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Birth-39
40-59
Birth death
All cancers,
1/69
1/52
1/11
1/3
Male/Female
Male/Female
Male/Female
Breast
1/229 Uterine corpus 1/567 Uterine cervix 1/2097 Prostate <1/10000 Lymphoma 1/591 1/1311 Lung 1/3060 1/3099 Colorectal 1/1508 1/1719 Melanoma 1/769 1/508
(Males)
Last 70 years statistics
GASTRIC CANCER down 4 times REASON? better nutrition? Probably
LUNG CANCER UP!!! 10 times (due to smoking and air pollution)
(Females)
Last 70 years statistics
UTERINE CANCER (including cervix) down 5 times due to early diagnostics
GASTRIC CANCER down 4 times Same as in males. LUNG CANCER UP!!! 10 times (due to smoking and air pollution)
NO!
Cancer type Pancreas Liver Uterine corpus Years 74-76 3% 4% 89% Years 83-85 3% 6% 85% Year 92-97 4% 6% 86%
NOT possible without understanding of the state of genes in every given tumor
Breast cancer
Brain cancer Liver cancer Colon cancer
Grading/staging (metastase/invasion)
2
Mucinous cystadenocarcinoma Carcinomas with spindle and/or giant cells
?
Ductal carcinoma in situ (DCIS) Lobular carcinoma in situ (LCIS)
malignant
High chances to become
benign
Low chances to become
TISSUE-based classification
Carcinoma
malignant neoplasm of epithelial origin, including internal epithelium (bladder lining, pancreatic duct lining etc. )
Adenocarcinoma
From tissue/cells producing secret milk or mucous or enzymes
Sarcoma
Sarcoma refers to cancer that originates in supportive and connective tissues such as bones, tendons, cartilage, muscle, and fat. Osteosarcoma or osteogenic sarcoma (bone) Chondrosarcoma (cartilage) Leiomyosarcoma (smooth muscle) Rhabdomyosarcoma (skeletal muscle) Mesothelial sarcoma or mesothelioma (membranous lining of body cavities) Fibrosarcoma (fibrous tissue) Angiosarcoma or hemangioendothelioma (blood vessels) Liposarcoma (adipose tissue) Glioma or astrocytoma (neurogenic connective tissue found in the brain) Myxosarcoma (primitive embryonic connective tissue)
Leukemia
cancers of the bone marrow (liquid phase) overproduction of immature lymphocytes, which do not perform as well as they should, therefore the patient is often prone to infection
Myelocytic/myelogenous
erythroblastic
lymphocytic
Lymphoma
tumors from the lymphocytes from lymph nodes (solid tumors) Can be present in extranodal (non-lymph nodes) sites stomach lymphoma, skin lymphoma.
Lymphoma goes through the same stages of generalization (metastase) as any solid tumor
Hodgkin disease
Non-Hodgkin lymphoma
Teratoma
Mixed type of tumor, often it is derived from embryonic or stem cells
medstat.med.utah.edu/
Chronic leukemia
Remission with latent residual disease Acute leukemic crisis (blast crisis)
Borders No invasion
newscenter.cancer.gov/sciencebehind/ cancer/cancer34.htm
Tumor histology
Metaplasia
Replacement of normal differentiated tissue by another (differentiated) type like epithelial to mesenchime transition in breast carcinoma progression
Anaplasia
Loss of differentiated phenotype
Dysplasia
Loss of tissue organisation
Hyperplasia
Increase in cell division
TUMOR STAGING
Staging is the classification of the extent of the disease in the body.
Most common systems are TNM system and Numerical system
The tumor, nodes, metastases (TNM) system classifies cancer : -- by Tumor size,
T N
Tumor (T)
T0 Tis
T14
(Increasing tumor size and involvement)
Node (N)
Nx
Lymph node involvement cannot be assessed
Metastases (M)
M0 No evidence of distant metastases M1 Evidence of distant metastases
Pancreatic carc. met. in liver
www.ikp.unibe.ch/lab2/cytostatics/ sld014.htm
Numerical system
Stage 0 Stage 1 Stage 2 Cancer in situ (limited to surface cells) Cancer limited to the tissue of origin with evidence of tumor growth Limited local spread of cancerous cells
Stage 3
Stage 4
newscenter.cancer.gov/sciencebehind/ cancer/cancer34.htm
CANCER TREATMENT
Radical
IDEAL GOAL:
Palliative
GOALS:
Hormonal therapy
IMMUNOTHERAPY
SURGICAL REMOVAL
Primary care for most of the tumors Ablastic principle (all cuts are done within normal tissue; can be PCR controlled)
MINUSES: -Not able to catch and remove micrometastases; -Not able to deal with ascytic (liquid) tumors
CHEMOTHERAPY
CHEMOTHERAPY is the treatment of cancer with drugs that can destroy cancer cells. Ideal anticancer drug should be able to kill tumor cell and be harmless for any normal cell Problem: No clear differences between normal and tumor cells
Normal cells with fast pace of divisions are also very susceptible to chemo
can help prevent such changes or help invent new drugs not producing common types of resistance
I. Alkylating agents:
Nitrogen mustards, Nitrosoureas, Platinum agents (Cisplatin), Cyclophosphamides The alkylating agents react with everything; impair cell function by forming covalent bonds with the amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules
Alkylating agents generally interact with DNA non-specifically: the more effective ones tend to crosslink DNA.
The electron-rich nitrogen at the N7 position of guanine in DNA is particularly susceptible to alkylation.
Monoalkylation
Alkylating agents interact with DNA non-specifically Active even for the resting cells
(not cell cycle/phase-specific)
Therefore Alkylating Agents can be used for the treatment of slow-growing tumors; extensive damage of DNA will lead to cell death
Nitrogen mustard
Cisplatin
(Same strand-linking agent)
BETTER
than INTERstrand-linking agent!! because of two reasons
Cisplatin
(Same strand-linking agent)
1. Same strand cross-links formed are harder" to repair than cross-links between strands. 2. Cisplatin is able to replace zinc(II) ion in zinc-finger containing transcription factors, directly destroying transcription regulation Cisplatin Therapy Type of Cancer
Testicular cancer
Ovarian
Bladder, Head & neck Cervix, Prostate, Esophegeal Various, eg.: Non-small cell lung, Ostegenic sarcoma, Hodgkins lymphoma
Synergy shown in combination with 5-fluorouracil, cytarabine and bleomycin, That allows for greater flexibility in the design of drug regimens.
-- Increase in glutathione synthesis conjugation with glutathione leads to chemical inactivation of alkylating agents (catalyzed by glutathione S-transferase)
Types of Antimetabolites:
Folate analogs -- Methotrexate (MTX)
(bind to catalytic site of dihydrofolate reductase DHFR)
Purine analogs -- Mercaptopurine,Fludarabine (inhibits enzymes involved in purine metabolism) Pyrimidine analogs -- Flurouracil (5-FU), Ara-C
(inhibits enzymes involved in pyrimidine metabolism)
Methotrexate (MTX)
www.vet.purdue.edu/ Looks very same to folic acid necessary nutrient.
Methotrexate
DHFR like MTX more than folic acid No production of No THF-co-enzymes tetrahydrofolic acid for one-carbon transfer No de novo purines and pyrimidines No DNA synthesis Treat leukemia, lymphomas, and osteosarcoma. It is also used in the treatment of AIDS and rheumatoid arthritis
Broad range
-- quantitative increase in DHFR concentration by DHFR gene amplification, or by increased DHFR mRNA production (more DHFR)
Vinblastine, Vincristine
-- Mechanism of action = mitosis block: bind to tubulin and induce microtubule depolymerization (Disassembly)
Vinca alcaloids bind to tubulin dimers at a specific recognition site on the protein. Tubulin form paracrystaline aggregates
www.staff.ncl.ac.uk/i.r.hardcastle/ antibiotics.html
www.chem.wisc.edu/~bestchem/ taxol.gif
+ Taxol
Used for treatment of otherwise resistant ovarian cancers and recurrent breast tumors
Etoposide inhibit topoisomerase II that catalyses transient breaking and re-joining of ds DNA strands (DNA becomes damaged
Doxorubicin
Bleomycin
Anthracyclines:
Doxorubicin (Adriamycin) and Daunorubicin
Mechanisms of action:
1) intercalation between DNA base pairs and inhibition of DNA topoisomerases I and II.
Bleomycin
Mechanisms of action - multiple: 1) binds to double- and single-stranded DNA produces site-specific and non-specific SS and DS breaks ratio single:double = 10:1; Cleave DNA at G-C and G-T sequences; DNA in open chromatin esp. sensitive (where genes are expressed)
Rapidly degraded by bleomycin hydrolase present in most tissues except skin and lung
No bone marrow and intestinal toxicity!! (Pulmonary fibrosis and skin effects are strong...)
P-glycoprotein
This is an ATP-dependent export pump (= efflux pump) of broad specificity This efflux pump expel hydrophobic drugs, natural products and peptides.
The transport function of P-glycoprotein can be blocked by the action of another group of compounds known as MDR modulators, or chemosensitizers
IMMUNOTHERAPY
Hormonal therapy
RADIOTHERAPY
General principle is the same reduce a mass of rapidly dividing cells (cytoreduction principle, the same as for chemo)
HORMONAL THERAPY
Good for hormone-dependent tumors
Speaking generally, hormonal therapy can be discussed as trophic factor removal therapy
Estrogens are trophic factors for breast
epithelium and uterine epithelium
Tamoxifen (Nolvadex)
Tamoxifen mimics the action of estrogene and binds to estrogen receptor (ER).
The tamoxifen-ER complex dimerises Than transported from the cytosol into the cell's nucleus The dimeric tamoxifen-ER complex binds to DNA
DNA-tamox-ER complex is unable to function in the same way as the DNA-estrogene-ER complex
In reality mechanism is not known completely !!!! In other tissues of the body Tamoxifen plays exactly like estrogene itself !!!
IMMUNOTHERAPY
Any intervention to enhance the body's natural ability to defend itself against malignant tumors. Cytokines: IFN-alpha, IL-2, Tumor necrosis factors (TNFs) Monoclonal antibodies: anti-CD20 Rituximab for lymphomas,
anti-HER2 trastuzumab (herceptin) for breast cancer
Hormonal therapy
IMMUNOTHERAPY