Cancer chemotherapy Flashcards
Alkylating agents
Create covalent linkage between DNA strands or within strand by crosslinking two guanines, thus impeding its replication.
N7 in the guanines is very nucleofil and probably the most important target for the alkylating compounds.
Side effects: depress bone marrow function and cause hair loss and diarrhea. Depression of gametogenesis, leading to sterility, and increased risk of a second malignancy occur with prolonged use.
Antimetabolites
Interfere with the normal metabolic pathways of essential cellular components, such as nucleotides or amino acids. By structurally resembling endogenous metabolites, antimetabolites can be incorporated into DNA, RNA, or proteins during cellular replication or synthesis. Once incorporated, antimetabolites disrupt essential cellular processes, such as DNA replication, RNA synthesis, or protein synthesis, leading to inhibition of cell proliferation and induction of apoptosis.
Includes folate antagonists, purine analogs, pyrimidine analogs.
Folate antagonists
The drug interferes with the synthesis of DNA and RNA by inhibiting the enzyme dihydrofolate reductase. This inhibition leads to depletion of tetrahydrofolate, a cofactor required for the synthesis of nucleotides. Without sufficient nucleotides, DNA replication and RNA synthesis are impaired, resulting in cell death.
Unwanted effects: depression of bone marrow and damage to the epithelium of the GI tract. High doses can lead to nephrotoxicity.
Purine analogs
Such as mercaptopurine and fludarabine. Mimic the structure of purine nucleotides. By interfering with purine metabolism and nucleotide synthesis, these analogues inhibit DNA and RNA synthesis, leading to cell death.
Pyrimidine analogs
Structural analogies of the pyrimidine nucleotides (such as fluorouracil and cytarabine). Once incorporated into DNA or RNA, these analogues disrupt nucleic acid synthesis and inhibit cell proliferation.
Antimitotics
Interfere with cell division by inducing the disaggregation of microtubules.
Such as Vinka alkaloids and Taxaner.
Vinka alkaloids (antimitotics)
Vinka alkaloids bind to tubulin subunits and inhibit microtubule polymerization. They bind to the β-tubulin subunit of microtubules, preventing the addition of new tubulin subunits to the growing microtubule, thereby inhibiting microtubule assembly. By inhibiting microtubule polymerization, vinka alkaloids disrupt the formation of the mitotic spindle during cell division, leading to cell cycle arrest at the metaphase stage.
Taxanes (antimitotics)
Taxanes stabilize microtubules by binding to β-tubulin subunits, promoting microtubule polymerization and inhibiting microtubule depolymerization. They promote the formation of stable microtubule bundles that cannot undergo depolymerization.
By stabilizing microtubules, taxanes disrupt the dynamics of the mitotic spindle and interfere with chromosome segregation during cell division. They also inhibit cell migration and angiogenesis, processes that are important for tumor growth and metastasis.
Topoisomerase inhibitor
Stops the DNA replication and destroys DNA.
Two types: topoisomerase 1 and topoisomerase 2 inhibitor.
Topoisomerase 1 inhibitor
Topoisomerase 1 function is to bind to DNA and cause single strand breakage, unwinding and re-ligation.
The topoisomerase 1 inhibitor bind to topoisomerase 1 and prevent DNA re-ligation, thus the DNA is left with single strand breaks, that later turns into double strand breaks.
Side-effects: GI effects, potentially life-threatening diarrhea.
Topoisomerase 2 inhibitor
Bind to topoisomerase 2 and prevent DNA re-ligation, thus the DNA is left with double strand breaks.Triggers cell cycle arrest and apoptosis.
Protein kinase inhibitors
An enzyme inhibitor that blocks the action of one or more protein kinases.
Many tyrosine kinase receptors that upon ligand binding activates intracellular signaling cascades that will eventually lead to increased growth and cell division. Many types of cancers over-express a tyrosine kinase receptor or express a mutated constitutively active tyrosine receptor.
There are different kinds:
BCR-ABL/C-kit/PDGFR inhibitor.
EGF receptor antagonist.
Erb2/HER2 inhibitor.
VEGFR inhibitor.
EGF receptor antagonist (protein kinase inhibitor)
EGF receptor antagonists target the epidermal growth factor receptors (EGFR), which is overexpressed or dysregulated in many solid tumors. They block the binding of EGF or other ligands to EGFR inhibiting downstream signaling pathways involved in cell proliferation and survival.
Erb2/HER2 inhibitor (protein kinase inhibitor)
ErbB2/HER2 inhibitors target the human epidermal growth factor receptor 2 (HER2), which is overexpressed in certain types of breast cancer. The drug bind to the HER2 receptor, leading to inhibition of downstream signaling pathways involved in cell growth and survival.
VEGFR inhibitor (protein kinase inhibitor)
Vascular endothelial growth factor receptor (VEGFR) inhibitors target the VEGF signaling pathway, which plays a critical role in angiogenesis (formation of new blood vessels) and tumor growth.
When inhibit the VEGFR signaling, this is leading to disruption of tumor vasculature and inhibition of tumor growth and metastasis.
