Anti-neoplastics Flashcards
Methotrexate
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)
Methotrexate - Uses
Curative for ALL
Rheumatoid Arthritis
Psoriasis
Abortifacient - causes abortions
Methotrexate - Adverse Effects
adverse effects - myelosuppression, mucositis, diarrhea, pulmonary fibrosis, neurotoxicity, hepatotoxicity
pregnancy category X
Methotrexate - Resistance
Resistance through impaired transport, decreased formation of polyglutamates. altered forms of DHFR, increased concentration of DHFR and production of efflux transporter.
5-Fluorouracil
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
5-Fluorouracil - uses
used for Colorectal Carcinoma
Upper GI Tract Carcinoma
Breast Cancer
5-Fluorouracil - adverse effects
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
Cytarabine
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
Cytarabine - Uses
AML
Non-Hodgkin Lymphoma
ALL, CML
Cytarabine - Resistance and Adverse Effects
Resistance
• Decreased conversion to active form
• Decreased transport
• Increased deactivation
AEs • Myelosuppression • Conjunctivitis • Stomatitis • Increased LFTs • Non-cardiogenic Pulmonary Edema • Neurotoxicity
6-Mercaptopurine
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
6-Mercaptopurine- Resistance and Contraindications
Resistance - def of HGPRT, decreased uptake or increased efflux
contraindicated with Allopurinol because of tumor lysis syndrome
6-Mercaptopurine- Adverse Effects
Myelosuppression Anorexia, nausea, vomiting Jaundice, increased LFTs Opportunistic infections Teratogenic
Alkylating Agents
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
Alkylating Agents- resistance and Adverse Effects
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
Cyclophosphamide
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)
Ifosfamide
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
Platinum Compounds
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
Platinum Compounds - Resistance and common AEs
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
Cisplatin, Carboplatin
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
Oxaliplatin
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
Vinca Alkaloids
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.
Vinblastine and Vincristine
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
Taxanes – Paclitaxel
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
Epipodophyllotoxins - Etoposide
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
Camptothecins
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
Doxorubicin and Daunorubicin
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
Doxorubicin and Daunorubicin - Uses and AEs
_-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
Imatinib
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.
BCR-ABL Kinase Inhibitors - special features of the individual drugs
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
BCR-ABL kinase inhibitors - Therapeutic Uses
CML and ALL - Ph Chr +
GIST which is c-Kit+
Mastocytosis - aggressive and systemic
Eosinophilic Leukemia
Myelodysplastic / myeloproliferative disease that is PDGFR+
Toxicities of BCR-ABL Kinase Inhibitors
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
EGFR Inhibitors - MOA
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
Resistance to EGFR Inhibitors
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)
Therapeutic Uses of EGFR Inhibitors
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
Toxicities of EGFR Inhibitors
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
HER2 Inhibitors - MOA
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.
Trastuzumab - Therapeutic uses
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
Ado-Trastuzumab Emtansine - Therapeutic Uses
Refractory HER2+ metastatic breast cancer
Trastuzumab Toxicities / Drug Interactions
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
Ado-Trastuzumab Emtansine Toxicities / Drug Interactions
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
Bevacizumab - MOA and Therapeutic Uses
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
Therapeutic Uses: Bevacizumab
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
Rituximab - MOA and AE
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
Rituximab - Therapeutic Uses
Non-Hodgkin lymphoma CLL Steroid-refractory chronic GVHD RA refractory pemphigus vulgaris post-transplant lymphoproliferative disorder Autoimmune hemolytic anemia in children chronic ITP
Proteasome Inhibitor
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
Immunomodulatory Agents
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
Immunomodulatory Drugs Adverse Effects
common - constipation, neuropathy, somnolence, fatigue, dry skin and dry mouth
thalidomide - peripheral neuropathy
Neutropenia, thrombocytopenia
DVT and pulmonary embolism, MI and stroke
-prophylaxis
embryotoxic
Cancer Immunotherapy
IMMUNE CHECKPOINT INHIBITORS
CTLA Inhibitor - Ipilimumab*
PD-1 Inhibitors - Nivolumab*
Pembrolizumab
PD-L1 Inhibitor - Atezolizumab
Ipilimumab
CTLA-4 Inhibitor
Blocks CTLA-4 → enhanced T-cell activation and proliferation
Used for melanoma
Nivolumab
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
CAR-T Cell - Tisagenlecleucel
Axicabtagene ciloleucel
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
