3.2 anti-cancer (antineoplastic drugs)

what mainly kills patients?

metastases

four cancer treatment options

• surgery: primary tumors and isolated metastases

• radiotherapy: not for disseminated

• cytotoxic chemotherapy: curative but high toxicity

• targeted chemotherapy: interfere w specific molecule involved in tumor growth and progression

tumor heterogeneity

more hetero= more drug resistance; vary in number of receptors, enzymes produced, etc.

what normal tissues also have rapid rate of cell prolif?

bone marrow, oral mucosa, GI mucosa, hair follicles

*brain (supportive cells not neurons) to but chemo drugs usually do not go past BBB

(specificity on rapidly dividing cells or cell cycle)

long-kill hypothesis:

chemotherapy cycles so bone marrow can recovery (it is suppressed) but not too long to let tumor grow significantly

chemotherapy involves combos of agents with different (blank) and act at different cell cycle points to (blank)

mechanisms of action

minimize drug resistance and side effects

main major toxicities of cancer chemotherapy

• oral toxicity of neoplastic drugs (methotrexate especially)

• nausea and vomiting

5-HT3 R antagonist

setrons (ex: ondansetron)

• in GI mucosa neuroendocrine cells secrete hormones like serotonin and act on 5-HT3 receptors and leads to nausea and vomiting; an antagonist would reduce these symptoms

the three phase specific anticancer agents:

• antimetabolites (S phase)

• antibiotics (G₂)

• vinca alkaloids, paclitaxel (taxol) and docetaxol, etoposide (M phase)

phase non-specific anti-cancer agents:

alkylating agents, platinum complexes

explain G₀, G₁, S, G₂, and M phases

1. G₀: quiescent

2. G₁: S checkpoint; growing and making necessary proteins

3. S: DA synthesis

4. G₂: mitosis checkpoint (proofread, excision and ligation if needed; double helix)

5. M: mitosis divide 2 daughter cells; microtubules

antimetabolites:

• what phase?

• what are the two types and mechanism of action?

• S phase

• anti-folate ex: methotrexate (oral toxcicity)

  • inhibits DHFR which reduces folate to tetrahydrolfolate ending with cofactors that provide DNA and RNA synthesis essentials like carbon groups

• pyrimidine (fluorouraciil) and purine (mercaptopurine) analogues

  • structurally similar to but functionally diff from bases; DNA cannot join

antibiotics:

• what phase?

• what are the two types and mechanism of action?

• G₂

• bloemycin: DNA scission and fragmentation inhibit repair

  • minimal nausea and vomit, little mylosuppression, and no local toxicity but possible pumonary toxciity (!!!)

  • superoxide and hydroxyl radicals = strand breaks

• doxorubicin (adriamycin): anthracycline Ab indices strand breaks in DNA

*reduce Fe and is free radical which is hramful to DNA synthesis

topoisomerase inhibitors like etoposide acts during which phase? what is its mechanism of action?

• G₂

• deactivates topoisomerases into inactive form and that leads to apoptosis of cancer cells

• natural alkaloid derived from mandrake root

the two types of M phase cancer agents that act around microtubules?

• vinca alkaloid: prevents microtubule formation

• paclitaxel (taxol and docetaxol): promotes microtuble formation

docetaxol MOA:

promote and stabilize microtubule assembly preventing physiological microtubule disassembly (depolymerization), additionally ells do not have infinite resources of tubulin which accumulates inside cell and cause apoptosis initiation

type and mechanism of action of alkylating agents:

• nitrogen mustards (cyclophosphamide/cytotxan) and nitrosoureas (carmustine and lomustine)

• MOE: react w proteins that bond together to form double helix structure of DNA and add alkyl group; incorporating alkaline groups and double helixes mess up linkage an cause breaking

• phase non-specific

cisplatin MOA:

phase non-specific anti-cancer agent

causes most severe nausea and vomiting; blu line on gingiva by platinum deposition (!!!!)

MOE: forms adducts to purine bases A and G interferes w repair mechanisms therefore damage and then apoptosis of cancer cells; not analogues just high affinity to A and G

two main forms for targeted chemotherapy drugs?

• monoclonal Ab: man-made large Abs attack secific cell targets or other cells (-mab)

• small-molecule drugs: not Abs (-ib)

tyrosine kinase inhibitor (imatinib-gleevec) MOA:

• small-molecule drug

• bind active site of tyrosine in cancer cells and lock enzyme in inactive form and blocks phosphorylation leading to apoptosis

apoptosis-inducing drugs like proteasome inhibitors MOA:

• small-molecule inhibitor

• normally proteasomes break down proteins that normally cause cell to die to prolong life; these drugs stop proteasome activity which makes cancer cell die

Rituximab MOA:

monoclonal Ab; target CD20 on mature B cells (lymphomas) to initiate cascade of complement dependent cell lysis and Ab dependent cellular cytotoxicity

Cetuximab MOA:

monoclonal Ab directed against EGFR (epidermal growth factor receptor) that is over-expressed on rapidly dividing cells and this interrupts phosphorylation and then apoptosis

Trastzumab (herceptin) MOA:

• HER2 breast cancer, over-expressed

• monoclonal Ab against human EGFR-2 or HER2; inhibition of homo or heterodimerization of receptor that prevents receptor kinase activity and leads to blocking of angiogenetic effects of HER2 signaling

other angiogenesis inhibitors

• bevacizumab/avastin and ramucircumab/cyramza

• block VEGF (vascular endothelial growth factor) proteins or VGEF receptors; these proteins using help new blood vessels form around tumor

• toxicity: vessel injury and bleeding, hypertension

steroid hormone antagonists:

• selective estrogen receptor modulators (SERMs); tamoxifen; estrogen receptor antagonist

• aromatase inhibitors: block aromatase, estrogen receptor blocked and cancer cels die

  • selective inhibition: low estrogen = cancer cell death

  • Anastrozole/arimidex, exemestane/armasin, letrozole/femara

ADCs

• antibody-drug conjugates= monoclonal Ab attached to toxins; maybe not toxic on their own but they carry something toxic and carry to cancer cells

• ex: radiolabeled Abs like Ibtrumomab/zevalin

  • CD20 antigen , non-hodgkin lymphoma

• chemolabeled Abs

  • Brentuximab vedotin has the drug MMAE to CD30 antigen on lymphocytes

  • rituximab-vcMMAE combines rituximab abd MMAE potent mitotic inhibitor

dental considerations

• NSAIDs are anti-platelet so bleeding is a problem; use another analgesic (thrombocytopenic)

• methotrexate renal clearance decreased by NSAIDs

• CYP3A4 substrates (cyclophosphamide, vincristine) and 3A4 inhibitors may delay elimination and enhance toxicity