Wk 7 Natural Chemotherapy Agents Flashcards
Name of 2 topoisomerase I inhibitor
Irinotecan
Topotecan
-both are Camptothecins
2 Topoisomerase II inhibitors
- Doxorubicin (an anthracycline)
- Etoposide (an epipodophyllotoxin)
Microtubular targeting agents
Vincristine - a vinca alkaloid
Paclitaxel - a taxane
Antibiotic chemotherapy
Bleomycin
Selective estrogen receptor modulator
Tamoxifen
LHRH agonist
Goserelin
What are the ABCDEs of melanoma?
A = asymmetry
B = border
C = color
D = diameter
E = evolution (melanomas change rapidly, nevi usually don’t)
What is a nevi?
a neoplasm that’s usually benign
-increase risk of melanoma
-common
What are tx options for malignant melanoma?
Immunotherapy: anti-CTLA4, anti-PD1
BRAF inhibitors
Melanoma Risk Factors
-lighter pigmentation, sunburns at young age, more UV exposure
-worse melanoma-specific survival w/ African ancestry
-p16 loss (encoded at CDKN2A)
-spontaneous melanoma w/ BRAF-activating mutations (others: NRAS, KIT, TERT promotor mutations)
MOA of Topoisomerase I inhibitors
Topoisomerase I relaxes supercoiled dsDNA
-inhibitors bind DNA and topo I together until the DNA replication fork reaches the cleavable complex and causes dsDNA breaks
-S-phase specific
-resistance can occur from mutations in topo I, decreased intracellular retention or reduced [topo I]
MOA Irinotecan
AKA SN-38
-is a prodrug
-activated by carboxylesterdase in tissues and serum
-glucuronidation = breakdown pathway
-need to check for genetic polymorphism b/c can be highly toxic w/ breakdown pathway
Irinotecan Tox
Diarrhea
-neutropenia, mucositis, N/V, alopecia
MOA Topo II inhibitors
-Topo II unwinds supercoiled dsDNA
-inhibitors bind DNA and topo II together, making transient cleavable complexes continually cleavable, preventing re-ligation
-S-phase sensitive
-Resistance due to p-glycoprotein upregulation, increase in drug degradation, or decreased [topo II]
Etoposide
AKA VP-16
IV/PO
-hepatic metabolism
-renal excretion
AE: myelosuppression, delayed secondary malignancies
Anthracycline (Doxorubicin) MOA
Intercalates w/ DNA, interferes w/ uncoiling:
-interferes w/ topo II preventing strand reconnection
-intercalation alters shape, impairing repair enzymes
-forms free radicals ->cell structure damage
-Resistance due to P-glycoprotein, alteration of topo fxn, or decreased topo II
Doxorubicin AE, route
IV
-hepatic elimination
-cardiotoxicity (acute & chronic - lifetime exposure can -> CHF)
-myelosuppression, mucositis, extravasation necrosis, alopecia, emesis
-red urine
What med acts as a heart protectant for anthracyclines?
Dexrazoxane
-chelates iron in the heart (necessary for free radical damage)
-not ideal b/c takes 1 of 3 MOAs from the anthracyclines
What are the 2 classes of microtubule targeting agents?
- Vinca alkaloids (know Vincristine)
- Taxanes (know Paclitaxel)
-both natural products from plants & trees
MOA Vincristine
Bind to tubulin PREVENTING microtubule assembly
-spindle poisons, arresting cells in mitosis
MOA Paclitaxel
binds to tubulin PROMOTING assembly into microtubules while simultaneously INHIBITING disassembly
-spindle poisons, arresting cells in mitosis
When would Vincristine be fatal?
If given intrathecally
Vincristine Tox
- neurotoxicity - peripheral neuropathy, autonomic neuropathy -> constipation
- minimal myelosuppression, SIADH, alopecia
Paclitaxel Tox
Myelosuppression, peripheral sensory neuropathies
-hypersensitivity rxn
-alopecia, bradycardia, myalgias
Natural antibiotic chemotherapy drug
Bleomycin
Bleomycin MOA
has DNA & metal binding region, which allow it to cause DNA breaks by free radical damage in G2
Bleomycin Tox
-lung fibrosis, skin marks (b/c don’t have bleomycin hydrolase in lungs or skin to break it down)
-minimal myelosuppression
Bleomycin resistance
Increased DNA repair
Increases bleomycin hydrolase
When is bleomycin used?
Testicular cancer
Hodgkin Lymphoma
What are 2 drug categories under endocrine therapies?
- Antiestrogens
- aromatse inhibitors
What is a SERM?
Selective estrogen receptor modulator
-Tamoxifen
Tamoxifen MOA
=estrogen antagonist
-reversibly binds ER receptor on breast cancer cells -> RNA transcription is impaired
=pro-estrogenic (agonist) in uterus (endometrial cancer) and bone (preserves bone density)
-use in pre-menopausal
Aromatase inhibitor MOA
Aromatase converts androgens to estrogen
-selective, irreversible binding to prevent production of estrogen
-structurally related to androstenedione
-use in post-menopausal
Tamoxifen pharmacokinetics
oral
-a prodrug, converted to active metabolite (endoxofen) by liver via CYP2D6
-CYP2D6 interactions (SSRIs)
Tamoxifen AEs
-> post-menopausal state and menopausal symptoms: hot flashes, nausea, fatigue
-endometrial carcinoma
-DVTs/PEs
-prevention of postmenopausal bone loss
Aromatase inhibitor AEs
-> menopausal symptoms: sweating, fatigue, hot flashes, flu-like symptoms
-myalgia
-N/V
-decreased bone density
What is Goserelin
An LHRH agonist
Describe the hormonal regulation of androgens
Goserelin (and other LHRH agonist) MOA
Suppresses pituitary gonadotropin release of LH and FSH by downregulating the LH receptors (a negative feedback inhibition)
-> initial surge of LH and FSH -> tumor flare from increased androgen synthesis (related to first doses and pulse dosing)
-continual dosing -> pituitary receptor down regulation and functional antagonism
LHRH Agonist AEs
Hot flashes
erectile impotence
decreased libido
injection-site reactions
LHRH Antagonist MOA
bind reversibly to pituitary GnRH receptors reducing release of androgens
-no tumor flare since antagonist
-Degarelix subcutaneous
Antiandrogen MOA
Competitive inhibitor of androgen receptors preventing androgen receptor activation
Antiandrogen AEs
-gynecomastia
-hot flashes
-diarrhea
-LFT abnormalities - monitor
What 2 agents require monitoring with LVEF?
- Doxorubicin
- Trastuzumab
Tumor Lysis Syndrome (TLS)
Caused by massive tumor cell ylsis and release of intracellular
-Allopurinol - decreased formation of uric acid. AEs - rash
-Rasburicase - rapid uric acid reduction by catalyzing oxidation
LHRH Agonist Surge Effect
Flare (cancer SE) and intentional LH/FSH stimulations (fertility use in non-cancer) are related to first doses and pulse dosing
-continual dosing leads to pituitary receptor down regulation and functional antagonism
