Antineoplastics: misc antimetabolite, mitosis inhibitors, tyrosine kinase inhibitors

pentostatin

pentostatin

(misc antimetabolite)

ROA: IV

MOA: indirect inhibition of ribonucleotide reductase

- inhibits adenosine deaminase, which leads to high levels of deoxyadenosine = inhibitor of ribonucleotide reductase, leading to stopping DNA synthesis in tumor cell

indication: b-cell chronic lymphocytic leukemia

- similar efficacy to fludarabine, but lower toxicity

AE: myelosuppression, rash

pentostatin

which b-cell chronic lymphocytic leukemia agent has less toxicity?

a. pentostatin

b. fludarabine

microtubules, mitotic arrest, apoptosis

Mitosis Inhibitors:

inhibits mitosis (cell division) by disrupting ______ of the spindle apparatus, which pulls the cell apart + divides

by inhibiting this essential hyperdynamic change in structure, it results in _____ ______ and ______

b-tubulin, elongation, disassembly

MOA of taxanes:

bind to polymerized ____ promoting stable tubulin conformation, which then renders the microtubules resistant to depolymerization + prone to polymerization.

this promotes the ______ phase of the microtubule dynamic instability at the expense of the shortening phase + inhibits the _______ of the tubule into the mitotic spindle

this whole process disrupts the normal process of cell division

paclitaxel

paclitaxel

(taxane -- mitosis inhibitor)

natural product isolated from Pacific yew tree, Taxus brevifolia

ROA: IV

- poor solubility = use mixture of water + alcohol + cremophor EL

- albumin bound formulation (Abraxane) = no hypersensitivity, improved solubility (better tumor penetration)

MOA: binds polymerized b-tubulin promoting stable tubulin conformation which leads to resistant microtubules + promotes elongation phase + inhibits disassembly of tubule into mitotic spindle

- resistance: cellular efflux via Pgp

indication: 1st line for advanced ovarian + NSCLC in combo w cisplatin

- anthracycline resistant metastatic breast cancer

ADME: extensive distribution into tissues + long t1/2

DDIs: with drugs metabolized by CYP2C8

AE: myelosuppression, neutropenia, hypersensitivity rxn

- avoid hypersensitivity by pre-admin antihistamine + corticosteroid

- pregnancy risk category D

poor

taxanes have (poor/good) water solubility

hypersensitivity

in the paclitaxel formulation with water, alcohol, and cremophor, what negative side effect is associated with cremophor?

thymidine phosphorylase

what does paclitaxel upregulate that increases the efficacy of the combo treatment with capecitabine?

no hypersensitivity, better solubility

what are the 2 advantages of the albumin-bound formulation of paclitaxel?

D

what pregnancy risk category is paclitaxel and cabazitaxel?

2C8

paclitaxel has DDIs with drugs metabolized by which CYP enzyme?

docetaxel

docetaxel

(taxane -- mitosis inhibitor)

ROA: IV

- slightly better solubility due to C10-OH group

MOA: binds polymerized b-tubulin promoting stable tubulin conformation which leads to resistant microtubules + promotes elongation phase + inhibits disassembly of tubule into mitotic spindle

- resistance: efflux via Pgp

indication: NSCL, prostate, gastric, and head/neck cancer

ADME: extensive tissue bound, metabolized by CYP3A4

better

docetaxel has (better/worse) solubility than paclitaxel

cabazitaxel

cabazitaxel

(taxane -- mitosis inhibitor)

ROA: IV

SAR: 7,10-dimethoxy analog of docetaxel = lower affinity for pgp = inc cellular retention + high BBB penetration

MOA: binds polymerized b-tubulin promoting stable tubulin conformation which leads to resistant microtubules + promotes elongation phase + inhibits disassembly of tubule into mitotic spindle

indication: docetaxel resistant metastatic prostate cancer

AE: myelosuppression, neutropenia, hypersensitivity

- pregnancy risk D

cabazitaxel

which taxane has high BBB penetration:

a. paclitaxel

b. docetaxel

c. cabazitaxel

ixabepilone

ixabepilone

(epothilone -- mitosis inhibitor)

SAR: semisynthetic epothilone B analog

- better water solubility + stability due to lactam group

- twice as potent as paclitaxel

MOA: promote cell death by inhibiting microtubule depolymerization

- low susceptibility to resistance

indication: in combo with capecitabine for anthracycline/taxane resistant advanced or metastatic breast cancer

AE: peripheral neuropathy, neutropenia

DDI: CYP3A4 substrates, inducers, and inhibitors

BBW: pts w impaired hepatic function (AST or ALT 2.5x higher than normal)

more

ixabepilone is (less/more) potent than paclitaxel

peripheral neuropathy, neutropenia

what are the 2 serious side effects associated with ixabepilone?

vincristine, vinblastine, vinorelbine

what are the 3 vinca alkaloids?

microtubule polymerization

vinca alkaloids stop cell division by inhibiting _______ _________.

IV

what is the ROA for all vinca alkaloids?

vincristine

which is cleared slower and has a longer t1/2:

a. vincristine

b. vinblastine

c. vinorelbine

vesicants

all vinca alkaloids are severe _____ that can induce necrosis, cellulitis, and/or thrombophlebitis

vincristine

vincristine

(vinca alkaloid -- mitosis inhibitor)

ROA: IV

MOA: inhibit microtubule polymerization

indication: advanced leukemia, Hodgkin's and non-Hodgkin's lymphoma, neuroblastoma

AE: severe vesicant

- inc toxicity risk in hepatic dysfunction

notes:

- longer t1/2 due to slower clearance

- over half of the children in US w cancer who receive chemo have been given this

vincristine

which drug have over half of the children in the US w cancer who receive chemo been given?

vinblastine

vinblastine

(vinca alkaloid -- mitosis inhibitor)

ROA: IV

MOA: inhibit microtubule polymerization

indication: Hodgkin's lymphoma, lymphocytic leukemia, testicular cancer, Kaposi sarcoma

AE: severe vesicant

- inc toxicity risk in hepatic dysfunction

vinorelbine

vinorelbine

(vinca alkaloid -- mitosis inhibitor)

ROA: IV

- has oral bioavailability, but only IV is available

MOA: inhibit microtubule polymerization

indication: NSCLC

AE: severe vesicant

- inc toxicity risk in hepatic dysfunction

- dose limiting granulocytopenia

intracellular domain

which part of the receptor tyrosine kinase (RTK) is able to phosphorylate selected substrates:

a. extracellular domain

b. transmembrane domain

c. intracellular domain

RTKs

EGFR/HER1, VEFGR, HER2, PDGFR are all examples of:

a. RTKs

b. NRTKs

NRTKs

Bcr-abl and Src are examples of:

a. RTKs

b. NRTKs

bcr-abl

which one is the philadelphia chromosome:

a. Bcr-Abl

b. Src

active, inactive

type 1 TK inhibitors bind the ____ conformation of the kinase

type 2 TK inhibitors binds the ____ conformation of the kinase

inhibit several kinases (AKA multikinase inhibitors)

what functional feature is common to promiscuous TK inhibitors?

bcr-abl, jak2, btk inhibitors

what are the 3 subclasses of NRTKIs?

imatinib, nilotinib, dasatinib

what are the 3 brc-abl inhibitors?

aberrant Ph chromosome

what is the viewed as the single cause of more than 90% of adult CML? (3)

imatinib

imatinib

(bcr-abl inhibitor --- NRTK)

ROA: oral

MOA: type 2 bcr-abl kinase inhibitor

- various resistance mechanisms

indication: 1Ph+ CML, Ph+ Acute Lymphoblastic Leukemia, GI stromal tumors, myelodysplastic/myeloproliferative diseases

ADME: high oral bioavailability and protein binding, t1/2 = 18 hr

AE: neutropenia, thrombocytopenia, anemia, rash

notes:

- greatest initial effect in the initial (chronic) phase of CML and significantly less effective later one

initial

imatinib has its greatest effect in the (initial/later) phase of CML

nilotinib

(bcr-abl inhibitor -- NTRKI)

ROA: oral, BID

MOA: type 2 bcr-abl kinase inhibitor

indication: Ph+ CML in chronic phase

ADME: low F (30%), t1/2 = 17 hr, mainly biliary elimination

AE: life threatening QT interval prolongation that can progress to torsades de pointes + sudden death

- inc risk w CYP3A4 inhibitors

- myelosuppression

nilotinib

which is associated with QTc prolongation + Torsades de pointes:

a. imatinib

b. nilotinib

c. dasatinib

dasatinib

(bcr-abl inhibitor -- NRTKI)

ROA: oral

MOA: mixed type 1 and 2 bcr-abl kinase inhibitor that also has significant affinity for cellular Src kinases

indication: Ph+ CML, Ph+ ALL

ADME: low F due to poor absorption + fast first pass

- 3A4 mediated metabolism

- highly protein bound

oral

what is the ROA of brc-abl inhibitors?

dasatinib

which is associated with type 1 and 2 bcr-abl inhibition PLUS some Src kinase:

a. imatinib

b. nilotinib

c. dasatinib

cytokine, kinase, phosphate

Janus Kinase (JAK2) inhibitor:

family of intracellular, NRTK that transduce ________-mediated signals via the JAK-STAT pathway

they possess 2 phosphate-transferring domains: one exhibits ____ activity and the other removes _____.

ruxolitinib (Jakafi)

ruxolitinib (Jakafi)

(jak2 inhibitor -- NRTKI)

ROA: oral

MOA: inhibits JAK1 and JAK2

indication: intermediate to high risk myelofibrosis

- polycythemia vera

AE: hematologic toxicity, infections, skin cancer

B cell maturation, lymphocytic leukemias

Bruton's Tyrosine Kinase (BTK) inhibitors

a cytoplasmic NRTK

plays an important role in __ ______ __________

BTK is constitutively phosphorylated by the oncogenic BCR-ABL1 fusion prodrug

BTK inhibition leads to dec malignant B cell proliferation and survival

defective expression of BTK is noted in ____

ibrutinib

(BTK inhibitor -- NRTKI)

ROA: oral

MOA: irreversible inhibitor of BTK

indication: CLL

AE: hematological effects (hemorrhage, neutropenia, thrombocytopenia, anemia), secondary malignancies (skin cancer)

hematological effects, skin cancer

what are the 2 most common side effects seen with JAK inhibitors (ruxolitinib) and BTK inhibitors (ibrutinib)?

EGFR, HER2

____ overexpression is correlated with dec life expectancy in solid tumors + found in almost all epithelial derived cancers

____ overexpression is a classic failure of treatment resistant breast, ovarian, lung, and gastric cancers

- called "antiapoptotic shield" = immortal

erlotinib, gefitinib

what are the 2 examples of EGFR/HER inhibitors (RTKIS)?

erlotinib

erlotinib

(EGFR inhibitor -- RTKI)

ROA: oral, QD

MOA: EGFR/HER1 inhibitor

indication: NSCLC, metastatic pancreatic cancer

ADME: biliary excretion, 60% absorption

AE: fatigue, rash, diarrhea, anorexia

- potentially fatal hepatotoxicity may be induced by this drug due to the formation of electrophilic quinoneimone

fatal hepatotoxicity

what is the consequence of erlotinib forming an electrophilic quinonemine?

gefitinib

gefitinib

(EGFR inhibitor -- RTKI)

ROA: oral

MOA: EGFR inhibitor

- first one launched

indication: 1st line for metastatic NSCLC w EGFR mutations detected by FDA approved test

ADME: 59% F, 6-49hr t1/2, hepatic excretion, 90% ppb

AE: rash (due to EGFR kinase specificity), diarrhea

NSCLC

what are both EGFR inhibitors indicated to treat?

VEGFR2

which VEGF receptor is more important + is involved with the mediation of angiogenic effects:

a. VEGFR1

b. VEGFR2

blood vessels

inhibition of VEGFR-2 blocks the formation of new _____ _______ around tumors thereby blocks oxygen and essential nutrients from reaching the tumor

sunitinib

(VEGFR2 inhibitor -- RTKI)

ROA: oral, QD

MOA: inhibits multiple receptor kinases including VEGFR2 (both active + inactive forms)

- also inhibits PDGFRa/b, KTI, FLT3, CSF-1R, RET in vitro

indication:

- GI stromal tumor after disease progression or imatinib intolerance

- advanced renal cell carcinoma

- progressive pancreatic neuroendocrine tumors

ADME; Pgp substrate, t1/2 = 40-60 hr, biliary elimination

AE: many targets = more side effects

- hand-foot syndrome, stomatitis, and other dermatologic toxicities

vandetanib

(VEGFR inhibitor -- RTKI)

ROA: oral, QD

MOA: inhibits VEGFR, EGFR, PTK6, and members of Src family of tyrosine kinases

indication: medullary thyroid cancer in patients with unresectable or metastatic disease

AE: diarrhea, rash, nausea, HTN, QTc prolongation, etc

rash

what is a common side effect with VEFGR inhibitors?

sunitinib, vandetanib, axitinib

what are the 3 VEFGR inhibitors?

axitinib

axitinib

(VEFGR inhibitor -- RTKI)

ROA: oral, BID

MOA: inhibits VEGFR1/2/3

indication: advanced RCC after failure of one prior systemic therapy

ADME: good F, high ppb, very high Vd

- strong CYP3A4/5 inhibitor

AE: diarrhea, HTN, fatigue, dec appetite, nausea