Cancer drugs.docx

Cancer drugs Cell cycle specific drugs Antimetabolies Methotrexate (1) Folic acid analog Inhibits dihydrofolate reductase Retards DNA/RNA synthesis (lack of nucleotide) Retards protein synthesis (lack of methionine) 5 fluroouracil (5-Fu) (2) Blocks thymidykate synthase after activation to 5 -F...

Cancer drugs Cell cycle specific drugs Antimetabolies Methotrexate (1) Folic acid analog Inhibits dihydrofolate reductase Retards DNA/RNA synthesis (lack of nucleotide) Retards protein synthesis (lack of methionine) 5 fluroouracil (5-Fu) (2) Blocks thymidykate synthase after activation to 5 -FDUMP Topical treatment for AK Cyatarabine (ara-C) (3) Cytosine analog that causes DNA synthesis to stall upon incorporation Also: inhibits DNA and RNA polymerase Topisomerase II inhibitors Lead to double stranded breaks in DNA Cause errors during DNA replication and eventually apoptosis Examples: Etoposide (4) Teniposide (5) Microtubules as targets Vinca alkaloids Bind tubulin and prevent polymerization/mitotic spindle formation (metaphase arrest) Examples Vinablastine(6) Vincristine (7) Taxoids/Taxanes First isolated from yew tree bark Induce stabilization of microtubules (mitotic spindle cannot break down, so anaphase cannot occur Examples: Paclitaxel (8) Cell Cycle Non specific drugs Alkylating agents Irreversible changes in DNA including crosslinking but also changes in RNA and protein Unwanted effects: mutagenic,teratogenic, carcinogenic Examples: Cyclophosphamide (9): a nitrogen mustard Platinum compounds Cisplatin (10) Intra-/interstrand crosslinks in DNA Carboplatin (11) Antitumor antibiotics Doxorubicin (12) Isolated from soil bacteria (streptomyces) Intercalates in DNA which can lead to DNA breakage and inhibit transcription Also generation of free radicals leading to cellular damage Toposiomerase I inhibitors Camptothecins Inhibition of topisomerase I leads to single strand breaks in DNA, blocking DNA replication and transcription Examples: Topotecan (13) Ironotecan (14) Nuclear hormone receptors as Targets Sex hormone receptors inhibitors Examples: Tamoxifen (15) Estrogen receptor Post menopausal breast cancer Enzalutamide (16) Androgen receptor Prostate cancer Letrozole (17) Targeting estrogen synthesis Prevent the conversion of testosterone to estradiol in advanced BC Aromatase inhibitor Abiraterone (18) Targeting androgen synthesis Inhibits CYP171A1, an enzyme involved in androgen synthesis Given to castration resistant prostate cancer patients Acute promyeolotcytic leukemia (APL) treatment Treatment induce the differentiation of undiferrererntiated cancer cells Retinoic acid receptor translocation Example: ATRA (19) : ALL TRANS RETINOIC ACID; acid form of vit A Also used in acne and keratosis Novel therapies Tyrosine kinase inhibitors Imatinib (1) TK1: BCR ABL, ABL, KIT, PDGFR Treatment of Ph+ CML GI stromal tumor (GIST) KIT as target RTKS as targets HER2 EGFR and Breast Cancer Examples: Trastuzumab (2) Humanized monoclonal anti-HER2 antibody Lapatinib (3) Kinase inhibitor of both HER2 and EGFR Ado-trastuzumab emantansine (4) Antibody conjugated with a toxin (chemo) Inhibits microtuble assembly Targeted chemo delivery EGFR and cancer Oncogenic activity in many tumors: non small cell lung cancer (NSCLC), GIST, pancreatic and breast cancers Kinase inhibitors Examples Erlotinib (5) NSCLC treatment ~3 month life extension Gefitinib (6) NSCLC treatment Antibody Examples Cetuximab (7) Prevents EGF binding Treatment for squamous cell carcinoma and Colon cancer Angiogenesis inhibitors Examples Bevacizumab (8) Vascular endothelial growth factor antibody Treatment for metastatic colorectal cancer and NSCLC BRAF inhibitors Melanoma Vemaurefenid (9) Melanoma : 60% have V600 E mutation in BRAF ( a SER/THR kinase) Inhibits V600 E BRAF; but not wild type BRAF Treatment for late stage melanoma Epigenetics DNA methylation changes in cancer Hypermethylation: silencing of tumor suppresoors RB BRCA1 Hypomethylation Promotes chromosomoal rearrangement leading to chromosomal instability Activation of growth promoting genes Melanoma antigen MAGE DNA methylating agents 5-azacytidine (10) Incorporated into DNA: direct and irreversible inhibition of DNA methyltransferase Also incorporated into RNA; effect unclear Reactiveation of tumor suppressor genes Treatment for myelodysplastic syndrome formerly known as preleukemia syndrome 5-aza-2’ deoxycytidine (11) Similar to 5 azacytidine No incorporation into RNA Immunotherapy Interleukin-2 (IL-2) (12) Antigen binding to T cell receptors, leads to IL 2 secretion IV admin 30-90 min half life Treatment for metastatic renal cell carcinoma and malignant melanoma Adverse reaction: especially capillary leaks Iplimuab (13) Humanized monoclonal antibody Blocks CTLA-4 Promotes initial activation of antitumor T-cells in lymph nodes Treatment for late stage melanoma Pembrolizumab (14) Humanized monoclonal antibody Blocks PD-1 Treatment for advanced melanoma Also treatment for any solid tumor with mismatch repair deficiency Chimeric antigen receptor T Cell therapy (CAR-T) (15) CD-19 specific Car (CD19-B cell antigen) Treatment for acute lymphoblastic leukemia Overcomes problems of “normal” T cell receptors Self antigen and not presented by MHC on cancer cell MHC is down regulated I cancer cell No costimulatory signal Bispecific antibodies (16) Engineer antibody that recognize both T cell antigen and a tumor cell antigen this leads to apoptosis of the cancer cell Virotherapy TVEC ( talimogene Laherparepvec) (17) Herpes simplex virus type 1 derived oncolytic immunotherapy Deletion of virulence factor ICP34.5 that blocks stress response of normal cells and thus allows replication; in tumor cells, stress response often disrupted GM-CSF expression treatment of advanced melanoma