elsaid - mechanisms of carcinogenesis and overview of anticancer drugs

neoplasia

new growth or autonomous growth of tissue

neopalsm

the lesion resulting form the neopalsia

benign

lesions characterized by expansive growth, frequently exhibiting slow rates of proliferation that do not invade surrounding tissues

malignant

lesions demonstrating invasive growth, capable of metastases to other tissues and organs

metastasis

secondary growths derived from a primary malignant neoplasm

cancer

malignant neoplasm

carcinogen

a physical or chemical agent that causes or induces neoplasia

genotoxic

carcinogn that interacts with DNA resulting in mutation

nongenotoxic

carcinogen that modify gene expression but do NOT damage DNA

carcinogenesis process:

• initiation

carcinogenic agent (chemicals, radiation, viruses) causes DNA damage and cell mutation —> mutated cell

• DNA modification

• mutation

• genotoxic damage

• one cell division is necessary to lock in mutation

• nonreversible

carcinogenesis process:

• promotion

activation of oncogenes (proteins that help the cell proliferation) by promoter agent

• no direct DNA modification

• nongenotoxic

• no direct mutation

• multiple cell divisions necessary

• clonal expansion of the initiated cell population

• increase in cell proliferation and/or resistance to cell apoptosis

• reversible

carcinogenesis process:

• progression

malignant tumor caused by over expression of oncogenes

• irreversible

• changes from preneoplasia to neoplasia

• mutation, chromosome rearrangement, DNA modification

original hallmarks of cancer

• sustained proliferative signaling

  • cancer cells always want to proliferate (S —> M phase)

• evading growth suppressors

  • cancer cells avoid signals from growth suppressor proteins

• including angiogenesis

  • making new blood vessels to gain more nutrients and oxygen for growth

• activating invasion and metastasis

  • different between different cancers (some can be more metastatic than others)

• resisting cell death

• enabling replicative immortality

enabling factors of cancer

• avoiding immune destruction

  • express misfolded proteins (immunogenic antigens) on surface to evade immune system

• deregulating cellular energetics

emerging hallmarks of cancer

• tumor promoting inflammation

• genome instability and mutation

chemical carcinogenesis

• chemical initiation causes DNA damage —> mutated/affected cell

  • DNA damage is greater than DNA repair

• muted cells proliferate more than p53 (tumor suppressors) can cause apoptosis of the mutated cells

• pre-cancer —> progresses into cancer

spectrum of DNA damage

• single strand and double strand breaks

  • ds breaks = more significant and more opportunities for repair to go wrong

• apurinic or apyrimidinic (abasic) sites (depurination or depyrimidation)

  • missing a base (either purine or pyrimidine base)

• DNA adduct formation and crosslinking

  • adduct formation = chemical moiety that reacts w/ purine or pyrimidine base (covalent bond)

  • crosslinking = chemical moiety reacts w/ bases on BOTH strands of DNA and joins them together

what can cause DNA damage?

• UV, x-rays, gamma rays

• chemicals (e.g. reactive oxygen and nitrogen species, environmental toxins)

• antineoplastic drugs (DNA-directed cytotoxic agents)

chromosomal rearrangements:

• deletion

nucleotide(s) removed from a chromosome

chromosomal rearrangements:

• duplication

a segment of DNA is duplicated

chromosomal rearrangements:

• insertion

extra nucleotide base(s) are added into the DNA sequence

chromosomal rearrangements:

• inversion

rearrangement of a segment of a chromosome is flipped/reversed

chromosomal rearrangements:

• translocation

part of one chromosome breaks off and attaches to another chromosome OR two chromosomes exchange pieces

outcomes of chromosomal rearrangements

• loss of function mutation in tumor suppressor genes

• gain of function mutation in oncogenes

• creation of fusion genes resulting in expression of fusion proteins (proliferation enhancement)

oncogenes

• genes for growth factor receptors

• EGFR or erbb1 (codes for epidermal growth factor receptor)

• HER2 or erbb2 (codes for a growth factor receptor)

• genes for signaling cascade proteins

• KRAS (codes for guanine nucleotide-proteins with GTPase activity)

• genes for cytoplasmic kinases BCR-ABL (codes for non-receptor tyrosine kinase)

tumor suppressor genes

• APC (colon/rectum carcinoma)

• BRC1 (breast and ovarian) and BRCA2 (breast)

  • encode for DNA repair proteins

• DPC4 (pancreatic)

• INK4 (melanoma, lung, brain)

• MADR2 (colon/rectum)

• P53 (multiple cancers)

  • induces apoptosis

• PTEN (brain, melanoma, prostate)

• Rb (retinoblastoma, bladder, breast)

• VHL (renal cell carcinoma)

cellular growth signals:

• stimulatory pathways

1. neighboring cells release growth-stimulatory factors

2. stimulatory factor binds to receptors on cell surface

3. cytoplasmic relay proteins activates transcription factors

4. transcription factors produce proteins that trigger cell division

cellular growth signals:

• inhibitory pathways

1. neighboring cells release growth-stimulatory factors

2. stimulatory factor binds to receptors on cell surface

3. cytoplasmic relay proteins activates transcription factors

4. transcription factors produce proteins that inhibit cell division

stimulatory abnormality

cell divides in the absence of external growth factors

inhibitory abnormality

relay molecule is lost —> cell divides when it should not because inhibitory signal fails to reach nucleus

what regulates progression through the phases of the cell cycle?

a family of proteins called Cyclins and associated kinases (Cyclin-dependent Kinases; CDKs)

cyclin and CDK that controls cell cycle phase activity in G1 phase

• Cyclin D1, D2, D3

• CDK 4 and CDK 6

cyclin and CDK that controls G1/S phase transition

• Cyclin E

• CDK 2

cyclin and CDK that controls cell cycle phase activity in S phase

• Cyclin A

• CDK 2

cyclin and CDK that controls G2/M phase transition

• Cyclin A

• CDK 1

cyclin and CDK that controls mitosis

• Cyclin B

• CDK 1

cyclin and CDK that controls CAK, all cell cycle phases

• Cyclin H

• CDK 7

regulation of the cell cycle by Cyclin-Dependent Kinases (CDKs)

cell cycle inhibitors

• palbociclib

• ribociclib

• abemaciclib

MOA of cell cycle inhibitors

inhibits CDK4 —> cells stuck in G1 and does NOT proliferate

• CDK4 + cyclin D1 phosphorylates Rb

• phosphorylated Rb activates E2F (elongation factor)

• E2F promotes transition from G1 —> S —> cellular proliferation

conventional antineoplastic agents

• alkylating agents

• antimetabolites

• antimitotic (antimicrotubules) agents

• topoisomerase inhibitors

• miscellaneous DNA directed agents

hormonal agents

• SERMS (selective estrogen receptor modulators)

• aromatase inhibitors

• anti-estrogens

• anti-androgens

• inhibitors of steroidogenesis

immunotherapy

• monoclonal antibodies

• immune checkpoint inhibitors

• therapeutic vaccines

targeted treatments

• tyrosine kinase inhibitors

• signal pathway inhibitors

• differentiating agents

drugs that block topoisomerase function

• camptothecins

• etoposide

• teniposide

• daunorubicin

• doxorubicin

drugs that forms adducts with DNA

• platinum analogs

• alkylating agents

• mitomycin

• cisplatin

• temozolomide

mechanisms of resistance to the effects of anti-cancer drugs

• up regulation of the MDR efflux pumps

• decreased cellular uptake (if the anticancer drug requires a transporter for cellular uptake) by down regulation of uptake transporters

• increased concentration of cellular target (enzyme, structural protein) or a mutated target (reducing binding affinity)

• detoxification of the reactive species of the drug by glutathione

• enhanced DNA repair and failure to induce apoptosis

distribution of anticancer agents

• cancer mass is heterogeneous with cancer cells having different rates of proliferation depending on the presence of blood vessels and nutrient supply

• hypoxic conditions can result in low cell proliferation and resistance towards anti-proliferative and cytotoxic agents

• off-target effects of anticancer drugs account for their toxicities

• EPR effect (enhanced penetration and retention):

  • molecules of certain size (liposomes, nanoparticles) accumulate more in cancer tissues than normal tissues