Onco Cummulative Final - Dearborn

All of Dearborn's Stuff in One!

What is the ultimate response to chronic inflammation?

Fibrosis

What is the MOA of NSAIDs?

Inhibition of COX1/COX2 enzymes that are involved in the production of prostaglandins

Which COX receptor is only in platelets?

COX1

What does COX1 produce that triggers thrombotic events?

Thromboxane A2

Why is platelet aggregation increased when Cox2 is blocked?

Blocking COX2 blocks the formation/production/function of PGI2 and and tips the axis towards TXA2 synthesis, which increases platelet aggregation

What is the role of PGE2 in NSAID use?

Primarily caused by cox1 in GI and kidney to promote blood flow and mucus production - blocking COX1 blocks this leading to nephrotoxicity and GI effects

What is the primary difference between COX enzymes?

The size and shape of the inhibitor binding sites within the enzyme active site; it’s 25% larger in Cox2

\
Also, cox2 has a secondary binding pocket that cox1 doesn’t have

What are the adverse effects of NSAIDs?

GI bleeding/ulcers; prolonged bleeding; renal insufficiency

Who should you avoid using NSAIDs in?

Patients with CV disease, hepatic disease, GI disorders, and elderly

What is the proposed mechanism for cardiovascular toxicity of NSAIDs?

A shift in the prothrombotic/antithrombotic balance on the endothelial surfaces towards thrombosis

\
When COX2 blocked, more cox1 activation leads to thrombosis

What are the gastroprotective agents used with NSAIDs and which are the first and second line options?

Misoprostol;

PPI (omeprazole) - first;

H2RA (famotidine) - second

What is the MOA of misoprostol for gastroprotection?

Synthetic PGE1 analog that can inhibit gastric acid secretion

Describe the HPA axis regulation and GC production.

GC production is regulated by the HPA axis; CRH released from the PVN induces the release of ACTH from the pituitary into systemic circulation. ACTH stimulates the synthesis of cortisol in the adrenal gland, which negatively regulates the HPA axis

What are the physiological functions of glucocorticoids?

Breakdown of skeletal muscle protein; breakdown of adipose tissue; breakdown of bone; suppression of immune system; gluconeogenesis; anti-inflammatory

What is the MOA of glucocorticoids in RA?

GCs down-regulate the synthesis of pro-inflammatory cytokines (TNFalpha, IL-1, IL-6) which are key players in triggering inflammation in RA

\
Also, TNFalpha and IL-1 stimulates the production of RANKL which is responsible for osteoclast production, and those are responsible for bone erosion in RA

What are the systemic adverse effects of GVs?

Early - insomnia, enhanced appetite, weight gain, emotional lability, leukocytosis, hyperclycemia

Sustained - cushingoid habitus, HPA suppression, infection, osteoporosis, impaired wound healing

Rare - psychosis, glaucoma, pancreatitis, pseudotumor cerebri

What is the definition of hyperuricemia?

Increase serum uric acid defined by a urate concentration over 7

What is the definition of gout?

Hyperuricemia; recurrent attacks of acute arthritis; tissue deposits of crystals

What is the most common cause of gout? (over production or under excretion)

Under excretion - defect in renal clearance of uric acid

Explain Uric Acid and purine metabolism?

Urate is freely filtered but up tulation of uric acid and the subsequent development of uric acid crystals in tissues

What is the MOA of colchicine?

A micro tubule disruptor that leads to decreased leukocyte motility, and decreased phagocytosis in joints and lactic acid production; prevents MT reassembly after it collapses

What is the metabolism of colchicine?

CYP3A4/P-gp - potent inhibitors may raise levels and risk serious toxicity

What are some potent inhibitors of CYP3A4/P-gp that would interact with colchicine?

Clarythromycine; diltiazem, cerapamil, ketoconozole, cyclosporine

What is the MOA of allopurinol?

Purine analog and structural isomer of hypoxanthine; xanthine oxidase inhibitor - blocks formation of uric acid

What is the MOA of febuxostat?

Selective xanthine oxidase inhibitor that is a non-purine analogue

What is the MOA of probenecid?

Increases uric acid excretion by inhibiting post-secretory renal proximal tubular reabsorption

What is the MOA of methotrextate?

DHR analog that is a competitive inhibitor of dihydrofolate reductase; inhibits purine and pyrimidine synthesis; inhibits immune cell proliferation; decreases NFkappaB dependent transcription by unknown mechanism

What is the MOA of azothioprine?

A prodrug for 6-MP that inhibits immune cell replication; 6-MP is converted to 6-TGN via HPRT and 6-TGNs are then incorporated into DNA/RNA to arrest replication and trigger cell death

What genetic deficiency will lead to severe toxicity of azothioprine?

TPMT deficiency

What is the MOA of leflunomide?

Converted to teriflunamide and inhibits dihydroorotate dehydrogenase depriving the cell of necessary building blocks for DNA synthesis

What is the MOA of mycophenolate mofetil?

Inhibition of IMP dehydrogenase which is involved in de novo GTP synthesis, depriving the cell of necessary building blocks; also decreases t-lymphocyte and b-lymphocyte proliferation

What is the MOA of Cyclophosphamide?

Alkylates DNA and suppresses T- and B-cell function

What are the MOAs of hydroxychloroquine?

Inhibition of MHC class II expression, antigen presentation, reduction in CD154 expression on T cells, inhibition of pro-inflammatory cytokine expression, decreased leukocyte chemotaxis, stabilization of lysosomal enzymes, oxygen radical trapping, and interference with toll-like receptor pathways

What is the MOA of cyclosporin?

Binds cyclophilin to inhibit calcineurin, subsequently blocking IL-1 and IL-2 transcription, leading to inhibition of t-cell proliferation

What is the MOA of sulfasalazine?

Prodrug metabolized to 5-ASA which acts as a COX inhibitor and inhibits cytokine release

What is the MOA of apremilast?

Inhibitor of PDE-4 which results in increased cAMP levels which reduces cytokine expression

What is the MOA of infliximab?

Binds to soluble and transmembrane forms of TNF-alpha with high affinity to disrupt the pro-inflammatory cascade

What is the MOA of golimumab?

Binds to both soluble and transmembrane forms of TNF-alpha with high affinity to disrupt pro-inflammatory cascade

What is the MOA of adalimumab?

Binds to both soluble and transmembrane forms of TNF-alpha with high affinity to disrupt pro-inflammatory cascade; lysis of cells expressing surface TNF-alpha

What is the MOA of certolizumab?

Blocks interaction of TNF-alpha with TNF receptor but doesn’t induce lysis or induce compliment

What does certolizumab not require that other full mAbs require?

Glycosylation

What is Etanercept? What is it’s MOA?

It is a TNF p75 receptor fusion protein; it binds to both TNF-alpha and TNF-beta

What is the MOA of Abatacept?

It is a fusion protein that is a selective co-stimulation modulator that binds to CD80/86 protein and thus blocks the interaction with CD28; blocks T-cell activation

What is the MOA of rituximab?

Binds to CD20 and triggers Ab-dependent cellular toxicity and complement dependent toxicity resulting in almost complete depletion of B-cells

What is the MOA of belimumab?

It is a fully recombinant mAb that binds to soluble human B-lymphocyte stimulator protein (BLyS or BAFF); inhibits BAFF to trigger apoptosis

What is the MOA of Ustekinumab?

Inhibition of IL-12 and IL-23 leading to reduced T-cell activation; it’s directed against the P40 protein subunit of IL-12/IL-23

What is the MOA of guselkumab?

Inhibition of IL-23 (P19 subunit)

What is the MOA of Tildrakizumab?

Inhibition of IL-23 (P19 subunit)

What are the IL-17 antagonists?

Secukinumab, ixekizumab, brodalumab

What is the MOA of tocilizumab?

Binds to the soluble and membrane bound IL-6 receptor leading to decreased B-cell differentiation and decreased T-cell activation

What is the MOA of sarilumab?

Binds to the soluble and membrane bound IL-6 receptor leading to decreased B-cell differentiation and decreased T-cell activation

What is the MOA of Anakinra?

IL-1 inhibition (IL-1 receptor antagonist)

What are the JAK/STAT pathway inhibitors and what is their MOA?

Tofacitinib, baricitinib, upadactinib; inhibit janus kinase-mediated cytokine production

Cyclophosphamide

Alkylating agent MOA: covalent attachment of alkyl groups to macro molecule Bis(chlorethyl)amine which forms an ethyleneimonium ion that reacts with a base (ex. N7 of guanine) to produce an alkylated purine - alkylation of nucleophilic sites Leads to mispairing (mono and bi), ring opening (mono and bi), and cross linking (bifunctional only) → apoptosis if can’t repair

Cisplatin

Platinum analog MOA: intra/inter-strand cross linking of cisplatin to DNA inhibits S-phase replication and activates p53 tumor suppressor activating transcription of pro-apoptotic proteins and stimulating intrinsic pathway of apoptosis

Oxaliplatin

Platinum analog MOA: intra/inter-strand cross linking of cisplatin to DNA inhibits S-phase replication and activates p53 tumor suppressor activating transcription of pro-apoptotic proteins and stimulating intrinsic pathway of apoptosis

Methotrexate

Antimetabolite MOA: inhibits purine and pyrimidine synthesis; competitive inhibitor of DHFR; inhibits cancer cell proliferation; Becomes polyglutinated by FPGS (folo polygluthate synthesis) so it has longer resident time in cells to work longer

5-Fluorouracil

Antimetabolite MOA: suicide inhibitor that inactivates thymidylate synthase preventing the production of dTTP depriving cell of needed metabolites, inhibits RNA processing; it’s also incorporated into DNA

Capecitabine

Antimetabolite MOA: 5-FU prodrug that is metabolized in the liver by carboxylesterase to 5-DFCR than by cytadine deaminase to 5-DFUR which is then metabolized within the tumor by thymidine phosphorylase to 5-FU; targets more preferentially than 5-FU because tumor cells exhibit increased thymidine phosphorylase expression

Cytarabine

Antimetabolite MOA: Cytarabine is a deoxyxytidine analog that is converted to Ara-C via deoxycytidine kinase

Ara-C

Antimetabolite MOA: Competitive inhibitor of DNA polymerase causing inhibition of DNA synthesis; it is also incorporated into DNA/RNA to affect elongation and ligation to disrupt the replication process

Gencitabine

Antimetabolite MOA: deoxycytidine analog that is a competitive inhibitor of DNA polymerase that inhibits DNA synthesis; it is incorporated into DNA/RNA to affect elongation and ligation; additionally inhibits ribonucleotide reductase to deplete cellular dNTP

6-Mercaptopurine

Purine Antagonist MOA: metabolized from azothiprime; converted to 6-thioguanine nucleotides (via HPRT enzyme) that are incorporated into DNA/RNA to arrest replication and trigger cell death - inhibit cancer cell replication

Vincristine

Vinca Alkaloids MOA: Binds to beta tubulin to prevent reassembly into a full microtubule, decreasing microtubule formation and leading to mitotic arrest

Vinblastine

Vinca Alkaloids MOA: Binds to beta tubulin to prevent reassembly into a full microtubule, decreasing microtubule formation and leading to mitotic arrest

Paclitaxel

Taxane MOA: Binds to beta-tubulin blocking depolymerization of microtubule, which destabilizes the microtubule itself causing mitotic arrest

Docestaxel

Taxane MOA: Binds to beta-tubulin blocking depolymerization of microtubule, which destabilizes the microtubule itself causing mitotic arrest

Abraxane

Taxane MOA: Albumin bound paclitaxel

Ixabepilone

Vinca alkaloid/taxane MOA: MT stabilizer, effective againts resistant tumors

Eribulin

Vinca alkaloid/taxane MOA: MT subunit sequester, effective against resistant tumors

Irinotecan

Topoisomerase Inhibitor MOA: Prodrug that gets activated by carboxylesterase into the active metabolite, SN-38, which allows for topo I to cause a strand break before freezing/inhibiting topo I to prevent it from resolving the break

Etoposide

Topoisonerase inhibitor MOA: stabilizes topo II/DNA complex by preventing the resealing of the cleaved DNA and it can interfere with replication and transcription, triggering apoptosis down the line

Doxorubicin

Topoisonerase inhibitor and anthracycline MOA: stabilizes topo II/DNA complex by preventing the resealing of the cleaved DNA and it can interfere with replication and transcription, triggering apoptosis down the line; also intercalates into DNA causing the formation of oxygen radicals and inhibiting DNA/RNA synthasis

Daunorubicin

Anthracycline MOA: intercalates into DNA causing the formation of oxygen radicals and inhibiting DNA/RNA synthasis

Bleomycin

Anthracycline MOA: iron binding attracts oxygen causing oxygen radical formation which leads to DNA strand breaks and chromosomal damage

Leuprolide

GnRH receptor agonist MOA: lowers testosterone levels (following initial upregulation caused by negative feedback) to reduce stimulation of androgen sensitive cancer cells, triggering apoptosis

Goserelin

MOA: synthetic analog of LNRH that reduces the production of testosterone/estradiol leading to decreased stimulation of cancer cell growth

Degarelix

GnRH receptor antagonist MOA: synthetic derivative of GnRH decapeptide that lowers testosterone levels via competitive inhibiiton of the GnRH receptor to reduce stimulation of androgen-sensitive cancer cells to trigger apoptosis

Flutamide

MOA: non-steroid competitive inhibitor of androgen receptor that blunts downstream response and inhibits transcription of AR genes to prevent cell growth and trigger apoptosis

Bicalutamide

MOA: non-steroid competitive inhibitor of androgen receptor that blunts downstream response and inhibits transcription of AR genes to prevent cell growth and trigger apoptosis

Enzalutamide

2nd generation MOA: non-steroid competitive inhibitor of androgen receptor that reduces subsequent transcription of AR genes and has higher affinity for AR genes than bicalutamide

Abiraterone Acetate

Androgen synthesis inhibitor MOA: progesterone derivative that inhibits 17-alpha-hydroxylase (CYP17) irreversibly to reduce testosterone production

Anastrozole

Estrogen synthesis inhibitor MOA: Non-steroidal aromatase inhibitor that decreases estrone/estradiol for transcription of HR+ breast canser; binds reversibly to heme

Letrozole

Estrogen synthesis inhibitor MOA: Non-steroidal aromatase inhibitor that decreases estrone/estradiol for transcription of HR+ breast canser; binds reversibly to heme

Exemestane

Estrogen synthesis inhibitor MOA: steroidal aromatase inhibitor for transcription of HR+/ER+ breast cancer insensitive to tamoxifen; irreversibly inactivates aromatase via reactive intermediate formation

Tamoxifen

SERM MOA: affects transcription when bound to ligand; specific effects depend on cofactors present; antagonist in breast tissue so used to treat ER+ breast cancer, but agonist in uterine tissue which leads to increased risk of uterine cancer

Raloxifen

SERM MOA: affects transcription when bound to ligand; specific effects depend on cofactors present; treats high risk breast cancer since its' an antagonist in breast tissue, treats osteoporosis since it is an agonist in bone stimulating bone cell proliferation which is good

Fluvestrant

SERD MOA: estrogen receptor antagonist that degrades the estrogen receptor by stimulating ubiquitinylation (takes receptor to proteasome and breaks it down)

Megestrol

MOA: progesterone derivative that inhibits pituitary gonadatropin release leading to decreased estrogen secretion; is a partial agonist/antagonist of androgen receptor and is agonist of glucocorticoid receptor

Rituximab

CD20 Receptor Antibody (chimeric mAb) MOA: triggers direct Ab-dependent cellular toxicity; complement dependent toxicity; antibody dependent cell-mediated cytotoxicity; antibody-dependent phagocytosis

Ibritumomab tiuxetan

CD20 Receptor Antibody MOA: radiolabeled rituximab conjugate

Obinutuzumab

CD20 Receptor Antibody MOA: fully humanized mAb derivative of rituximab that is glycoengineered to increase binding to effector cells which enhances ADCC and direct cell death relative to rituximab; CDC and ADP are alt MOA

Ibrutinib

Non-receptor tyrosine kinase inhibitor MOA: irreversible potent inhibitor of Brutons tyrosine kinase which inhibits downstream signalling via PLCgamma, blocking cell growth, survival, and proliferation of malignant B-cells by silencing NF-kappaB dependent transcription

Bevacizumab

Tyrosine Kinase inhibitor with Vascular Endothelial Growth Factor signaling targets MOA: Binds to the VEGFR and prevents VEGF binding leading to a decrease in angiogenesis

Sorafenib

Tyrosine Kinase inhibitor with Vascular Endothelial Growth Factor signaling targets MOA: inhibits VEGFR receptor kinase by blocking ATP binding (short circuits it, preventing dimer polymerization) and inhibits PDGFR signaling

Sutnitinib

Tyrosine Kinase inhibitor with Vascular Endothelial Growth Factor signaling targets MOA: inhibits VEGFR receptor kinase by blocking ATP binding (short circuits it, preventing dimer polymerization) and inhibits PDGFR signaling

Cetuximab (IgG1)

Tyrosine Kinase inhibitor with Epidermal Growth Factor Receptor Signalling targets Externally MOA: Chimeric mAb directed against EGFR, blocks ligand binding domain, inhibiting EGFR signalling pathway (only works if no KRAS mutation)

Panitumumab (IgG2)

Tyrosine Kinase inhibitor with Epidermal Growth Factor Receptor Signalling targets Externally MOA: fully humanized mAb that targets EGFR (only works if no KRAS mutation)

Erlotinib

First generation Tyrosine Kinase inhibitor with Epidermal Growth Factor Receptor Signalling targets Internally MOA: reversible EGFR kinase inhibitor that blocks all ATP binding

Afatinib

Second generation Tyrosine Kinase inhibitor with Epidermal Growth Factor Receptor Signalling targets Internally MOA: Irreversible inhibitor of EGFR kinase and HER2