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Pharmacology Unit 1 > Cancer IV > Flashcards

Cancer IV Flashcards

1
Q

molecular targeted therapy overview

A
  • becoming possible to determine which defective molecules or pathways dirving malignant progression
  • can take a rational approach to develop mechanism based cancer meds to target defective molecules/pathways
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2
Q

preclinical studies

A
  • new drug is tested on normal and cancer cell lines in a lab setting
  • animal testing for efficacy and tox
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3
Q

investigational new drug app

A

-new drug sponsor files an IND application with the FDA for clinical testing in humans

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4
Q

phase I

A
  • determines safe and appropriate doses for subsequent studies
  • determines toxic effects, preferred mode of admin, pharm behavior.
  • usually 10-30 patients with different types of malignancies who have failed standard trt
  • need life expectancy of 1-2 months with functioning organs capable of metabolism and excretion
  • patients divided into cohorts of 3-6 and each treated with increasing dose
  • if no serious side effects in first dose, second group goes until dose limiting tox
  • highest dose with acceptable tox recommended for phase II
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5
Q

phase II

A
  • determines effectiveness and side effects of new drug in one type of cancer
  • up to 100 patients with same malignancy and no effective trt, 3 month life expectancy
  • all usually given same dose and effectiveness evaluated, closely monitored
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6
Q

phase III

A
  • it evaluates the effectiveness of new drug and compares it to best available standard trt
  • large and long term trials involving 100 to 1000s of patients
  • specific types of malignancy
  • eligibility varies-stage, first time trt, status of prior trt, goals
  • conducted at multiple centers, randomly assigned to a group
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7
Q

new drug app

A
  • drug sponsor files this of biologics license application with FDA
  • submit phase III data
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8
Q

FDA approval

A
  • if satisfied with phase II results, FDA approves new drug, which can take about 1.5 years
  • after approval can be marketed to public under a label, which includes dosage, safety, indications, and side effects
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9
Q

phase IV

A

-determine long term safety and effectiveness of new drug

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10
Q

CML

A
  • clonal hematopoietic stem cell disorder
  • 15-20% of all leukemias
  • cytogenetic analysis- Ph chromosome in more than 90% of cases
  • 9;22 translocation
  • BCR-ABL- Tyrosine kinase
  • chronic, accelerated, blast phases
  • chronic is excess number of myeloid cell that differentiate normally but 4-6 years transforms to accelerated and blast-fatal
  • used to be treated with hydroxyurea or interferon alpha and allogenic stem cell transplant
  • late age disease so difficult to find donors, treatment sucked
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11
Q

new trt for CML

A
  • imatinib/gleevec
  • lead compound with selective activity agains abl tyrosine kinase
  • BCR-ABL activates signaling pathways, but needs ATP to phosphorylate other proteins
  • imatinib binds where ATP binds
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12
Q

preclinical studies with imatinib

A
  • showed specific inhibition of BCR-ABL expressing cell in vitro and in animals
  • showed acceptable animal tox profile
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13
Q

clinical studies with imatinib

A
  • phase I- CML patients who failed INF-a
  • at oral doses of 300 mg and higher 98% of patients displayed complete hematologic response within 3 weeks of therapy
  • response was maintained in 96% with median duration of follow up of 3 weeks
  • cytogenetic response were noted in 53% of patients with 13% displaying complete cytogenetic response
  • minimal side effects of nausea, vomiting, fluid retention, muscle cramps and arthralgia
  • myelosuppression in 29% of patients
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14
Q

pharmacokinetics of imatinib

A

-orally has relatively long half life of about 13-16 hours and good for daily dosing
-with oral admin of 400 mg peack Css was 2.3 micrograms/ ml, which is higher than needed
-metabolized by cyto p450 (3A4)
-

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15
Q

phase II imatinib

A
  • more than 1000 patients at 27 centers in 6 countries

- confirmed phase I

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16
Q

phase III imatinib

A
  • started to compare to INF+cytarabine
  • imatinib was superior
  • standard first line therapy
  • 8 year follow up show effective and safe
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17
Q

intrinsic resistance of imatinib

A
  • patients with persistent BCR-ABL kinase activity and could occur due to mutations in BCR-ABL or drug efflux or increased plasma protein binding
  • relapse involves reactivation of BCR-ABL
  • some patients have ABL mutations, less sensitive
  • some who relapse show peristent inhibition on BCR-ABL, must be additional abnormal growth
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18
Q

second generation TKIs

A

-nilotinib- june 2010 FDA approved for newly diagnosed
-first approved in 07 for imatinib resistant
-300 mg twice daily oral
dasatinib- oct 2010 approved for newly diagnosed
-06 for imatinib resistant
-100 mg twice daily oral

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19
Q

GI stromal tumors

A

-most common mesenchymal malignancies of the GI tract
-accounts for 1% of all GI malignancies
-can be benign and malignant, although all may be potentially malignant
-stomach is most common site then small intestine, esophagus, color and rectum less freq
-generally do not involve lymph nodes
-predominantly to liver
-generally affect older adults, 50-65
-mostly present with abd pain and GI bleeding, 20-25% asymptomatic
-about 90% are CD117 (KIT) pos
-kit is a receptor tyrosine kinase
GISTs harbor activating mutations in genes that encode KIT and PDGFRA (another TK)
-75-85% KIT, 5-10% PDGFRA
-10-15% no mutations

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20
Q

management of GISTs

A

-complete surgical resection of primary tumor is approach of choice and is usually associated with 48-65% 5 year survival
-sometimes due to site/size complete resection not possible
-high chance of metastatic relapse to liver and peritoneal surface, and response to conventional chemo/ radiation is poor
-imatinib beneficial for these patients and approved by the FDA for trt of unresectable and metastatic GISTs
-400 mg/day, no added benefit at higher dose
some patients show primary resistance or develop secondary resistance

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21
Q

acute promyelocytic leukemia

A

-paradigm for differentiation therapy
-type of acute myeloid leukemia, M3
-7-10% of all AML cases
-up to 30% incidence in latin american countries
-distinct blockage of myeloid differentiation resulting in accumulation of immature promyelocytes in marrow and peripheral blood
-reciprocal translocation 15,17 occurs in 98% of all cases
-other rare translocations, but always involves 17 (RARa)
-fuses retinoic acid receptor a (RARa) with promyelocytic leukemia gene- PML-RARa
-oncoprotein responsible for transformation
PML on 15, RARa on 17

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22
Q

all trans retinoic acid trt for APL

A
  • metabolite of vitamin A
  • first used in china- complete remission of APL
  • published results in 1988
  • provided to a french group-also had remission
  • published in 1990
  • one of earliest examples of molecular targeted therapy, mechanism discovered later
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23
Q

mechanism of retinoic acid

A
  • in APL the malignant immature promyelocutes continue to self renew and proliferate without differentiation
  • retinoic acid induces terminal differentiation of the cells, which then undergo apoptosis
  • acid binds to RARa, which in association with other similar receptors binds to DNA and induces the expression of gene involved in myeloid differentiation
  • the abnormal RARa in APL associates with other proteins, and at physiologic levels of retinoic acid is unable to cause cells to differentiate
  • drug causes RARa to turn on differentiation genes again
24
Q

dosage of retinoic acid

A
  • total dose of 25 mg/m^2 to 45 mg/m^2 per day in two oral doses
  • complete remission can be induced in more than 80-90% of previously untreated cases
  • since all cases invariably relapse if retinoic acid is monotherapy, administered concurrrently with anthracycline based meds
  • maintenence trt with retinoic acid in combo with low dose chemo is mostly recommended to reduce incidence of relapse
  • current general practice is to start with retinoic acid plus anthracycline based regimens as induction trt
  • gived two courses of anthra based for consolidation
  • then maintenence is retinoic plus low dose chemo for 2 years
  • such trt can achieve complete remission in more than 90% and relapse is less than 10% by year 2
25
Q

pharmacokinetics of retinoic acid

A
  • reaches circulation via portal vein
  • peak plasma levels in 1-2 hours following ingestion
  • plasma t1/2 is 1 hr
  • binds to albumin and transported as a complex
  • metabolites and glucuronic acid conjugates are mostly secreted into bile and excreted in urine and stools
26
Q

tox of retinoic acid

A
  • if used alone, 1/3 of pts develop increase in white blood count- leukocyte activation syndrome or retinoic acid syndrom
  • fever, resp distress, weight gain, pleural or pericardial effusion and occasionally renal failure
  • concurrent use of chemo plus acid plus corticosteroids have shown to block the syndrome
  • dryness of skin and lips, nausea, headache, arthralgias, bone pain
27
Q

mechanism of relapse/resistance to RA

A
  • induction of cytochrome p450 that enhance RA catabolism and reduces Cp
  • alterations in level of cytosolic RA binding protein II (CRBP II) that could affect transport
28
Q

EGFR family

A
  • ErbB1
  • ErbB2
  • ErbB3
  • ErbB4
  • cell surface proteins with extracellular domain, transmembrane segment and intracellular tyrosine kinase domain (except B3)
  • receptors activated by ligands
  • activation involves dimerization between two identical or two different dimers
  • ligand binding induces dimerization, so can high receptor density
  • following dimerization, receptors are auto phosphorylated on tyrosine residues and transduce proliferative and survival signals inside the cells
  • overexpression in cancer cells results in hyperproliferation and enhanced cell survival
  • good targets for anticancer therapy
29
Q

ErbB2

A
  • her 2/neu
  • no ligand
  • forms heterodimers with all other receptors
  • believed to function as a master coordinator that shares the ErbB ligands
  • overexpressed in breast, ovarian, gastric
30
Q

ErbB1

A
  • EGFR or Her1
  • bound by EGF and TGFa
  • overexpressed in different cancers
  • gastric, breast, prostate, bladder, ovarian, colorectal, non small cell lung and glioblastomas
31
Q

ErbB3/4

A

HER3/4

-bound by neuregulin

32
Q

anti-ErbB2 monoclonal antibodies

A
  • trastuzumab is humanized monoclonal antibody against ErbB2 (HER2/neu) GF receptor
  • overexpressed in about 25-30% of advanced breast cancers and is predictive of worse prognosis
  • approved in 1998 for trt of HER2 pos cancers
33
Q

dosage of trastuzumab

A
  • loading dose of 4 mg/kg as a 90 min iv infusion
  • maintenance dose of 2 mg/kg per week as a 30 min iv infusion
  • usually give in combination with taxanes
34
Q

pharmacokinetics of trastuzumab

A
  • plasma concentration varies from patient to patient due to presence of circulating extracellular domain of ErbB2 shed receptor
  • in general, Cp is about 10-25 ug/ml
  • half life is 8.3 +/- 5 days
35
Q

tox of trastuzumab

A
  • hypersensitivity- can still occur even with humanized version
  • ventricular dysfunction and CHF
  • can enhance cardiac tox of doxorubicin
36
Q

mechanism of trastuzumab

A
  • not known exactly
  • appears to prevent the transduction of proliferation and survival signals
  • induces cytostatic growth inhibitory effects agains HER2/neu overexpressing cells, which could occur due to antibody induced downregulation of the receptor and subsequent degradation
  • antibody probably disrupts proliferative signals from other receptors
  • monotherapy only modest response
  • better if combined with paclitaxel or doxorubicin, the antibody enhances cytotoxic effects of these drugs
37
Q

anti ErbB1 antibodies

A
  • cetuximab
  • competes for binding with ligands
  • inhibits tyrosine kinase activity and growth signals
  • redicted to work better in combination with cisplatin and other chemo
  • 2004- FDA accelerated approval for combo with irinotecan for trt of metastatic colorectal carcinomas that express EGFR and are refractory to irinotecan based chemo
  • approved for single use in pts who can’t tolerate irinotecan
  • 2006- approved in combo with radiation therapy for sp cell carcinoma of head and neck and as single agent in ppl treated previously with platinum
  • 2012- approved for use with irinotecan, 5FU, and leucovorin as 1st line management for patients with Kras wild type EGFR expressing metastatic colorectal cancer
38
Q

dosage of cetuximab

A
  • supplied as single dose vials of 50ml containing 100g (2mg/ml)
  • recommended dose as a single agent of in combo with irinotecan
  • 400mg/m^2 as initial loading dose administered as a 120 min IV infusion
  • weekly maintenance is 250 mg/m^2
39
Q

FOLFIRI

A
  • FOL-folinic acid-leucovorin
  • F-5FU
  • IRI-irinotecan
  • cetuximab is 400 mg/m^2 IV infusion in 120 min initial dose followed by 250 mg/m^2 over 30 min weekly in combo with FOLFIRI
  • cetuximab completed 1 hr before FOLFIRI
40
Q

non-hodgkins lymphoma

A
  • lymphoid neoplasms
  • include more than 20 distinct entities affecting B or T cells
  • 6th most common cause of cancer related deaths in the US
41
Q

follicular lymphoma

A
  • type of NHL
  • involves mature B cells
  • 75-80% of indolent B cell lymphomas are follicular lymphomas
  • mostly affects older adults
  • classified into grade 1,2,3
  • t14:18 present in about 95% of grade 1 and II and smaller portion of III
  • about 40% transform into diffuse large b cell lymphomas
  • transformed into diffuse are aggressive with worse prognosis
42
Q

standard trt for follicular lymphoma

A
  • only about 15 % of grade 1 and 2 diagnosed at early stage- can use radiation therapy for these
  • majority of grade 1 and 2 have advanced disease
  • conservative-no initial trt, single agent, CHOP and/or radiation as needed
  • aggressive-initial CHOP plus radiation
  • meaningful response lasts up to 2 years
  • grade 3 represents about 10% of follicular lymphomas, aggressive form, trt is CHOP based
43
Q

trt with rituximab

A
  • for FL
  • chimeric monoclonal antibody with variable region of mice igG but constant region and Fc from humans
  • effective in many relapsed or refractory follicular lymphomas
  • 375 mg. m2 weekly for 4 weeks
  • binds to CD20, which is a transmembrane protein in all B cells
  • eliminates CD20 pos by activating apoptosis, complement, and cell mediated cytotox
44
Q

melanoma

A
  • highly aggressive
  • melanocytes
  • cutaneous, acral, mucosal, uveal
  • cutaneous most commone
  • acral-skin of palsm, soles, and underneath nails
  • uveal-other organs-iris of eye
  • in 2013, 76,690 people and 9,480 die
45
Q

types of cutaneous melanoma

A
  • superficial spreading-70%
  • nodular- 15%, common in males and older
  • acral lentigious-about 5%, more common in darker skin
  • lentigo maligna- 10%, middle aged to older
46
Q

BRAF mutations and melanoma

A
  • found in 45-50% of cutaneous melanomas
  • more freq in melanomas not associated with sun induced damage
  • less common in acral, mucosal, uveal
  • serine threonin kinase
  • BRAF v600e mutation in kinase activation domain-leads to constitutive activation of kinase
  • v600k second most common
47
Q

management of melanoma

A
  • surgical excision with or without lymphadenectomy

- metastatic managed medically by dacarbazine-only FDA approved for metastatic melanoma

48
Q

vemurafenib

A
  • BRAF inhibitor, binds to oncogenic kinase
  • clinical trials- see notes
  • led to 63 % reduction in risk of death and 74% reduction in risk of tumor progression in previously untreated patients
  • 13.2 months vs 9.9 on dacarbazine
  • improvement in overall survival and progression free survival

previously trted patients

  • response rate of 53%, 6% complete remission
  • median duration of response 6.5 months, 1.4 months to response
  • manageable side effects
49
Q

current status of vemurafenib

A
  • effective and well tolerated
  • approved in 2011 for unresectable stage III and IV or metastatic melanomas that harbor BRAF v600 mutations
  • approved in europe in 2012
  • 906 mg BID orally
  • until disease progression or unacceptable side effects
50
Q

side effects of vemurafenib

A
  • arthralgia, fatigue, photosensitivity, alopecia, nausea, diarrhea
  • cutaneous sq cell, keratoacanthoma, or both
  • QT prolongation, inc risk for arrhythmias
  • new primary cutaneous melanoma
51
Q

contraindications of vemurafenib

A
  • not for melanomas with WT BRAF
  • electrolyte anomalies
  • long QT syndrome
  • patients on drugs that will cause long QT interval
52
Q

Dabrafenib

A
  • approved in 2013 for BRAF pos unresectable or met melanomas
  • next gen agent
  • 150 mg BID + dacarbazine at 1000 mg/m2 IV every three weeks
  • acceptable safety profile, improvement in PFS and ORR
53
Q

side effects of darbrafenib

A
  • higher risk to develo cutaneous sq cell, keratoacanthoma, and melanoma
  • serious febrile drug reactions- fever or fever associated with hypotension, rigors, chills, dehydration, kidney failure
  • uveitis and iritis
  • hyperglycemia
  • hyperkeratosis
  • may inhibit fertility in males
54
Q

trametinib

A

-approved in may 2013 for BRAF mutated melanoma
-inhibits MEK- extracellular signal regulated kinase
-2 mg orally once daily
side effects:
-cardiomyopathy
-retinal pigment epithelial detachment
-retinal vein occlusion
-interstitial lung disease
-serious skin tox- rash, dermatitis, acneiform rash, palmar/plantar erythrodysesthesia syndrome/ erythema
-rash, diarrhea, lymphedema, dermtitis, stomatitis, hypertension, abd pain, hemorrhage, dry skin, pruritus, paronychia
-male infertility
-not for wt BRAF or pts previously trted with BRAF inhibitors

55
Q

immunotherapy for melanoma

A

-ipilimumab- cytotoxic T cell Antigen 4 inhibitor
-CTLA4 is a receptor on T cells to down regulate immune system- without this, immune system stimulation
IL2
-increases immune response
-10-20% response rate, 4-6% complete remission

Pharmacology Unit 1 (10 decks)

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