Anti-cancer treatment טיפול בסרטן

Cancer progression

Cancer progression Proliferation Dedifferentiation Invasiveness Angiogenesis Oncogen activation Tumor-supressor genes inhibition Apoptosis יכולת חלוקה מוגברת ובלתי מוגבלת

Pathology Tumors can either be benign or malignant. Benign: Localized, encapsulated, non-cancerous Usually do not metastasize Resemble the cell of origin Do not recur. Malignant: Invade surrounding tissues Unstable Don't resemble the cell of origin. Lose their ability to function properly. Malignant tumors tend to metastasize and recur

Diagnosis Cancers may be diagnosed: Develop symptoms and seek medical attention Asymptomatic people who take part in screening efforts Medical attention for unrelated problems Routine physical exams Signs and symptoms Invading, obstructing or displacing other normal tissues. May be related to the metastasis

Diagnosis Tissue biopsy Serum tumor marker “Must have meat to treat” Alpha-fetoprotein (AFP), CA-125, Carcinoembryonic antigen (CEA) and Prostate specific antigen (PSA)

Staging Dividing cancer cases into groups according to stages Survival rates higher for cases in which the disease was localized than for those in which the disease had extended beyond the organ or site of origin. Cancers of similar histology or site of origin share similar patterns of growth and extension. Optimal treatment plan to be designed.

Staging The American Joint Committee on Cancer (TNM) The TNM describes the anatomic extent of the disease based on the assessment of three components: T - primary tumor (0-4) N - lymph node mets (0-3) M - distant mets (0-1)

2.Topoisomerase inhibitors 3. Hormonal treatments Anti-cancer therapy 1. Cell cycle inhibitors 2.Topoisomerase inhibitors 3. Hormonal treatments 4. Monoclonal antibodies 5. Tyrosine kinase inhibitors 6. Interferons

Resistance: Enzyme mutations, antiapoptotic proteins Anti-cancer therapy Limitations of therapy: Resistance: Enzyme mutations, antiapoptotic proteins Toxicity: Dose limiting and other side effects Myelosuppression (=bone marrow supression) Allopecia Gastric epithelium destruction (מוקוזיטיס) Emesis, nausea Cardiotoxicity – Anthracyclines (Doxorubicin) Neurotoxicity – Vinca alkaloids (Vincristine) Nephrotoxicity - Cisplatinum Other toxicities

Anti-cancer therapy 1. Cell cycle inhibitors Mitotic inhibitors DNA alkylating drugs DNA intercalating drugs Mitotic inhibitors DNA synthesis inhibitors

Dehydrofolate reductase 1. Cell cycle inhibitors Anti-cancer therapy DNA synthesis inhibitors Anti-metabolites: purines, pyrimidines (עקיף) Folate antagonists Dehydrofolate reductase Folic acid Tetrahydrofolate Synthesis of purins, pyrimidins methotrexate pemetrexol

ALL Colon cancer Breast cancer AML

Anti-cancer therapy DNA synthesis inhibitors 1. Cell cycle inhibitors Anti-cancer therapy DNA synthesis inhibitors Purine antagonists (Adenine, Guanine): HGPRT Mercaptopurine (6-MP) , Thioguanine DNA destruction HGPRT deletion = resistance Cell death Mercaptopurine - allopurinol interaction, hepatotoxicity Pyrimidine antagonists (Cytosine, Uracil. Thymine): Cytarabine, Fluorouracil (5FU)- dual action- also inhibit DNA polymerase

Vinblastine, Vincristine 1. Cell cycle inhibitors Anti-cancer therapy Mitotic inhibitors Mitosis requires microtubules association and dissociation: Tubuline polymerization and depolymerization Vinca alkaloids: Vinblastine, Vincristine Taxanes: Paclitaxel, Docetaxel Side effects: neurotoxicity, exrtavasation

Anti-cancer therapy DNA alkylating agents 1. Cell cycle inhibitors Anti-cancer therapy DNA alkylating agents Cross-linking of DNA because of drug-[G] bonding Nitrogene mustards: Cyclophosphamide- side effect of hemorrhagic cystitis, reduced by Mesna Chlorambucil Nitrosourea drugs: Carmustine, Lomustine- high CNS penetration- brain tumors. Side effect: pulmonary toxicity Platinum compounds: Cisplatin, Carboplatin: cross linking by bonding of 2 [G]s- abnormal DNA structure. Cisplatin side effect: nephrotoxicity (reduced by mannitol). Abnormal DNA structure DNA destruction Cell death

Anti-cancer therapy DNA intercalating agents Anthracyclines: 1. Cell cycle inhibitors Anti-cancer therapy DNA intercalating agents Anthracyclines: Doxorubicin, Daunorubicin Intercalation between nucleotide base pairs Topoisomerase II inhibition Free radicals formation- attacking the DNA Side effects: extravasation, cardiotoxicity. Dexrazoxane: cardioprotective Bleomycin

Anti-cancer therapy Topoisomerase inhibitors 2. Topo inhibitors Anti-cancer therapy Topoisomerase inhibitors Topoisomerase I and II: Maintain DNA structure during replication / transcription, break and re-seal DNA. I: single strand DNA. II: double strand Topoisomerase inhibition No DNA resealing Abnormal DNA structure DNA destruction Cell death Top I inhibitors: Topotecan, Irinitecan Top.II inhibitors: Etoposide, Teniposide

Anti-cancer therapy Hormonal treatments For tumors activated by hormones, through hormone receptors Breast cancer: Tamoxifen- estrogen receptor antagonist, prevention of relapse Anastrozole- aromatase inhibitor- no estrogen synthesis Prostate cancer: Flutamide- androgen antagonist Leuprolide- GNRH analog- no testosterone synthesis Lymphoma, Myeloma, Leukemia: corticosteroids

Anti-cancer therapy Monoclonal antibodies 1 2 Trastuzumab (herceptin): HER2- breast cancer Rituximab: CD20- non-Hogkin’s lymphoma Gemtuzumab: toxin attached- CD33- blood cancers - WITHDRAWLED Cetuximab (erbitux): EGFR, Bevacizumab (avastin): VEGF- colorectal cancer

Anti-cancer therapy Tyrosine kinase inhibitors: Imatinib (gleevec): inhibition of bcr-Abl (tyrosine kinase) in CML (Chronic myelogenous leukemia ) Interferons: Interferon alpha: Up-regulates cytotoxic T cells, and inhibits cell proliferation 6. Interferons

Anti-cancer therapy B-raf inhibitors: B-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases. This protein plays a role in regulating the MAP kinase/ERKs signaling pathway, which affects cell division, differentiation, and secretion. Acquired mutations in this gene have also been found in cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma and others. B-raf inhibitors Some pharmaceutical firms are developing specific inhibitors of mutated B-raf protein for anticancer use. One example is Vemurafenib (RG7204), which was licensed by the US FDA as Zelboraf for the treatment of metastatic melanoma in August 2011. More general B-raf inhibitors include GDC-0879, PLX-4720, Sorafenib.