Chemotherapy Exam #1 (copy)

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141 Terms

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What is cancer?

a collection of diseases characterized by the abnormal growth and spread of mutant cells in the body

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angiogenesis

The physiological process by which new blood vessels grow from pre-existing ones.

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How does cancer kill?

(not fatal if confined within non-essential organs)

  • spread or metastasize

  • compromise essential organ functions

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Non-essential organs

  • appendix

  • gallbladder

  • spleen

  • reproductive organs

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Tissue - Epithelial → cancer type?

Carcinoma

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Tissue - Connective Tissues → cancer type?

Sarcoma

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Tissue - Blood-related cells and tissues → cancer type?

Leukemia, lymphoma, and myeloma

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Tissue - Nervous system → cancer type?

Glioma, glioblastoma, neuroblastoma

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Cancer type → Carcinoma

  • Skin, breast, lung, prostate, etc

  • Most common human cancer

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Cancer type → Sarcoma

  • bones, cartilage, tendons and fibrous tissues

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Cancer type → Leukemia, lymphoma, myeloma

  • blood marrow, lymphocytes, plasma cells

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Cancer type → Glioma, glioblastoma, neuroblastoma

  • glial and immature nerve cells

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What was chemotherapy originally described as?

The use of chemicals (drugs) that are selectively toxic to invading microorganisms 

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What was chemotherapy described as now?

describing drugs in cancer treatments

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What does chemotherapy refer too?

the type of anticancer drugs that are generally toxic to rapidly-dividing/growing cells

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What are the three types of cancer treatment?

  1. surgery

  2. radiation therapy

  3. chemotherapy

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Surgery

solid (non-hematological) cancers may be cured if entirely removed by surgery, but this is not always possible

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Radiation Therapy 

is the use of ionizing radiation to kill cancer cells and shrink tumors

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Chemotherapy

is a cancer treatment with systemic application of drugs to kill or inhibit the growth of cancer cells

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What can cancer treatments be used for?

  • cure cancer

  • control cancer

  • ease cancer symptoms

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What does cure cancer refer to?

  • remission

  • complete remission for 5 years or more

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Remission

the condition in which treatments have reduced the signs and symptoms of the cancer

can be partial or complete

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control cancer

continually use of chemotherapy to keep cancer from growing/spreading or to slow the growth 

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ease cancer symptoms

shrinks tumors that are causing pain or pressure

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Traditional Chemotherapy

  • target dividing cells (kill or inhibit the growth of cancer cells)

  • it can also harm normal cells that divide rapidly. Damage to normal cells may cause serious side effects.

  • Selectively target cancer cells while sparing normal cells in the body

  • understanding the differences between normal and cancer cells is fundamental to developing cancer therapeutics

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Forms of anticancer agents

  • small molecules

  • biologics

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Small molecules

  • chemicals 

    • chemotherapy

    • targeted therapy

    • immunotherapy

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Biologics

  • antibodies

  • Engineered immune cells 

    • targeted therapy

    • immunotherapy

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Common adverse effects of cancer drugs

  • immunosuppression

  • myelosuppression

  • anemia

  • gastrointestinal distress

  • nausea

  • vomiting

  • fatigue

  • hair loss

  • secondary malignancy 

  • infertility 

  • teratogenicity 

  • death 

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What are serious adverse effects due to?

the lack of selectivity between normal and tumor cells

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Majority of cells in human bodies are…

differentiated (they no longer grow)

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differentiated cells…

acquired one or more DNA mutations that cause cells to re-enter into cell proliferation phase

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Uncontrolled cell growth is…

one characteristic of cancer

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cancer treatments

  • surgery 

  • radiation therapy 

    • chemotherapy 

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Surgery

solid (non-hematological) cancers may be cured if entirely removed by surgery, but this is not always possible

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radiation therapy

is the use of ionizing radiation to kill cancer cells and shrink tumors

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Chemotherapy

a cancer treatment with systemic application of drugs to kill or inhibit the growth of cancer cells 

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Definition of Chemotherapy

  • originally used to describe the use of chemicals (drugs) that are selectively toxic to invading microorganisms 

  • more recently, frequently used for describing drugs in cancer treatments

  • refers to the type of anticancer drugs that are generally toxic to rapidly-dividing/ growing cells

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Forms of anticancer agents

  • small molecules

  • biological agents

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Small molecules

chemicals

used in

  • chemotherapy

  • targeted therapy

  • immunotherapy

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Biological Agents

  • antibodies 

  • nucleotides 

  • engineered immune cells 

used in 

  • targeted therapy 

  • immunotherapy 

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goal of chemotherapy

to inhibit cell proliferation and tumor multiplication, thereby avoiding cancer invasion and metastasis

3 main goals for chemotherapy in cancer treatment

  • cure

  • control

  • palliation

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cancer cells depend on cell cycle to duplicate cancer DNA to pass on to daughter cells

Cells depend on the cell cycle to efficiently duplicate their genomes and undergo cell division

There are four phases of the cell cycle: G1, S, G2, and M

  • note G0 phase is when cells exit the cell cycle and enter quiescent phase

Traditional chemotherapeutic drugs are anticancer drugs that can affect all cell types (cancer and non-cancer)

work by killing or inhibiting growth of cancer cells due to the fast cancer cell proliferation

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Anti-cancer drugs 

Although different chemotherapeutic drugs have different mechanisms of action, they all either inhibit cell growth or induce cell death 

Traditional chemotherapy agents primary interfere with DNA, RNA, or protein synthesis or affecting appropriate function of enzymes

Chemotherapeutic agents can either be specific or independent of cell cycle stage 

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4 major classes of chemotherapy agents

  • alkylating agents

  • antimetabolites

  • plants alkaloids

  • antitumor antibiotics

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cell cycle specific drugs

more effective to cancers in which cells proliferate very fast

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cell cycle-independent drugs 

typically useful in both slow and fast growing cancers 

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mechanisms of chemotherapy drugs

  • dna

  • dna replication

  • mitosis

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Mechanisms of chemotherapy drugs - DNA

alkylating agents

  • cyclophosphamide

  • ifosfamide

Platinum

  • cisplatin

  • carboplatin

  • oxaliplatin

DNA corsslinks

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Mechanisms of chemotherapy drugs - DNA Replication 

topoisomerase inhibitor

  • irinotecan 

  • etoposide 

antitumor antibiotics 

  • doxorubicin 

  • epirubicin 

  • bleomycin 

Antimetabolites 

  • methotrexate 

  • 5-fluourourcil 

  • gemcitabine 

  • hydroxyurea 

Blocking enzymes involved in DNA replicaiton

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Mechanisms of chemotherapy drugs - Mitosis

Microtubule inhibitors

  • docetaxel

  • paclitaxel

  • vinblastine

  • vincristine

  • vinorelcine

Impairing the formation of spindle microtubules formation

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Alkylating agents

Mechanism: alkylating agents directly damage DNA by

  1. adding an alkyl group to the guanine residue in DNA (monoalkylated)

  2. cross-linking two adjacent Guanine residues together

    1. intra-strand cross-links

    2. inter-strand cross-links

  3. Inhibit DNA replication and transcription

  4. Cell cycle independent agents

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Examples of Alkylating Agents

Nitrogen mustard - bendamustine, cyclophosphamide, ifosamide

Nitrosoureas - carmustine, lomustine

Platinum analogs - carboplatin, cisplatin, oxaliplatin

Triazenes - darcarbazine, procarbazine, temozolamide

Ethyleneimine - thiotepa 

Alkyl sulfonate - busulfan 

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Clinical use of alkylating agents

  1. leukemia

  2. lymphoma

  3. hodgkin disease

  4. multiple myeloma

  5. sarcome

  6. lung

  7. breast

  8. ovarian

  9. brain

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Platinum coordination complexes - Mechanism

usually with alkylating agents as DNA-damaging agents because they also form intra- or inter-strand crosslinking

generally most effective at treating slow-growing cancers

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Platinum coordination complexes - Examples

  • cisplatin (platinol): effective against testicular cancer

  • oxaliplatin (Eloxatin): often used in combination therapies for the treatment of advanced colorectal cancer

  • Carboplatin

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Platinum coordination complexes - Clinical use (Cisplatin)

  1. leukemia

  2. lymphoma

  3. breast cancer

  4. testicular cancer

  5. ovarian cancer

  6. head and neck cancer

  7. cervical cancer

  8. sarcoma, cancer that starts in bone and soft tissue

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Cytotoxic antibiotics

  • several antibiotics have potent antitumor activity (too toxic to use as antibiotics) and were developed as anticancer agents

    • They are grouped together, even though they act through different mechanisms and have widely different indications

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Examples of Cytotoxic antibiotics

  • Belomycin (Blenoxane)

  • Dactinomycin (Cosmegen)

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Cytotoxic antibiotics - Belomycin

mechanism: the exact one is unclear, but it involves an oxygen and metal-ion-mediated reaction. Overall, it induces single- and double-strand DNA breaks

Clinical use:

  1. squamous cell carcinoma

  2. melanoma

  3. sarcoma

  4. testicular cancer

  5. Hodgkin’s & non-Hodgkin’s lymphoma

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Cytotoxic antibiotics - Dactinomycin 

Mechanism: intercalates into DNA (binds in between double-stranded DNA) and blocks the progression of transcription machinery. Does not usually generate DNA breaks 

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Topoisomerase (Topo) inhibitors

inhibits two different classes of enzymes

  1. topo 1 (Class 1 enzyme)

  2. topo 2 (class 2 enzyme)

Mechanism: binds to the enzymes on DNA and locks the enzyme into a covalent-lined protein DNA adduct. This is also known as topoisomerase poisoning. Enzyme-DNA adducts inhibits DNA replication, causing the DNA replication machinery to collapse, thereby generating DNA double-strand breaks

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Examples of Topo inhibitors

  1. etoposide (plant alkaloid)

  2. doxorubicin (anthracycline antibiotic)

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Topoisomerase 1 poison - Camptothecin

inhibits Topo 1 enzyme at the religation step of the single stranded DNA by covalently bind enzyme to DNA adduct 

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Topoisomerase 2 poison - Etoposide & doxorubicin

mechanism: they bind to human topoisomerase 2 (alpha and beta) on DNA and convert a topoisomerase 2 (an essential enzyme) into a covalently-linked protein adduct (a cellular poison) on the genome (topoisomerase poisoning)

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DNA replication process

copy the DNA with high fidelity

incorporating nucleotides to complement pair A-T and C-G during DNA replication

dNTPs - N refers to any nucleotides (A, T, C, G or U)

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Anti-metabolites - mechanism of action 

  • interfere with DNA and RNA synthesis, disrupting the growth and division of rapidly proliferating cells, including cancer cells 

  • maximal cytotoxic effect in S phase (thus considered as cell-cycle specific chemotherapeutic agent)

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Anti-metabolites - types

antifolate antimetabolites 

  • methotrexate 

Anti-pyrimidine and anti-purine antimetabolites 

  • 5-fluorouracil 

Nucleotide analogs 

  • cytarabine 

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antifolate antimetabolite - methotrexate

undergoes a series of transformations and is eventually converted into a compound called methotrexate polyglutamate. This active form of methotrexate inhibits the enzyme dihydrofolate reductase (DHFA)

inhibits purine (dATP and dGTP) synthesis, causing imbalance dNTP pools, thereby pausing DNA replication and repair

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anti-pyrimidine antimetabolite - 5-fluorouracil

5FU - analogue of Uracil with a Fluorine atom at C-5 position instead of a hydrogen

5FU converts to 3 main active metabolites

  • fluorodeoxyuridine monophosphate (fdUMP) - major metabolite

  • fluorodeoxyuridine triphosphate (FdUTP)

  • fluorouridine triphosphate (FUTP)

FUTP disrupts RNA synthesis

FdUMP inhibits Thymidine synthase, causing imbalance in dNTP pool, thereby perturbing DNA replication & repair

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Nucleotide analogues - cytarabine 

instead of developing inhibitors targeting enzymes in dNTP production, we can also develop nucleotide analogues to mimic the natural dNTP molecule 

converts from Ara-cytosine to Ara-CTP (CTP analogue)

Blocks DNA polymerase from synthesizing new DNA strand 

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What is crucial for separating chromosomes in mitosis?

Microtubules

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Microtubules polymerization/depolarization is…

GTP hydrolysis dependent

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Microtubules inhibitors 

Vinca alkaloid - assembly inhibition (polymerization)

Taxanes - disassembly inhibition (depolymerization) 

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Vinca Alkaloid

Vincristine

Vinblastine

  • binds to tubulin dimers, inhibiting assembly of microtubules structures → arresting mitosis in metaphase

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Taxanes

Paclitaxel

  • stabilizes microtubule polymers and blocks their disassembly → blocks the progression of mitosis

  • prolonged cells in mitosis by activating mitotic checkpoint triggers apoptosis

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Pharmacological Approaches to Cancer Treatment

Understanding the differences between normal and cancer cells is fundamental to developing cancer therapeutics

Selectivity

Specificity

eliminate cancer cells or suppress cancer cell growth/speed

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Selectivity

targeting cancer cells while sparing normal calls

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specificity 

affecting a specific molecular target 

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Selectivity (Cancer vs Normal Cells)

proliferating (rapid) vs non-proliferating (slow)

Alkylating agents (platinum)

  • crosslinking DNA

  • Cell cycle-indep

Antimetabolites (5-FU)

  • DNA synthesis

  • cell cycle specific

Microtubule inhibitors (Taxanes)

  • mitosis

  • cell cycle specific (M-phase)

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fundamental features underlying cancer growth and metastasis

  • sustaining proliferative signaling

  • evading growth suppressors

  • enabling replication immortality

  • activating invasion and metastasis

  • inducing angiogenesis

  • resisting cell death

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Aberrant growth and Metastasis 

aberrant growth 

  • Proliferate 

    • sustaining proliferative signaling 

    • enabling replication immortality 

    • evading growth suppressors 

  • Survive

    • Resisting Cell Death

Size increase

  • inducing angiogenesis

Metastasis

  • activating invasion and metastasis

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Sustaining proliferative signaling - Cell proliferation signals 

  • extracellular signals instruct cells to proliferate 

    • growth signals - growth factors, cytokines, hormones

  • Receptors

    • cell surface receptors (ex: growth factor receptors)

    • Nuclear receptors (ex: hormone receptors)

    • Transduce signals to promote cell growth

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Sustaining proliferative signaling - epidermal Growth Factor (EGF) signaling 

An example of growth factor signaling 

Growth factors 

  • extracellular proteins 

  • EGF family 

Receptors 

  • receptor tyrosine kinases 

  • EGFR family (EGFR, HER2, HER3, HER4)

Signal transduction pathways 

  • cascades of protein phosphorylation 

  • MEK/ERK pathway 

  • PI3K/AKT pathway

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Deregulation of Growth Signaling in Cancers - Genetic mutations that deregulate growth signaling

gain-of-function mutations

  • oncogene

    • a gene that drives cancer development

      • viral gene:v-RAS, mutated cellular gene RasV12

  • proto-oncogene

    • a gene with normal cellular functions that becomes an oncogene due to mutations

      • RAS, PI3K, EGFR

Loss-of-function mutations

  • tumor suppressor

    • a gene that normally suppresses cancer development

      • PTEN

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Sustaining proliferative signaling - therapeutic intervention 

For deregulated EGFR signaling activation 

  • EGFR inhibitors

  • MEK/ERK signaling

  • PI3K/AKT signaling inhibitors

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Evading growth suppressors - Cell cycle control

a tightly regulated process through which cells divide

  • G1 → S → G2 → M

Cell cycle machineries

  • positive, regulators:

    • cyclins, cyclin-dependent kinases (CDK) (proto-oncogenes)

  • Negative regulators

    • cyclin-dependent kinase inhibitors (CDKI) (tumor suppressors)

Cell cycle checkpoints

  • DNA replication defects

  • DNA damage

  • chromosome spindle attachment defects

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Evading growth suppressors - Defective cell cycle control in cancers 

mutation or deregulated expression of cell cycle machineries 

  • CyclinD, CDK6 

Mutation or loss of cell cycle checkpoint regulators 

  • p53 

Note:

  • p53 is a major tumor suppressor 

  • later studies found that gain-of-function p53 can drive cancer growth (oncogene)

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Evading growth suppressors - Therapeutic intervention

CDK4/6 inhibitors

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Enabling Replication Immortality - Cell Replication Limit

Hayflick limit

  • a finite number of divisions before normal cells stop replicating and senesce (irreversible growth-arrest)

Replicative Senescence

  • a cellular mechanism that prevents unlimited cell replication

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Enabling Replication Immortality - Chromosome end replication  

telomere

  • a repetitive DNA sequence at chromosome ends 

  • allows replication of the chromosome ends 

  • protects chromosomes from deteriorating or fusing 

  • critically short telomeres trigger cellular senescence 

Telomerase 

  • an RNA-dependent DNA polymerase 

  • adds telomere sequences to chromosome ends to maintain telomere length 

  • low level in normal somatic cells

  • higher levels in stem cells 

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Enabling Replication Immortality - Deregulated telomerase expression in cancers

elevated telomerase activities in many cancer

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Enabling replication immortality - Therapeutic intervention

oligonucleotide telomerase inhibitors (approved in june 2024)

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Resisting cell death - cell death induction

intrinsic trigger

  • genome damage

  • lack of survival signal

  • activation of oncogenic signals

Extrinsic trigger

  • tumor necrosis factor (TNF) signaling

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Resisting cell death - Apoptosis

programmed cell death

regulated by the Bcl-2 protein family

  • anti-apoptotic: Bcl-2, Bcl-xL, Mcl1

  • pro-apoptotic: Bim, Bax, Bid, Bad

mediated by a cascade of Caspase-dependent events

  • caspase is a protein family of cysteine proteases

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Resisting cell death - Deregulated Apoptosis in Cancers

cancer cells can deregulate apoptosis by altering:

  • pro-apoptotic and anti-apoptotic protein levels

  • pro-apoptotic and anti-apoptotic protein phosphorylation (regulates functions)

  • caspase expression

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Resisting cell death - therapeutic intervention

inhibitors of anti-apoptotic proteins

  • ex: Bcl-2 inhibitors

!note: other types of programmed cell death are also involved in cancer!

  • necroptosis

  • ferroptosis

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Inducing angiogenesis - Angiogenesis 

a process of sprouting new blood vessels from existing ones 

Tumors cannot grow beyond a certain size without blood vessels to supply oxygen and nutrients 

Induced by vascular endothelial growth factor (VEGF) signaling 

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Inducing angiogenesis -  Therapeutic intervention

VEGF inhibitors

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Activating Invasion and Metastasis

tumor cells spread and grow in distant organs - metastasis

advanced stages of cancer

<p>tumor cells spread and grow in distant organs - metastasis </p><p>advanced stages of cancer </p><p></p>