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Pharmacology > Anti-neoplastics > Flashcards

Anti-neoplastics Flashcards

1
Q

Methotrexate

A

folate antimetabolite

Competitively inhibits DHFR causing decreased production of THF

IV, intrathecal, oral with renal excretion

50% bound to plasma proteins

Effects can be reversed via Leucovorin (5-formyltetrahydrofolate)

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2
Q

Methotrexate - Uses

A

Curative for ALL

Rheumatoid Arthritis

Psoriasis

Abortifacient - causes abortions

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3
Q

Methotrexate - Adverse Effects

A

adverse effects - myelosuppression, mucositis, diarrhea, pulmonary fibrosis, neurotoxicity, hepatotoxicity

pregnancy category X

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4
Q

Methotrexate - Resistance

A

Resistance through impaired transport, decreased formation of polyglutamates. altered forms of DHFR, increased concentration of DHFR and production of efflux transporter.

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5
Q

5-Fluorouracil

A

Pyrimidine Analog of uracil; 5-FU activated to various metabolites which causes inhibition of DNA and RNA synthesis

efficacy is increased with levocortin

inhibits thymidylate synthase

incorporated into RNA which inhibits translation

incorporated into DNA which inihibits DNA synthesis

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6
Q

5-Fluorouracil - uses

A

used for Colorectal Carcinoma

Upper GI Tract Carcinoma

Breast Cancer

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7
Q

5-Fluorouracil - adverse effects

A

Inactivated by dihydropyrimidine dehydrogenase (DPD) in which an Inherited deficiency of enzyme which leads increased risk of toxicity

adverse effects - myelosuppression, mucositis, diarrhea, hand-foot syndrome

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8
Q

Cytarabine

A

Pyrimidine Analog which is metabolized to Ara-CTP

Inhibits DNA polymerase A – inhibits DNA synthesis
Inhibits DNA polymerase B – inhibits DNA repair
Incorporated into DNA – inhibits chain elongation
S-phase specific

IV, intrathecally and degraded by cytidine deaminase, continuous infusion for 5 to 7 days

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9
Q

Cytarabine - Uses

A

AML
Non-Hodgkin Lymphoma
ALL, CML

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10
Q

Cytarabine - Resistance and Adverse Effects

A

Resistance
• Decreased conversion to active form
• Decreased transport
• Increased deactivation

AEs
• Myelosuppression
• Conjunctivitis
• Stomatitis
• Increased LFTs
• Non-cardiogenic Pulmonary Edema
• Neurotoxicity
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11
Q

6-Mercaptopurine

A

purine analog - Converted to active metabolites via HGPRT > incorporates into DNA and inhibits chain elongation (6-TGMP) and interfere with purine synthesis (TIMP)

Inactivated by xanthine oxidase, TMPT – polymorphisms exist

Oral with first pass metabolism and increased bioavailability with MTX

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12
Q

6-Mercaptopurine- Resistance and Contraindications

A

Resistance - def of HGPRT, decreased uptake or increased efflux

contraindicated with Allopurinol because of tumor lysis syndrome

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13
Q

6-Mercaptopurine- Adverse Effects

A 
Myelosuppression 
Anorexia, nausea, vomiting 
Jaundice, increased LFTs 
Opportunistic infections 
Teratogenic
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14
Q

Alkylating Agents

A

All agents can form reactive intermediates which transfer alkyl group to DNA (N7 guanine)

this causes abnormal base pairing and the DNA strand breakage when DNA pair mechanisms excise guanine

most active in G1-S cell cycle phase

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15
Q

Alkylating Agents- resistance and Adverse Effects

A

Resistance
• Increased ability to repair DNA damage
• Decreased transport of drug into cell
• Increased expression of glutathione

Adverse Effects
• Bone Marrow Suppression
• Carcinogenic – AML risk
• Mucosal Toxicity
• Alopecia
• Sterility
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16
Q

Cyclophosphamide

A

Alkylating Agent - Nitrogen Mustard – Oral, IV and is metabolized by CYP2B

used for Non-Hodgkin Lymphoma, Breast and Ovarian cancers

Non-phase specific

Adverse effects - Hemorrhagic Cystitis: risk is decreased with Mensa which neutralizes toxin, also provide IV hydration

causes SIADH (Syndrome of Inappropriate Antidiuretic Hormone Secretion)

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17
Q

Ifosfamide

A

Alkylating Agent - Cyclophosphamide analog

Metabolized by CYP3A4 to active mustard metabolite

Used for Testicular Cancer

Adverse Effects are Hemorrhagic Cystitis, CNS toxicity – hallucinations, coma,, and Urinary tract toxicity

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18
Q

Platinum Compounds

A

Enters cells through copper transporter - CRT1

ligands are displaced by water because of a positive charge > reacts with nucleophilic sites on DNA:

  • Inhibits DNA replication
  • Inhibits DNA transcription
  • Single and double-stranded DNA breaks

Extruded via ATP7A,B

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19
Q

Platinum Compounds - Resistance and common AEs

A

Resistance
• Decreased expression of CTR1 transporter
• Upregulation of ATP7A/B efflux
• Increased expression of inactivating enzymes
• Overexpression of DNA repair enzymes

Common AEs
• Secondary leukemia
• Pulmonary Fibrosis
• Myelosuppression

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20
Q

Cisplatin, Carboplatin

A

Platinum Compounds

Used for Testicular cancer, NSCLC, SCLC, Ovarian cancer, and Bladder cancer

Given IV

Adverse effects – Nephrotoxicity (prevention with hydration and diuresis) and Ototoxicity (tinnitus, hearing loss)

carboplatin is less nephrotoxic

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21
Q

Oxaliplatin

A

Platinum Compound

No cross-resistance with Carboplatin/Cisplatin

Used for Colorectal Cnacer -

FOLFOX - combination therapy with 5-FU, Leucovorin, Oxaliplatin

Adverse Effect is Peripheral Nephropathy which is worse in the cold

22
Q

Vinca Alkaloids

A

Derived from Catharanthus roseus and inihibts tubulin polymerization

  • binds to B-tubulin, inhibits polymerization of alpha-tubulin and disrupts assembly of microtubules.
  • this all leads to mitotic arrest in metaphase

Given IV and metabolized by CYP3A4

Resistance is seen through increase efflux associated with increased MDR gene and mutation in beta-tubulin or decreased expression of beta-tubulin.

23
Q

Vinblastine and Vincristine

A

Vinca Alkaloids

Vinblastine – used for many solid tumors and Hodgkin Lymphoma. Adverse effects are bone marrow suppression

Vincristine — used for ALL and Non-Hodgkin Lymphoma. Adverse Effects are peripheral neuropathy and constipation

24
Q

Taxanes – Paclitaxel

A

Alkaloid ester derived from the yew plant

Binds to beta-tubulin and antagonizes disassembly causing cell cycle arrest

given IV and metabolized by CYP2C8

Used for ovarian cancer, breast cancer, NSCLC and SCLC, and Head and Neck cancer

Adverse Effects – Bone Marrow Suppression, Peripheral Neuropathy, and Hypersensitivity reaction

pretreat for hypersensitivity with antihistamines or glucocorticoids

25
Q

Epipodophyllotoxins - Etoposide

A

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

26
Q

Camptothecins

A

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

27
Q

Doxorubicin and Daunorubicin

A

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

28
Q

Doxorubicin and Daunorubicin - Uses and AEs

A

_-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

29
Q

Imatinib

A

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.

30
Q

BCR-ABL Kinase Inhibitors - special features of the individual drugs

A

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

31
Q

BCR-ABL kinase inhibitors - Therapeutic Uses

A

CML and ALL - Ph Chr +

GIST which is c-Kit+

Mastocytosis - aggressive and systemic

Eosinophilic Leukemia

Myelodysplastic / myeloproliferative disease that is PDGFR+

32
Q

Toxicities of BCR-ABL Kinase Inhibitors

A

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

33
Q

EGFR Inhibitors - MOA

A

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

34
Q

Resistance to EGFR Inhibitors

A

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)

35
Q

Therapeutic Uses of EGFR Inhibitors

A

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

36
Q

Toxicities of EGFR Inhibitors

A

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
37
Q

HER2 Inhibitors - MOA

A

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.

38
Q

Trastuzumab - Therapeutic uses

A

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

39
Q

Ado-Trastuzumab Emtansine - Therapeutic Uses

A

Refractory HER2+ metastatic breast cancer

40
Q

Trastuzumab Toxicities / Drug Interactions

A

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

41
Q

Ado-Trastuzumab Emtansine Toxicities / Drug Interactions

A

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

42
Q

Bevacizumab - MOA and Therapeutic Uses

A

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
43
Q

Therapeutic Uses: Bevacizumab

A

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

44
Q

Rituximab - MOA and AE

A

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
45
Q

Rituximab - Therapeutic Uses

A 
Non-Hodgkin lymphoma
CLL
Steroid-refractory chronic GVHD
RA 
refractory pemphigus vulgaris
post-transplant lymphoproliferative disorder 
Autoimmune hemolytic anemia in children 
chronic ITP
46
Q

Proteasome Inhibitor

A

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

47
Q

Immunomodulatory Agents

A

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

48
Q

Immunomodulatory Drugs Adverse Effects

A

common - constipation, neuropathy, somnolence, fatigue, dry skin and dry mouth

thalidomide - peripheral neuropathy

Neutropenia, thrombocytopenia

DVT and pulmonary embolism, MI and stroke
-prophylaxis

embryotoxic

49
Q

Cancer Immunotherapy

IMMUNE CHECKPOINT INHIBITORS

A

CTLA Inhibitor - Ipilimumab*

PD-1 Inhibitors - Nivolumab*
Pembrolizumab

PD-L1 Inhibitor - Atezolizumab

50
Q

Ipilimumab

A

CTLA-4 Inhibitor

Blocks CTLA-4 → enhanced T-cell activation and proliferation

Used for melanoma

51
Q

Nivolumab

A

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

52
Q

CAR-T Cell - Tisagenlecleucel

Axicabtagene ciloleucel

A

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

Pharmacology (23 decks)

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