Antineoplastic and Anticancer drugs Flashcards
Cancer definition
Loss in the normal control mechanisms that govern cell survival, proliferation, and differentiation
Oncogenes
Normally tightly regulate growth and differentiation of cells
Always on = cancer
Ex: Bcl-2 is up or downregulated in cancer
Tumor suppressor genes
Normally suppress overgrowth of cells
Missing = cancer
Ex: p53 is downregulated or absent in many cancers
4 most common cancers in Canada and their 4 year survival rate
Lung (17%)
Prostate (95%)
Breast (87%)
Colorectal (64%)
Stages of cancer
0: early cancer, not detectable
1-3: higher number reflects increase in size and spread
4: Invasion of other tissues and metastasis
3 ways cancer is treated
- Surgical removal of tumor
- Radiation (non-specific cytotoxicity and cell death)
- Chemotherapy
3 Processes chemotherapy targets
- Targets cell cycle (kill rapidly dividing cells - traditional agents)
- Target proliferation pathways (newer agents)
- Target cancer specific molecules (targeted anticancer agents)
3 Principles of chemotherapy
- Chosen dose must be tolerable (so that course can be completed - administer maximum tolerated dose (MTD))
- Dose and regimen must be chosen to maximize effectiveness (cyclic therapy - multiple growth cycles of tumor)
- Use combinations to increase efficacy
4 Classes of traditional antineoplastic agents
Alkylating and platinum agents (cross link DNA molecule)
Antimetabolites (nucleotide synthesis)
Topoisomerase inhibitors and antibiotics (interfere with DNA replication and transcription machinery)
Vinca alkaloids and taxanes (mitotic spindle)
Alkylating and Platinum Agents
Covalently (irreversibly) bind to DNA
Inhibits synthesis and function = death
Not cell cycle specific
Cyclophosphamide
Alkylating agent
Has a bis(chloroethyl)amine group
Needs to be activated in the liver (its a prodrug) - end up with Phosphoramide mustard
Metabolites cross link DNA (instead of H bonds holding the DNA together you get covalent bonds - cannot unwind)
Can bind to other molecules with similar functional groups - causes issues
Platinum containing agents
Similar to the alkylating agents, but do not necessarily contain alkyl groups
Cause inter and intra DNA strand cross links in cells, similar to mechanism of alkylating agents
Antimetabolites
Similar in structure to endogenous compounds (folic acid, nucleotide bases)
Prevents DNA synthesis
S phase specific
Purine antagonists
An antimetabolite
Ex: Mecaptopurine (structurally similar to adenine, interacts with enzymes involved in purine nucleotide synthesis)
Incorporated into RNA and DNA like adenine would be, but is unable to make correct base pair
Interferes with DNA replication and RNA translation
Pyrimidine antagonists
An antimetabolite
Ex: Flurouracil (Similar structure to uracil and thymine)
Binds thymidylate synthase, preventing further synthesis of thymidine nucleotides
Interferes with DNA replication and RNA translation
Folic acid antagonists
Folic acid is an essential co-factor in DNA and protein synthesis
Methotrexate is structurally similar to folic acid (an antimetabolite)
Topoisomerase 1 inhibitors
Ex: Topotecan
Bind to enzyme, produces a fixed complex that prevents further DNA replication and transcription
Halting the replication process signals cell death
Topoisomerase 2 inhibitors
Anthracyclin antibiotics (ex: doxorubicin) Prevents re-ligation of DNA strands by TopoII Strand breaks in DNA signal Cell death pathways
Anthracycline Antibiotics
Ex: Doxorubicin
Natural products from Strep.
Intercalate between strands, stabilize DNA-TopoII complex
Forms free radicals that can cause additional DNA damage
Side effect: cardiotoxicity
Vincristine
mechanism and adverse effects
A Vinca alkaloid
Prevents microtubule formation of mitotic spindles (inhibits cellular division)
Adverse effects: abdominal pain, bone pain, constipation
Neuropathic pain
Docetaxel
A taxane
Stabilizes microtubules of mitotic spindles (can’t disassemble)
Inhibits cellular division
Adverse effects of antineoplastic drugs
Do not differentiate between cancerous and non-cancerous cells
Cells with high turnover rate are more susceptible to damage (oral cavity, GI tract, skin/hair, immune system)
Some cause immunosuppression (kill actively dividing immune cells)
Infections
Example of combination therapy
CAV for lung cancer
C (cyclophosphamide - alkylating agent)
A (doxorubicin - intercalates DNA, stabilizes TopoII, generates free radicals)
V (vincristine - anti-mitotic agent)
5 things the newer targeted anticancer drugs effects
Cellular markers Growth and proliferation New blood vessel growth Survival proteins Hormone sensitive growth
CD-20
Protein expressed on surface of immune B cells
Many forms of lymphoma and leukemia are CD-20 positive
Normal B cells also have CD-20 but they are replaced by progenitor stem cells after treatment
Rituximab
Membrane bound Ab targeted to CD-20 (flags B cells for destruction by immune system)
Given by IV
Once bound, immune cell recognizes and kills via ADCC
Results in the death of CD-20 positive B cells
Radioimmunoconjugates
Radiation therapy effective in treating localized solid tumors (significant damage to neighbouring tissues)
mAb conjugated radioactive isotopes (targets radioactivity to tissues expressing antigen)
Tositumomab
CD-20 targeted radionuclides - conjugated with I-131
Radiation kills CD-20 positive cell and adjacent cells
Sipuleucel-T vaccine
Provenge
Personalized medicine
Remove cells patient’s tumor or blood, manipulate them and re-inject into patient
Angiogenesis
Growth of blood vessels Inhibit VEGF (vascular endothelial growth factor) to decrease blood vessel growth
3 drug target sites in tyrosine kinases
- Bind circulating ligand
- Block receptor
- Prevent receptor activation (inhibit phosphorylation)
Bevacizumab
mAB targeted against VEGF
Binds ciruclating VEGF so less available to bind to receptor
Results in reduced blood vessel growth in tumors
Sorafenib
Small molecule TK inhibitor
Binds to intracellular domain of VEGFR
Prevents initiation of signalling cascade
Epidermal growth factor (and its receptors)
Stimulates cellular growth and proliferation
2 receptors: EGFR and HER-2
Both tyrosine kinase receptors
HER-2 upregulated in breast cancer
2 main types of tyrosine kinases and their receptors
- Receptor TKs (membrane bound) - Ex: HER-2
2. Cytosolic TKs (cytosolic) - Ex: Bcr-Abl
Trastuzumab
Interferes with EGF signalling (mAb against EGFR)
Specifically targets HER-2
First line therapy in HER-2 positive breast cancer
It prevents intracellular binding and flags for immune system to destroy
Also enhances the effects of chemo
Trastuzumab emansine
Trastuzumab and antimicrotubule agent
Drug circulates and targets HER-2 positive cells
Cytotoxic drug enters cell and inhibits microtubule assembly (like vincristine)
Gefitinib
Binds to intracellular domain of EGFR (small molecule TK inhibitor)
Prevents initiation of signalling cascade
Inhibits cell growth and proliferation
Bcl-2
Pro-survival signal on mitochondrial membrane
Elevated levels of Bcl-2 allow cells to ignore signals to undergo apoptosis
Imatinib
Inhibits intracellular TK receptor BCR-ABL
BCR-ABL activation results in upregulation of Bcl-2 (drug prevents this)
Primary resistance
Drug is ineffective on first attempt
Acquired resistance
Drug worked at first, then become ineffective
Related to adaptation and mutation of tumor cells
Altered expression of proteins in tumor cells
Increased DNA repair mechanisms
Alterations in drug targets
Removal of drug from target cells
P-glycoprotein pumps
and what are particularly sensitive to them
Increase drug efflux = decrease drug effect!
Particularly sensitive are the: antibiotics, vinca alkaloids, taxanes, small molecule inhibitors (the -nib agents)
Leuprolide
Synthetic analogue of GnRH
Agonist-Antagonist (antagonist long term, agonist short term)
Over time, decrease in FSH and LH production (negative feedback) = decreased estrogen (yay!)
Also decrease testosterone
Letrozole
Inhibits the aromatase enzyme necessary for the conversion of estrogen
Tamoxifen
Estrogen antagonist
Competes for estrogen receptor binding in tumor cells (binds to receptor and prevents downstream signalling and proliferation)
Slows growth of estrogen sensitive tumor cells
Combination therapy
More targets available
Principles of combo therapy are the same
Combos of old and new agent antineoplastics are first line chemo in most cancers
R-CHOP regimen
Combination therapy used in non-Hodgkin’s lymphoma
R: Rituximab
C: cyclophosphamide
H: doxoribicin
O: vincristine
P: prednisone (corticosteroid, reduces some side effects)
