tissue basic cell type benign tumor malignant tumor · skin tissue basic cell type benign tumor...
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Carcinoma
adenoma Specific epithelium Solid organs
Carcinoma
adenoma Bronchial
epithelium
Nasolarynx
Carcinoma
adenoma Columnar
epithelium
Stomach
Bowel
Carcinoma
papilloma Squamous
epithelium
Alimentary Tract
Carcinoma
Papilloma
(squamous)
Melanoma
(pigment)
Squamous
epithelium; basal
cell; pigment cell
Skin
Malignant Tumor Benign Tumor Basic Cell Type Tissue
Skin and Soft tissue Malignancies
Lymphangiosarcoma Lymphangioma Endothelium Lymph vessels
Hemangiosarcoma Haemangioma Endothelium Blood vessels
Rhabdomyosarcoma Rhabdomyoma Muscle cells Striated muscle
Leiomyosarcoma Leiomyoma Smooth muscle cells Smooth muscle
Chondrosarcoma Chondroma Chondrocyte Cartilage
Osteosarcoma Osteoma Osteocyte Bone
Liposarcoma Lipoma Adipocyte Fat
Fibrosarcoma Fibroma Fibrocyte Fibrous tissue
Mesenchymal Malignancies
Tissue Basic Cell Type Benign Tumor Malignant tumor
Teratocarcinoma Teratoma Mixed tissues Embryonic
Non-Hodgkin’s;
Hodgkin’s
lymphoma
none Lymphocyte
Fixed reticulo-
endothelial
Lymph Node
Erythroleukemia none Erythrocyte Red Blood Cell
Lymphocytic
leukemia
None Lymphocyte White Blood Cell
Myeloid leukemia
Granulocytic
leukemia;
monocytic
leukemia
None Myeloid cells
•Granulocyte
•Monocyte
White Blood Cell
Malignant Tumor Benign Tumor Basic Cell Type Tissue
Hematopoeitic and Embryonic Malignancies
Types of Human Carcinogens
Physical Carcinogens
Biological Carcinogens
Chemical Carcinogens
(UV exposure, Ionizing radiation)
(Viruses - EBV, HBV, HIV, HPV;
Bacteria - H. pylori;
Parasites - liver flukes,
Schistosoma)
(Organic, Inorganic,
Fiber,Hormones)
Types of DNA Damage
Bulky DNA adducts (e.g., BPDE-dGuo)
Unstable DNA adducts (by one-electron oxidation; e.g.,
DMBA)
Apurinic sites (depurination or depyrimidination)
Deamination
Oxidative damage (e.g., 8-oxodG, thymidine glycols etc.,)
Alkylated DNA bases (ethylated or methylated bases)
Strand breaks (single strand or double strand)
Crosslinks (DNA-protein, intra strand, interstrand)
Indigenous compouds (I-compounds)
Exocyclic adducts (Malondialdehyde, 4-hydroxynonenal,
acrolein, crotonaldehyde)
Mechanisms of DNA repair
• Direct reversal of DNA damage – Alkyltransferases
• Base excision repair – Glycosylase and AP endonuclease
• Nucleotide excision repair – T-T, C-C, C-T repair
– “Bulky” adduct repair
• Double strand break repair – Homologous recombination (HR)
– Nonhomologous DNA end joining (NHEJ)
• Mismatch repair – Repair of deaminaition of 5-Me-cytosine
– Repair of mismatches in DNA due to defective repair, etc.
Small GTP-
binding protein
(v-ras)
Growth factor
receptors
(v-erbB, v-fms)
Signal Transduction Oncogenes
GTP
Phospholipase C
(v-crk)
Growth factors
(v-sis)
MAP kinase
kinase kinase
(v-raf)
Transcription factors
(v-myc, v-jun)
WhyAren’tProto-oncogenes Oncogenic
fms
crk ras
GTP
• Proto-oncogenes never expressed
• Oncogenes over-expressed
• Unscheduled expression
Oncogenes as Signal Transducers
Growth Factors
v-sis, int-1, int-2, hst, fgf-5
Growth Factors Receptors
v-erb-B, v-fms, v-kit, v-ros
Signal Transducers
v-ras,, v-src, v-raf/mil, v-abl, v-mos, v-crk
Transcription Factors
v-ets, v-myc, v-myb, v-rel, v-ski, v-erb-A
C
Y
T
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L
A
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EXTRACELLULAR
NUCLEUS
Oncogenes and Signal Transduction
Transcription Factors-Myc
c-Myc plays a role in many human cancers.
Translocations c-myc and Ig genes (, , and
-Burkitts Lymphoma
-Low-grade follicular lymphomas (sometimes with BCL-2)
-Diffuse large cell lymphomas
Amplifications of c-myc
-Breast carcinoma
-neuroblastoma (involve the related N-myc gene)
-Small cell lung cancer (involve the related L-myc gene)
Antiproliferative agents
•
IGF-1/IGFBP-3 lycopene
Her-2/neu Celecoxib
EGFR, NF-kb, CDK2,4, p21, p27 Tea polyphenols (ECGC)
5-alpha reductase Finasteride, eprosteride, soy
isoflavones
Aromatase Vorozole, arimidex
Androgen receptor Flutamide
Inhibit oncogene activity Farnesyl transferase-Ras Perillyl alcohol, FTIs
(SCH66336, Manumycin A)
G1 arrest
Inhibit polyamine synthesis
Modulate growth hormone
activity, reduce cell
proliferation
Restore normal DNA
methylation
Inhibit DNA synthesis
MECHANISM
Retinoid receptors (RARs/RXRs) Retinoids (ATRA,13-cRA, 9-
cRA, 4HPR)
Ornithine decarboxylase (ODC) Difluoromethylornithine (DFMO)
Estrogen receptor Tamoxifen, raloxifene (SERMS)
soy isoflavones (genistein)
Methyl transferases Folic acid, budesonide
Topoisomerase II Oltipraz, genistein, elagic acid,
indole-3-carbinol, sulforaphane
TARGETS AGENT
Modified from Steele, J Biochem and Molec Biol, 2003
Examples of Tumor Supressor Genes
DPC-4 involved in pancreatic cancer; participates in a cytoplasmic pathway that inhibits cell division
NF-1 involved in neurofibromas of the nervous system and myeloid leukemia; codes for a protein that inhibits Ras, a cytoplasmic inhibitory protein
NF-2 involved in cancers of the nervous system; codes for a nuclear protein
RB involved in retinoblastoma as well as bone, bladder, small cell lung, and breast cancers; codes of the pRB protein, a nuclear protein that is a major brake in the cell cycle
p53 involved in a wide range of tumors; inactive or lost in more than 50% of cancerous cells; codes for the cytoplasmic p53 protein that regulates cell division and can induce cells to kill themselves (apoptosis); inheritance of p53 mutations through the germ line is also associated with the Li-Fraumeni cancer syndrome
WT1 involved in Wilms tumor of the kidneys
BRCA1 involved in breast and ovarian cancer
BRCA2 involved in breast cancer
Apoptosis inducing agents
•
Many others (Vitamin E, monoterpenes,
SAHA, HMBA, SUS, silymarin, aspirin,
curcumin, genestein)
Induction of apoptosis-related genes (ICE, TGF-b, p53,
BAX, p21, TRPM2)
Scavenging of ROS Tea polyphenols (ECGC)
Generation of oxidative free radicals Selenite and selenocysteine
Regulation of intracellular calcium Vitamin D and analogs (EB1089)
Inhibition of COX-2 activity and or expression NSAIDs (celecoxib), curcumin, resveratrol
Increase in arachidonic acid leading to ceramide
production, JNK1 activation
NSAIDs (sulindac sulfide, CP248,
indomethicin)
Increased BAX activity, cyto C release, PARP cleavage
Activation of p53 Resveratrol
Multiple pathways
Activation of retinoid receptors
Increase in ROS production, ceramide production,
cytochrome C release
MECHANISM
hCG
Tributyrin
Type I interferons (IFN/)
Retinoids (ATRA, 9-cRA, 13-cRA, 4-HPR)
Fenretinide (4-HPR)
AGENT
Modified from Steele, J Biochem and Molec Biol, 2003
ALKYLATINGAGENTS
NATURALPRODUCTS
ANTIMETABOLITES HORMONES ANDANTAGONISTS
MISCELLANEOUS AGENTS
ANTINEOPLASTIC
DRUGS
ANTINEOPLASTIC
AGENTS
2 MAIN GROUPS OF AGENTS:
CELL CYCLE - NONSPECIFIC (CCNS)
ALKYLATING AGENTS
cytotoxic in any phase of cell cycle
effective against slowly growing tumors
CELL CYCLE - SPECIFIC (CCS) 3 TYPES
ANTIMETABOLITES - cytotoxic is S phase
MITOTIC INHIBITORS - cytotoxic in M phase
CYTOTOXIC ANTIBIOTICS (some are CCNS)
effective against rapidly growing tumors
ALKYLATING AGENTS
SELECTED AGENTS:
•Mechlorethamine (Mustine, Mustargen)
IV only (adult use only)
•Cyclophosphamide (Cytoxan, Neosar)
IV and PO, adults and pediatric use
•Carmustine (BiCNU)
IV, adult only, can cross blood-brain barrier,
therefore used to tread brain lesions
OTHER AGENTS: Chlorambucil, Streptozotocin
ANTIMETABOLITES
SELECTED AGENTS:
• PURINE ANALOG
- MERCAPTOPURINE (6-MP, Purinethol)
- Purine antagonist
- PO only, adult and pediatric use
• PYRIMIDINE ANALOG -
•CYTARABINE (Ara-C, Cytosar-U)
-Pyrimidine antagonist
-IV and intrathecal (within spinal canal)
MITOTIC INHIBITORS
SELECTED AGENTS:
ETOPOSIDE (VP-16, VePesid)
IV and PO, adult use only
PACLITAZEL (Taxol)
IV only, adult use only
drug of choice for ovary and breast ca
VINCRISTINE (LCR, VCR,Oncovin)
IV only, adult and pediatric use
drug of choice for acute leukemia
MISCELLANEOUS ANTINEOPLASTICS
HORMONES AND ANTAGONISTS.
1. Adrenocortical Suppressant:
Mitotane, Aminoglutethimide. (Adrenal Cortex)
2.Adrenocortical Steroids.
Prednisone. (Lukemias, Lymphomas, Breast)
3.Progestins.
Hydroxyprogestrone.(Endometrium, (Breast)
Medroprogestrone, Megesterol acetate.
4.Estrogens.
DES, Ethinylesterdiol.(Breast, Prostate)
5.Antiestrogens.
Tamoxifen .(Breast)
6.Androgens.
Testosterone (Breast)
7.Antiandrogens.
Flutamide (Prostate).
8.Gonadotropin Releasing Hormone Analog.
Leuprolide. (Prostate)