Cancer 2.0 Flashcards
Explain the cell cycle and involved drug classes
Go= resting phase (dormant, hidden cancer cells)
Growth factors between G1 and G0
Temsirolimus works on G1
Checkpoint 1 between G1 and S
DNA synthesis inhibitors work on S phase
G2 = bleomycin, etoposide, and teniposide
Checkpoint 2 between G2 and M
M= mitotic inhibitors
Nonspecific= all DNA alkylating and most DNA intercalating
Explain tumour hypoxia
Limits chemo ability
Further from capillary = less oxygen
Less vasculature to get chemo
Explain clonal selection
Increased resistance from second round of chemo, increases w/ more rounds.
Commensalism
Explain tumour initiation and metastasis
- Initiation of growth of tumour
- metastasis initiation = invasion, angiogenesis
- metastasis progression = remodelling, immune evasion
Leads to metastasis virulence= organ specific function
Simply, blood vessel breaks and primary tumour spreads. No pattern in brain. Bone pattern= prostate.
Explain tumour staging
TNM method to provide informed plan
T= size of primary tumour (0-3)
N= extent of lymph node spread (0-3)
M= distant metastasis (organ specific)
Principles of chemotherapy
Treat blood cancers that cannot be surgically removed
Combined w/ surgery or radiation to treat solid tumours
Palliative therapy
Limitations of chemo
Drug resistance:
- abnormal gene mutations/expression
- proapoptotic expression changes
Multidrug-resistance protein (MRP) and P-glycogprotein (Pgp)
Drug toxicity:
- myelosuppression (RBC, WBC)
- N/V
- Alopecia
- Tumour lysis syndrome
- Secondary cancers
Methotrexate class and MOA
DNA synthesis inhibitor / folate antagonist
Inhibit dihydrofolate reductase (DHFR) to prevent conversion of dihydrofolate to tetrahydrofolate. Stop DNA synthesis.
Pemetrexed class and MOA
DNA synthesis inhibitor / folate antagonist
Inhibit DHFR, TS, and GARFT to prevent conversion of dihydrofolate to tetrahydrofolate. Stop DNA synthesis. Tetra=DNA synthesis.
Methotrexate PK
Oral or intrathecal
Does not penetrate CNS, intrathecal only
Renal excretion
DNA synthesis inhibitor indications
Methotrexate- trophoblastic (repro), blood, and solid.
Pemetrexed- solid
DNA synthesis inhibitor ADR
- Myelosuppression (RBC and WBC- bone marrow suppression, anaemia, fatigue, low O2, immunocompromise, febrile neutropenia)
- GI toxicity - N/V
- Stomatitis
- Hepatotoxicity
- Renal toxicity
Toxicitiy can be reduced w/ folinic acid supplements. Leucovorin.
Mercaptopurine class and MOA
Purine analogue (A and G)
Inhibit purine biosynthesis to interfere w/ DNA synthesis.
Thioguanine class and MOA
Purine Analogue (A and G)
Inhibit purine biosynthesis to interfere w/ DNA synthesis.
Purine analogue ADRs
Dose-limiting myelosuppression w/ thioguanine. Mild w/ mercaptopurine.
Hepatotoxicity w/ mercaptopurine.
2nd cancers from both
Allopurinol in purine analogues
Mercaptopurine dose must be reduced in allopurinol
Purine analogue indications
Blood cancers
Cladribine for hairy cell leukaemia
Fludarabine class and MOA
Purine analogue
DNA chain termination. Incorporates itself into developing DNA to disrupt DNA synthesis.
Cladribine class and MOA
Purine analogue
DNA chain termination. Incorporates itself into developing DNA to disrupt DNA synthesis.
Cytarabine class and MOA
Pyrimidine antagonist (CTU)
Cytarabine active metabolites (di and triphosphates) block DNA synthesis. Inhibit DNA polymerase. Incorporate drug into growing chain to cause DNA chain termination.
Fluorouracil class and MOA
Pyrimidine antagonist (prodrug)
Converted to 5dUMP and 5dUTP. 5dUMP inhibits TS to stop thymidine synthesis.
5dUTP incorporated into RNA by RNApolymerase.
Gemcitabine class and MOA
Pyrimidine antagonist
Converted from mono to di and triphosphate (RNA integrity). Inhibits DNA synthesis during S phase.
Explain use of leucovorin w/ fluorouracil
Synergy.
Counter effects.
Synergy at receptor to bind more effectively.
Synergy w/ DUMP of fluorouracil.
Pyrimidine antagonist indications
Cytrabine IV or SC combined w/ daunorubicin
Fluorouracil IV for solid tumours. Topical for actinic keratosis.
Gemcitabine for pancreatic carcinoma w/ cisplatin for inoperable solids.
Pyrimidine antagonist ADRs
N/V usually mild
Myelosuppression
GIT and oral ulcers
Fluorouracil bolus injection (IV push) = myelosuppression
Mucosal damage = continuous IV
High doses= liver, heart, and organ damage
Rapid tumour lysis syndrome
Cyclophosphamide class and MOA
DNA alkylating drug
Converted to phosporamide mustard. Cross-link DNA strands by forming covalent bonds between alkyl groups and guanine bases. DNA synthesis disrupted. Partly converted to acrolein.
DNA alkylating drug ADRs
Alopecia
N/V - severe w/ IV
Myelosuppression - dose-limiting
Tumour lysis syndrome
Hemorrhagic cystitis (caused from acrolein, depletes thiol groups. Protect by mesna to replenish thiol groups).
Platinum compound drug example and MOA
Cisplatin and carboplatin.
Cross-link DNA by forming intra and interstrand covalent bonds w/ DNA bases. DNA synthesis disrupted.
Platinum compounds indications and ADR
IV- testicular, ovarian, cervical, bladder, melanoma.
ADR= significant N/V and nephrotoxicity. Mild myelosuppression.
Mitomycin C class and MOA
DNA alkylating drug
Alkylates DNA to break strand and inhibit DNA synthesis.
Mitomycin C indication and PK
Parenteral = activated by hepatic reduction
Indicated for salvage therapy for breast cancer in combination w/ vincristine.
DNA intercalating drugs/anthracyclines example and MOA
Daunorubicin, doxorubicin, and dactinomycin.
- Intercalate DNA.
- Inhibit topoisomerase.
- Produce free radicals
Bleomycin class and MOA
DNA intercalating drug
Intercalate DNA and produce free radicals.
G2 cell cycle specific.
DNA intercalating drugs / anthracyclines PK
IV= rapidly distributed to all tissues except CNS
Long half-lives. Bind to tissues. Large Vd. Liver metabolised.
DNA intercalating drug / anthracyclines ADR
Myelosuppression and cardiac damage (dose limiting)
NV dose related
Alopecia
Mucosal ulcerations
Tumor lysis syndrome
IV infusion can lead to severe localised tissue ulceration and necrosis (shai’s example)
Advantages of PEG liposomal doxorubicin
Pegylated liposomal coating allows drug to evade detection and destruction by immune system.
Increase blood circulation time.
Remain stable in blood.
increase delivery to tumour.
Less systemic side effects.
Drug stays encapsulated within liposome during circulation.
Coat and stability = better delivery, safer. Less cardiovascular events and less toxicity.
Bleomycin / DNA intercalating drug ADR
Very little myelosuppression
Often combined w/ myelosuppressive drugs
Pulmonary and mucocutaneous reactions (no aminohydrolase in skin)
Pneumonitis that progresses to interstitial fibrosis (lose elastic), hypoxia, and death.
Mild stomatitis, skin hyperpigmentation, erythema, and edema.
Why do you see hyperpigmentation w/ bleomycin use
Aminohydralase inactivates drug.
Not a high conc in skin or lungs
Drug build up = toxicity
Vinca alkaloids / mitotic inhibitor examples and MOA
Vincristine and vinblastine
Inhibit mitosis by blocking microtubule assembly. = Continued disassembly.
Vinca alkaloid / mitotic inhibitor PK
IV administration only, intrathecal will kill.
Does not enter CNS.
Biliary excretion, extensive metabolism.
Vinca alkaloids indications
Blood.
Solid= small-cell lung cancer and neuroblastoma
Vincristine and vinblastine ADR
Dose-limiting neurotoxicity (peripheral neuropathy)
Suppress deep tendon reflexes.
Parasthesia.
Cranial nerve damage= hoarse, facial palsies, jaw pain.
Autonomic neuropathies= orthostatic hypotension, abdominal pain, and constipation.
Vinblastine= dose-limiting myelosuppression. Little neurotoxicity.
Taxanes / mitotic inhibitor drug examples and MOA
Paclitaxel and docetaxel
Inhibit mitosis by blocking microtubule disassembly. = Continued assembly.
Taxane PK and indications
Given IV.
Eliminated via metabolism and biliary excretion.
Paclitaxel indicated for metastatic ovarian/breast cancer in combination w/ cisplatin or if unresponsive to first-line therapy.
Docetaxel indicated for castrate-resistant prostate cancer.
Taxanes ADR
Dose-limiting myelosuppression.
Alopecia.
Neurotoxicity.
Hypersensitivity reactions at site of infusion.
Explain nAB paclitaxel
Albumin-bound paclitaxel = better delivery and less toxicity
Etoposide class and MOA
Topoisomerase inhibitor / podophyllotoxin
Cause double stranded DNA breaks by inhibiting topoisomerase 2.
Camptothecin analogue / topoisomerase inhibitor examples and MOA
Topotecan and irinotecan.
Cause single stranded DNA breaks by inhibiting topoisomerase 1.
Etoposide (T2) PK and indications
TDM important- oral bioavailability varies between patients, so check for over/underdosing.
Unchanged in urine.
Synergy w/ platinum compounds.
Indicated for preoperative treatment for bone marrow transplant
Etoposide ADR
Well tolerated.
Alopecia, mild N/V, dose-limiting myelosuppression.
Low incidence of secondary nonlymphocytic leukemias.
Camptothecin analogue (topotecan and irineotecan) PK and indications
IV. Prodrugs.
Indicated for colorectal cancer that has recurred or progressed following fluorouracil therapy.
Camptothecin analogue ADRs
Myelosuppression - dose-limiting - both.
Irinotecan = diarrhoea
Both = alopecia and mild N/V
Imatinib class and MOA
Protein kinase inhibitor
Inhibit BCR-ABL tyrosine kinase that decreases transformation and proliferation. Increases apoptosis.
Erlotinib class and MOA
Protein kinase inhibitor
Inhibit epidermal growth factor (EGFR), which decreases proliferation, metastasis, and angiogenesis.
Increases apoptosis.
Abemaciclib class and MOA
Protein kinase inhibitor
Inhibit CDK4 and 6. Prevents transition from G1 to S phase.
Arrests cell in G1 phase to prevent DNA synthesis.
Encorafenib class and MOA
Protein kinase inhibitor
Inhibit BRAF gene. Prevent activation of RAF/MEK/ERK signalling pathway to prevent tumour proliferation.
Venetoclax class and MOA
Monoclonal antibody.
Inhibit BCL-2 and promote apoptosis.
Sunitinib class and MOA
Protein kinase inhibitor
Inhibit VEGFR to decrease angiogenesis.
Rituximab class and MOA
Monoclonal antibody.
Bind to CD20 antigen on surface of non-Hodgkins lymphoma cell to prevent cell cycle initiation.
Cetuximab class and MOA
Monoclonal antibody.
Antobody to EGFR. Decrease proliferation, metastasis, and angiogenesis.
increase apoptosis.
Bevacizumab class and MOA
Monoclonal antibody
Antibody binds to VEGF that inhibits angiogenesis.
Trastuzumab class and MOA
Monoclonal antibody
MAB binds to HER2/neu receptor which inhibits cell proliferation.
Ipilimumab class and MOA
MAB / immunomodulator
Antibody binds to CTLA-4 and leads to T-cell activation.
Pembrolizumab and nivolumab class and MOA
MAB / immunomodulator
MAB binds to PD1 receptor. Blocks interactions between ligands, PD1, PDL1 and 2. = Increase T cell activation.
Trastuzumab ADRs
Chills, fever, N/V, chest pain, and dyspnoea.
Ipilimumab (Yervoy) ADR
Immune-related
- colitis
- hepatitis
- dermatitis
- neuropathies
Pembrolizumab (Keytruda) ADR
Pneumonitis
Colitis
Hepatitis (and autoimmune)
Hypophysitis
If SE, stop drug forever.
Abemaciclib indication
HR+ve or HER2-ve
metastatic breast cancer
Tamoxifen class, MOA, and use.
Oestrogen antagonist. Starve tumour of hormones. Prevent breast cancer. Combination w/ surgery to treat.
Aromatase inhibitors examples and MOA
Anastrozole and letrozole.
- prevent oestrogen synthesis
Gonadotropin-releasing hormone agonist example and MOA
Leuprorelin
Increase testosterone levels, increase DHT, then hypothalamus stops production of T.
Bad SE at first because tumour size increases for 2-3weeks at start
Gonadotropin-releasing hormone receptor antagonist example and MOA
Degarelix
Block GNRH on testes. Androgens release T from testes.
Corticosteroid MOA in cancer
switch off hypothalamus androgen production. Block ACTH.
5a-reductase inhibitor example and MOA
Finasteride
Decrease DHT = stop tumour proliferation.
ADT side effects
Sexual - erectile dysfunction, libido loss, genital shrinkage
Physical - weight gain, gynaecomastia, muscle atrophy
Metabolic - osteoporosis, anaemia, hypertension, diabetes, heart disease, dyslipidemia
Emotional
Systemic - fatigue
Tumour “flare” - GnRH agonist
Principles of radiotherapy
Direct= radiation->DNA damage-> cell death
Indirect= radiation-> free radicals-> DNA damage-> cell death. (increase cytokine production)
External vs internal radiotherapy
External= x-ray, gamma, proton beams
Internal= brachytherapy.
ADR of radiation
Psychological= depression
Fatigue
Skin= dermatitis.
Cardio/pulm= CVD. Pneumonitis.
GIT= dry mouth, esophagitis, diarrhea, N/V.
Genitourinary= erectile dysfunction, dry vagina, infertile, cystitis, teratogenic.
Radiation recall= skin necrosis, inflammatory response. Only problem if radiation+chemo.
