Onco 1

Cyclophosphamide MOA

covalent attachment of alkyl groups to macromolecules : cross-linking DNA

Cisplatin, Oxaplatin MOA

cross-linking DNA, alkylating agent

methotrexate MOA

competitive inhibitor of DHFR

5-FU MOA

Suicide inhibitor of thymidylate synthase and will inactivate it. Inhibition of RNA processing, incorporation into DNA. Prevents production of TTP and starve cell of necessary nucleic acids

Capecitabine MOA

prodrug of 5-FU gets metabolized by carboxylesterase to 5-DCFR and to 5-DFUR by cytidine deaminase then metabolized to 5-FU by thymidine phosphorylase. Tumors have increased thymidine phosphorylase = selective

Cytarabine, Ara-C MOA

deoxycytidine analog works in S-phase. competitive inhibitor of DNA polymerase to inhibit DNA synthesis

Gemcitabine MOA

deoxycytidine analog in S-phase. Competitive inhibitor of DNA polymerase to inhibit DNA synthesis. Also effect elongation and ligation. Also inhibits ribonucleotide reductase to deplete cellular dNTPs (makes it effective in solid tumors)

6-MP MOA

converted to 6-TGNs via HPRT and those get incorporated into DNA/RNA, arrest replication and trigger death. Inhibits cancer cell replication

Vincristine/ Vinblastine MOA

binds to beta tubulin and decreased microtubule formation (m-phase)

Paclitaxel/Docetaxel MOA

binds to beta-tubulin and blocks MT depolymerization (M-phase)

Ixabepilone MOA

microtubule stabilizer

Eribulin MOA

prevents the microtubule assembly

Irinotecan MOA

inhibition of topoisomerase I- double DNA strand breaks. Prevents releasing of nicked DNA

Etoposide and Doxorubicin MOA

topoisomerase II inhibition. Stabilize the topo II/DNA complex by preventing re-sealing of cleaved DNA and interferes with both replication and Tx. Accumulation of double strand breaks

Bleomycin MOA

intercalation into DNA helix. Formation of O2 radicals. Inhibits RNA/DNA syn. Iron binding. Inhibits Topoisomerase II. Anthracycline

Leuprolide MOA

GnRH receptor agonist. Lowers testosterone after initial increase, because of negative feedback.

Goserelin MOA

synthetic analog of LHRH reducing the production of testosterone/estradiol

Degarelix MOA

GnRH receptor antagonist. lowers testosterone levels as a competitive inhibitor of the GnRH receptor

Flutamide and Bicalutamide MOA

non-steroid competitive inhibitors of the androgen receptor. Inhibit transcription of AR genes.

Enzalutamide MOA

non-steroid competitive inhibition

Rituximab MOA

triggers direct cellular toxicity and complement dependent toxicity, ADCC and ADP

rituximab resistance

decreased complement activation, decreased Ab dependent cellular toxicity

ibritumomab tixuetan moa

radiolabeled rituximab conjugate with higher complete remission

obinutuzumab moa

glycoengineered to increase binding to effector cells, enhancing ADCC and direct cell death

ibrutinib moa

irreversible, potent inhibitor of Btk inhibiting down-stream signaling via PLC. Blocks cell growth and survival of malignant B-cells

bevacizumab moa

binds to VEGFR and prevents ligand binding= decreased angiogenesis

Sorafenib/ Sunitinib moa

blocks ATP binding to kinase which inhibits VEGFR

cetuximab moa

Ab directed against EGFR and blocks the ligand binding domain

Panitumumab moa

targets EGFR

erlotinib moa

reversible EGFR kinase inhibitor- blocks ATP binding

afatinib moa

irreversible EGFR kinase and HER2 inhibitor

osimertinib moa

irreversible EGFR inhibitor

ipatinib moa

reversible inhibitor of EGFR and HER2 tyrosine kinases - blocks ATP binding site

trastuzumab moa

HER2/neu inhibitor : Ab-dependent cellular toxicity, decreased proliferation, anti-angiogenic effects

Enhertu moa

antibody drug conjugate: anti-HER2 and mAb linked to a topoisomerase I inhibitor

imatinib moa

inhibitor of Bcr-Abl kinase

ponatinib moa

same as gleevec but avoids steric clash

nilotinib moa

same as gleevec but can overcome resistance due to most mutations

dastinib moa

like gleevec but has increased binding affinity, and resistant to fewer mutations

midostaurin moa

small molecule inhibitor of FLT-3 preventing dimerization of the receptor to prevent down-stream signaling

bortezomib moa

proteosome inhibitor with greater susceptibility of myeloma cells to inhibition

carfilzomib moa

irreversibly inhibits threonine protease activity of proteasome

ivosidenib moa

IDH1 inhibitor = promoting differentiation and terminating over-proliferation

alkylating agents

cyclophosphasmide, cisplatin, oxplatin

anti-metabolites

methotrexate, 5-FU, capecitabine, cytarabine, gemcitibine

purine analogs

6-MP

5-FU resistance

decreased activation of 5-FU, increased dUMP. altered thymidylate synthase

Cytarabine resistance

decreased deoxycytidine kinase, increased cytidine deaminase, increased dCTP

6-MP resistance

decreased HPRT

vincristine resistance

P-gp efflux, B-tubulin mutation

Irinotecan resistance

decreased carboxylesterase

abiraterone acetate moa

inhibits 17-alpha hydroxylase to reduce testosterone production

anastrozole and letrozole moa

target aromatase for inhibition = no production of estradiol, non-steroidal

exemestane moa

steroidal irreversible inhibitor of aromatase

Tamoxifen moa

SERM: antagonist in breast tissue, agonist in uterus

raloxifene moa

SERM, antagonist in breast, agonist in bone

megestrol moa

progesterone derivation that inhibits pituitary gonadotropin release. Partial agonist/ antagonist of androgen receptor and agonist of the glucocorticoid receptor

fulvestrant moa

SERD= binds to estrogen receptor and acts as an antagonist to stimulate ubiquitination

PD1 inhibitor

Nivolumab, Pembrolizumab

PDL1 inhibitor

durvaluman, avelumab, atezolizumab

partial response

> >30% decreased in sum of diameters of target lesions from baseline

OR

summation of CR and PR

SD

no bigger, no smaller

PD

despite therapy, >20% growth of a new lesion

TMN model

Tumor size 0-4

Nodal involvement 0-3

Metastatic disease 0-1

cancer spread

angiogenesis

neutrophils

takes 14 days to mature in bone marrow, produces cytokines and key function in protection against infection

T-cells

cell-mediated response, migrate to thymus where they mature

B-cells

humoral response, antibodies, become plasma cells that produce immunoglobulin specific for an antigen

Null cells

lack marks, direct cytotoxic like NK cells

AML

cancer of the white blood cells= no basophils, neutrophils, eosinophils or macrophages

risk factors for AML

older age, prior chemo, radiation, benzene, smoking, antecedent blood disorders, hereditary chromosomal abnormalities

Patient presentation AML

fatigue, anemia, dyspnea, infection (neutropenia), bleeding, confusion

Labs AML

elevated WBC, overcrowding, TLS, DIC , leukocytosis

AML diagnosis

>20% myeloid blasts isolated on bone marrow or peripheral blood OR t(8:21), t(15:17), t(16:16), inv16

high risk mutations

Del 5, Del 7, Ilq23

favorable mutations AML

NPM1 without FLT3-ITD or FLT3-ITD low

poor mutation AML

t(Ilq23.3) KMT2A

\-5del5q-7/-17 abn 17p

wild-type NPM1 and FLT3-ITD high (ratio over 50%)

poor risk AML

increasing age, secondary AML, high WBC at diagnosis, relapsed AML

Induction therapy

cytarabine 100-200 IV daily continuous for 7 days

daunorubucin 60-90 IV over 1-2 hours for 3 days

induction therapy >60

cytarabine 100-200 daily continuous for 7 days

daunorubicin 60 IV over 1-2 hours for 3 days

AML induction if CD33+

add gemtuzumab ozogamicin

AML induction therapy if FLT3

add midostaurin

AML induction >60 if therapy related

liposomal cytarabine and daunorubicin

>75 AML induction

venetoclax and hypomethylating agent or low-dose cytarabine

cytarabine low dose AE

myelosuppresion, rash, fever

cytarabine high dose AE

N/V, neurotoxicity (frequent neuro checks), conjunctivitis (need steroid drops or artificial tears), mucositis

cytarabine excretion

mostly renal, don’t use in renal dysfunction

anthracycline metabolisim

hepatic, doxorubicin 2D6 and 3A4

anthracyclines renal impairment

Scr> 3 mg/dL= 50% of dose

anthracycline hepatic impairment

* Bilirubin 1.2 to 3= 75% of dose​
* Bilirubin 3.1 to 5= 50% of dose​
* Bilirubin >5= Avoid use

anthracycline BBW

extravasation (cold, DSMO), myelosuppression, cardiomyopathy (arrhythmias, CHF), hepatic impairment, renal impairment

anthracycline AE

discoloration of secretions, mucositis, alopecia, rash, N/V

anthracycline cardiotoxicity risk factors

cumulative dose, female gender, HTN, AA, age>65 or

liposomal daunorubicin and cytarabine AE

myelosuppresion longer, copper toxicity, purple secretions

Decitabine dose adjustments

hold if SCr, Alt/ T. bili >2 during tx

decitabine AE

myelosuppression, hepatoxicity, hyperglycemia, low emetic potential

azacitidine excretion

urine 50-85%

azacitidine AE

injection site reactions, moderate emetic potential

gemtuzumab ozogomicin MOA

CD33 directed mAb internalized and releases calicheamicin derivative