1. Anti-cancer treatment טיפול בסרטן

2. Cancer progression

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

4. 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

5. 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

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

7. 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.

8. 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)

9. 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

10. 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

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

12. 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

13. ALL
Colon cancer
Breast cancer
AML

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. Anti-cancer therapy Monoclonal antibodies1 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

21. 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

22. 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.