Anti-neoplastics Flashcards

Question

Epipodophyllotoxins - Etoposide

Answer 1

Derivative of podophyllotoxin, Inhibits topoisomerase II -- primarily affects cells in G2 and S phases given IV and Oral with renal excretion Uses - - Testicular Concer, NSCLC, SCLC, and Lymphoma Adverse effects are Bone Marrow Suppression, nausea and vomiting, and hypotension

Answer 2

Irinotecan and Topotecan S-phase specific and Inhibits topoisomerase I Metabolized by UGT1A128 - inactive (Irinotecan) and metabolite is Topotecan which is renal metabolized Uses: • Irinotecan – Colon Cancer with 5-FU and Leucovorin • Topotecan – SCLC, Ovarian Cancer Adverse Effects -- Severe diarrhea caused by irinotecan and myelosuppresion

Answer 3

Anthracyclines Four mechanisms for action --- inhibits topoisomerase II, intercalates in DNA and blocks synthesis, generates free radicals. binds to cell membranes to alter fluidity and ion transport given IV with extensive hepatic metabolism

Answer 4

_-Doxorubicin for variety of solid and hematologic cancers -Daunorubicin – AML Adverse Effects --- Myelosuppression, mucositis Doxorubicin leading to cardiotoxicity > dilated cardiomyepathy, contraindicated with trastuzumab and causes free radial generation

Answer 5

BCR-ABL Kinase Inhibitors Other ones Dasatinib, Nilotinib, Ponatinib and Bositinib Occupy ATP binding pocket which prevents substrate phosphorylation and signal transduction inhibits many kinases -- BcrAbl, c-kit, PDGFR Drug resistance mechanisms through mutations in kinase domain which prevents tight binding of the drug, amplification of wild-type kinase gene or Philadelphia chromosome-negative clones which arent apparent until after treatment.

Answer 6

Imatinib Dasatinib//Bositinib -active against all imatinib resistant except T315I and F317V mutants Nilotinib -- active against imatinib-resistant mutations but T315I Ponatinib -- resistant against all mutations including T5=315I

Answer 7

CML and ALL - Ph Chr + GIST which is c-Kit+ Mastocytosis - aggressive and systemic Eosinophilic Leukemia Myelodysplastic / myeloproliferative disease that is PDGFR+

Answer 8

Imatinib and others Common - Diarrhea, nausea, vomiting (usually easily controlled) and also erythema multiform, Stevens-Johnson syndrome and DRESS Fluid retention and dose-related myelosuppression Interacts with substrates of P-gp and CYP3A4

Answer 9

Monoclonal antibodies - Cetuximab Small molecule drugs - Erlotinib Cetuximab- Competitive inhibition of the ligand, EGF and blocks receptor dimerization, inhibits cell growth and induces apoptosis Erlotinib and Afatinib - intracellularly acting, competitively inhibits ATP at active sire of kinase and signaling cascade

Answer 10

Cetuximab; Panitumumab -- resistant tumors carry mutations in KRAS oncogene Erlotinib -- resistance is seen through many mechanisms: overexpression or amplification of EGFR, lack of sensitizing EGFR, tumors harboring KRAS mutations and EMY4-ALK translocations, mutation which prevents drug binding to kinase or amplification of met oncogene (activates downstream growth factors)

Answer 11

Cetuximab: KRAS wild-type EGFR-expressing metastatic colorectal cancer > first line combination: FOLFOX or FOLFIRI Erlotinib: NSCLC with known mutation in EGFR ("driver mutation") and pancreatic cancer that is locally advanced or metastatic (given with gemcitabine) NSCLC: non-small cell lung cancer

Answer 12

Erlotinib; Afatinib; others - most common are diarrhea, acneiform rash, anorexia and fatigue - Rare but serious include SJS/TEN, interstitial lung disease, renal failure, GI perforation, hand-foot skin reaction Cetuximab; Panitumumab - Diarrhea; acneiform rash - cardiopulmonary arrest, interstitial lung disease, hypomagnesemia, anaphylactoid reaction

Answer 13

Trastuzumab, Lapatinib, Ado-Trastuzumab Emtansine Trastuzumab MOA - has high affinity for EC domain of Her2and prevents dimerization of receptor and downstream signalling, downregulation of Her2, induction of ADCC and blocks angiogenic effects Ado-Trastuzumab Emtansine -- conjugate which inhibits Her2 signalling, antibody with drug binds receptor > receptor is internalized and chopped up, inhibits microtubule assembly by binding tubulin which results in cell cycle arrest and apoptosis.

Answer 14

metastatic breast cancer - adjunctive w/ Paclitaxel or monotherapy upon relapse metastatic gastric or gastroesophogeal junction adenocarcinoma syngergystic with other cytotoxis agents in HER2/neu tumors

Answer 15

Refractory HER2+ metastatic breast cancer

Answer 16

cardiomyopathy, highest risk in anthracycline chemo regimen -- underlying cardiac disease should be ruled out infusion reactions -- fever, chills, nausea, dyspnea, rash pulmonary toxicity with pul infiltrates and edema, interstitial pneumonitis Interacts with Doxorubicin, cyclophosphamide increased risk of cardiac toxicity

Answer 17

AE w/ Cardiomyopathy, Infusion reactions, Pulmonary toxicity Hepatoxicity - Elevated transaminases, liver failure Peripheral neuropathy thrombocytopenia - caution with antiplatelets or anticoagulants interaction with doxorubicin, cyclophosphamide, CYP3A4

Answer 18

Inhibitors of Angiogenesis - monoclonal antibodies binds to and neutrolizes VEGF preventing it from binding its endothelial receptors Used for - metastatic colorectal cancer FOLFOX or FOLFIRI - NSCLC, nonsquamous, unresectable - persistant, recurrent or metastatic cervical cancer - ovarian cancer - progressive glioblastoma - metastatic Clear-cell renal cell cancer - off laber Rx for age related macular degeneration

Answer 19

Severe hemorrhage: GI, pulmonary or intracranial - depending on aim of rx/type of cancer Poor wound healing / Wound dehiscence Hypertension Arterial thromboembolic events proteinuria, GI perforation, infusion reaction

Answer 20

Anti-CD20 Monoclonal Antibody depletes CD20+ B cells by ADCC, complement-depenent tumor cell lysis, apoptosis, downregulation of BCR Given IV ``` AE severe infusion infections opportunistic infection tumor lysis syndrome severe skin reactions reactivation of latent HBV infection, PML ```

Answer 21

``` Non-Hodgkin lymphoma CLL Steroid-refractory chronic GVHD RA refractory pemphigus vulgaris post-transplant lymphoproliferative disorder Autoimmune hemolytic anemia in children chronic ITP ```

Answer 22

Bortezomib, Carfilzomib Proteasome inhibition → inhibit NF-κB activation-- ↓ Anti-apoptotic factors, ↓ Inflammatory molecules, ↓ Cell adhesion molecules and ↓ Cytokines NF-kB is consitiutively expressed in myeloma cells Used for refractory or relapsed multiple myeloma or mantle cell lymphoma used off label for Waldenstrom macroglobulinemia AE - neutropenia, severe thrombocytopenia, peripheral neuropathy. hypotension, QT prolongation and pulmonary toxicity

Answer 23

Thalidomide Lenolidomide* Pomalidomide EFFECTS 1- Inhibits secretion of proinflammatory mediators; potent inhibitor of TNFα 2- Stimulates activation and proliferation of cytolytic T cells → ↑ IL-2 and ↑ IFN-γ, which ↑NK cell cytotoxicity 3- Inhibits trophic signals to angiogenic factors in cells. 4- Inhibits growth of myeloma cells by inducing cell cycle arrest and cell death Therapeutic Uses - multiple myeloma, myelodysplastic syndrome, CLL

Answer 24

common - constipation, neuropathy, somnolence, fatigue, dry skin and dry mouth thalidomide - peripheral neuropathy Neutropenia, thrombocytopenia DVT and pulmonary embolism, MI and stroke -prophylaxis embryotoxic

Answer 25

CTLA Inhibitor - Ipilimumab* PD-1 Inhibitors - Nivolumab* Pembrolizumab PD-L1 Inhibitor - Atezolizumab

Answer 26

CTLA-4 Inhibitor Blocks CTLA-4 → enhanced T-cell activation and proliferation Used for melanoma

Answer 27

PD-1 Inhibitor Block PD-1/PD-L1 interaction → release immune suppression → immune response against the tumor used for melanoma; NSCLC with clinical trails for other cancers

Answer 28

Engineered T cells to bind CD19 on tumor cells CAR activates downstream cascades leading to T cell activation, expansion and secretion of inflammatory cytokines leading to the destruction of CD19 cells Tisa: B cell precursor ALL Axi-cel: Large B cell lymphoma - relapsed or refractory, in adults