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

O

P

L

A

S

M

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)‏