays onset other variables (environment?) seem to be speeding onset
BRCA protein function? BRCA proteins have unique domain structures that bind phosphorylated regulatory proteins BRCA1 is an E3 ubiquitin ligase that participates in DNA repair and BRCA2 seems to be involved in homologous recombination. Both are required for genomic stability
Position of mutation in BRCA determines risk for breast versus ovarian cancer
Tamoxifen antagonizes estrogen action in breast cancer cells and affects growth factor synthesis Tamoxifen IGF-1 IGF-1 TGF TGF plasminogen activator plasminogen activator laminin receptors laminin receptors TGF TGF
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 Chemotherapy Herceptin (trastuzumab) humanized monoclonal antibody against HER2 (human epidermal growth factor receptor 2) humanized monoclonal antibody against HER2 (human epidermal growth factor receptor 2) Avastin (bevacizumab) humanized monoclonal against VEGF (vascular endothelial growth factor) humanized monoclonal against VEGF (vascular endothelial growth factor) Cetuximab antibody against the EGF receptor antibody against the EGF receptor
Clinical trial of herceptin
Induction of VEGF and angiogenesis HIF = hypoxia inducible factor oxygen dependent proline hydroxylation regulates degradation of HIF- by proteasome low oxygen leads to increased HIF and induction of VEGF and other genes
Tumor vasculature regrowth after anti-VEGF therapy stopped?
Avastin (bevacizumab) benefits may not persist
Assembly of tubulin into microtubules Vinca alkaloids (vincristine, vinblastine, vindesine) inhibit polymerization Taxol: binds microtubules and prevents depolymer- ization.
Microtubules do more than just help segregate chromosomes at mitosis: for example, they are involved in vesicle transport in neurons.
Gleevec (imatinib) is a specific inhibitor
Imatinib (Gleevec) highly effective in treatment of CML 5000 pts develop CML each year in US 2.1 billion $ for Novartis
Protein kinase inhibitors on the market and in development
Many new drugs targeted to the EGF and VEGFR pathways FDA Tarceva Avastin
Tarceva (erlotinib) is an EGFR tyrosine kinase inhibitor that also promotes regeneration
HDAC inhibitors:promising
Proteasome inhibitor: Bortezomib small molecule inhibitor of the 26S proteasome approved by FDA for relapsed multiple myeloma one-year survival rate was 80 percent among patients taking bortezomib and 66 percent among patients taking dexamethasone