CHEMOTHERAPEUTIC DRUGS Flashcards
Cytarabine (arabinofuranosyl cytidine)
Mechanism:
Incorporation of pyrimidine analog into DNA→ ↓ DNA synthesis (via termination of DNA chain)
At higher concentrations, inhibits DNA polymerase.
S-phase specific
Clinical Use:
Leukemias (especially AML), lymphomas
Adverse Effects: Myelosuppression (pancytopenia) Megaloblastic anemia Hepatotoxicity Pancreatitis Sudden respiratory distress syndrome Neurotoxicity (e.g., seizures, cerebellar toxicity)
Pemetrexed
Mechanism: Multitargeted antifolate (pemetrexed inhibits dihydrofolate reductase, thymidylate synthase, glycineamide ribonucleotide formyltransferase, and, potentially, other enzymes involved in folate metabolism) Inhibition of thymidylate synthase → ↓ synthesis of deoxythymidine monophosphate (dTMP) → ↓ DNA and RNA synthesis
Clinical Use:
Pleural mesothelioma
NSCLC
Ovarian cancer
Adverse Effects: Alopecia Erythematous, pruritic rash (pemetrexed) Desquamation Anemia Pharyngitis GI symptoms (e.g, diarrhea)
5-Fluorouracil (5-FU)
Mechanism:
Activation of 5-fluorouracil to 5-FdUMP
Complex formation with thymidylate synthase and folic acid → inhibition of thymidylate synthase → ↓ dTMP production → ↓ DNA synthesis
Incorporation of pyrimidine analog into DNA and RNA → ↓ DNA and RNA synthesis
Leucovorin enhances antineoplastic efficacy of 5-fluorouracil
Clinical Use: Systemic treatment -Breast cancer -Gastric cancer -Colorectal cancer -Pancreatic cancer Topical treatment -Actinic keratosis -Basal cell carcinoma
Adverse Effects:
Myelosuppression
Palmar-plantar erythrodysesthesia (hand-foot syndrome)
Cardiotoxicity
GI symptoms (e.g. nausea, diarrhea, mucosal ulcerations)
Higher toxicity in patients with dihydropyrimidine dehydrogenase deficiency
Hepatotoxicity
Hyperammonemic encephalopathy
Capecitabine
Prodrug for 5-FU
Mechanism:
Activation of 5-fluorouracil to 5-FdUMP
Complex formation with thymidylate synthase and folic acid → inhibition of
thymidylate synthase → ↓ dTMP production → ↓ DNA synthesis
Incorporation of pyrimidine analog into DNA and RNA → ↓ DNA and RNA synthesis
Leucovorin enhances antineoplastic efficacy of 5-fluorouracil
Clinical Use:
Myelosuppression
Palmar-plantar erythrodysesthesia (hand-foot syndrome)
Cardiotoxicity
GI symptoms (e.g. nausea, diarrhea, mucosal ulcerations)
Higher toxicity in patients with dihydropyrimidine dehydrogenase deficiency
Hepatotoxicity
Hyperammonemic encephalopathy
Adverse Effects: Systemic treatment -Breast cancer -Gastric cancer -Colorectal cancer -Pancreatic cancer Topical treatment -Actinic keratosis -Basal cell carcinoma
Gemcitabine
Mechanism:
Incorporation of pyrimidine analog into DNA → ↓ DNA synthesis
Clinical Use: Breast cancer NSCLC Ovarian cancer Pancreatic cancer
Adverse Effects: Myelosuppression Capillary leak syndrome Hemolytic uremic syndrome Pulmonary toxicity Hepatotoxicity
Azathioprine
Prodrug for 6-MP
Mechanism:
6-Mercaptopurine is converted into the active metabolite by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) → ↓ de novo synthesis of purines
Incorporation of purine analog (thiol analog) into DNA → ↓ DNA synthesis
Clinical Use:
Acute lymphoblastic leukemia
Non-neoplastic conditions: immunosuppression
Prevention of organ transplant rejection
Treatment of autoimmune diseases
For example, inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis
Used in patients with steroid-resistance or to reduce steroid dose
Adverse Effects:
Myelosuppression
GI symptoms (e.g., CINV, diarrhea)
Hepatotoxicity
Secondary malignancy (cases of AML have been reported after prolonged administration of 6-MP in the therapy of Crohn disease)
Metabolized by xanthine oxidase; therefore, toxicity increases with concurrent use of allopurinol and/or febuxostat
Fludarabine
Mechanism:
Incorporation of purine analog into DNA → ↓ DNA and RNA synthesis
Clinical Use:
CLL
Low-grade lymphomas (e.g., follicular B-cell lymphoma)
Myeloablation prior to hematopoietic stem cell transplant
Adverse Effects:
Autoimmune effects (e.g., autoimmune hemolytic anemia, idiopathic thrombocytopenia)
Myelosuppression
Neurotoxicity
Cladribine
Mechanism:
Incorporation of purine analog into DNA → breakage of DNA strand → ↓ DNA synthesis
Inhibits DNA polymerase
Selectively toxic to lymphocytes and monocytes that have a high deoxycytidine kinase and a low deoxynucleotidase content.
Deoxycytidine kinase phosphorylates cladribine (low deoxynucleotidase content prevents dephosphorylation)
Monophosphorylated cladribine is resistant to adenosine deaminase and accumulates within the cells.
Clinical Use: Hairy cell leukemia CLL Low-grade lymphomas Nonneoplastic conditions: multiple sclerosis
Adverse Effects: Myelosuppression Headache Nephrotoxicity Neurotoxicity Cardiotoxicity Hepatotoxicity
Hydroxyurea (hydroxycarbamide)
Mechanism:
Inhibition of ribonucleotide reductase → ↓ DNA replication (S phase) → massive cytoreduction
Increases production of hemoglobin F (HbF)
Clinical Use: Myoproliferative disorders Chronic myeloid leukemia Polycythemia vera Essential thrombocythemia Leukostasis syndrome Head and neck cancer Sickle cell crisis prophylaxis
Adverse Effects: Myelosuppression Macrocytosis, megaloblastic anemia Secondary malignancy Birth defects Pulmonary toxicity
Cyclophosphamide
Alkylating agent
Mechanism:
Alkylation of DNA/RNA → cross-links DNA at guanine N–7 → ↓ DNA replication
Cyclophosphamide and ifosfamide require activation in the liver.
Clinical Use: Malignancies -Solid tumors (e.g., breast cancer, ovarian cancer, small cell lung cancer) -Leukemias -Lymphomas -Multiple myeloma Nonneoplastic conditions -Autoimmune diseases (e.g., systemic lupus erythematosus, granulomatosis with polyangiitis) -Nephrotic syndrome
Adverse Effects: Bladder toxicity -Hemorrhagic cystitis (inflammation of the bladder, damaging to the epithelium and blood vessels; bladder carcinoma) Myelosuppression Syndrome of inappropriate antidiuretic hormone secretion (SIADH) Pulmonary toxicity Cardiac toxicity Infertility
Mesna (2-MErcaptoethane Sulfonate Na) and fluids prevent bladder toxicity (sulfate group of mesna binds toxic metabolites)
Ifosfamide
Alkylating agent
Mechanism:
Alkylation of DNA/RNA → cross-links DNA at guanine N–7 → ↓ DNA replication
Cyclophosphamide and ifosfamide require activation in the liver.
Clinical Use: Solid tumors (e.g., testicular germ-cell cancer, osteosarcoma)
Adverse Effects: Bladder toxicity -Hemorrhagic cystitis (inflammation of the bladder, damaging to the epithelium and blood vessels; bladder carcinoma) Myelosuppression Syndrome of inappropriate antidiuretic hormone secretion (SIADH) Pulmonary toxicity Cardiac toxicity Infertility Fanconi syndrome (ifosfamide) Neurotoxicity (ifosfamide)
Mesna (2-MErcaptoethane Sulfonate Na) and fluids prevent bladder toxicity (sulfate group of mesna binds toxic metabolites)
Chlorambucil
Alkylating agent
Nitrogen mustard
Mechanism:
Alkylation of DNA/RNA → cross-links DNA at guanine N–7 → ↓ DNA replication
Cyclophosphamide and ifosfamide require activation in the liver.
Clinical Use:
Chronic lymphocytic leukemia
Hodgkin lymphoma
Non-Hodgkin lymphoma
Adverse Effects: Myelosuppression Oral ulcerations GI symptoms (e.g., CINV) Pulmonary fibrosis Infertility
Melphalan
Alkylating agent
Nitrogen mustard
Mechanism:
Alkylation of DNA/RNA → cross-links DNA at guanine N–7 → ↓ DNA replication
Cyclophosphamide and ifosfamide require activation in the liver.
Clinical Use:
Multiple myeloma
Ovarian cancer
Amyloidosis
Adverse Effects: Myelosuppression Pulmonary toxicity Hypokalemia Peripheral edema Secondary leukemia
Temozolomide
Alkylating agent
Mechanism:
Alkylation of DNA/RNA → cross-links DNA at guanine N–7 → ↓ DNA replication
Cyclophosphamide and ifosfamide require activation in the liver.
Clinical Use:
Glioblastoma
Anaplastic astrocytoma
Adverse Effects:
Myelosuppression
Neurotoxicity
Pneumocystis pneumonia
Carmustine
Alkylating agent
Nitrosourea
Mechanism:
Alkylation of DNA/RNA → cross-links between DNA → ↓ DNA synthesis
Require bioactivation
Due to their high lipophilicity, carmustine and lomustine can cross the blood-brain barrier and act in the CNS.
Clinical Use:
Brain tumors (e.g., glioblastoma multiforme)
Multiple myeloma (carmustine, lomustine)
Hodgkin lymphoma
Adverse Effects: Neurotoxicity (e.g., convulsions, dizziness, ataxia) Myelosuppression Pulmonary toxicity Secondary leukemia
Lomustine
Alkylating agent
Nitrosourea
Mechanism:
Alkylation of DNA/RNA → cross-links between DNA → ↓ DNA synthesis
Require bioactivation
Due to their high lipophilicity, carmustine and lomustine can cross the blood-brain barrier and act in the CNS.
Clinical Use:
Brain tumors (e.g., glioblastoma multiforme)
Multiple myeloma (carmustine, lomustine)
Hodgkin lymphoma
Adverse Effects: Neurotoxicity (e.g., convulsions, dizziness, ataxia) Myelosuppression Pulmonary toxicity Secondary leukemia
Streptozocin
Alkylating agent
Nitrosourea
Mechanism:
Alkylation of DNA/RNA → cross-links between DNA → ↓ DNA synthesis
Require bioactivation
Do not cross the blood-brain barrier
Clinical Use:
Hodgkin lymphoma
Pancreatic neuroendocrine tumors (streptozocin)
Adverse Effects: Neurotoxicity (e.g., convulsions, dizziness, ataxia) Myelosuppression Pulmonary toxicity Secondary leukemia
Busulfan
Alkylating agent
Mechanism:
Cross-links between DNA strands → ↓ DNA replication
Clinical Use:
Myeloablation prior to hematopoietic stem cell transplantation
CML
Adverse Effects: Severe myelosuppression (expected effect) Pulmonary fibrosis Hyperpigmentation Electrolyte imbalance Cardiotoxicity Hepatotoxicity Neurotoxicity (e.g., convulsions)
Procarbazine
Alkylating agent
Mechanism:
Mechanism of action is not fully understood
Inhibition of transmethylation of methionine into transfer RNA → ↓ DNA, RNA, and protein synthesis
Also acts as a weak MAO inhibitor
Clinical Use:
Hodgkin lymphoma
Brain tumors (e.g., gliomas)
Adverse Effects: Myelosuppression Pulmonary toxicity Secondary leukemia Disulfiram-like reaction Tyramine crisis Gonadal damage
Cisplatin
Alkylating agent
Platinum-based agent
Mechanism:
Cross-links between DNA strands → ↓ DNA replication
Clinical Use: Lymphomas Solid tumors -Bladder cancer (cisplatin) -Testicular cancer (cisplatin) -Ovarian cancer (cisplatin, carboplatin) -Lung cancer (cisplatin, carboplatin) -Cervical cancer (cisplatin) -Osteosarcoma (cisplatin)
Adverse Effects:
Myelosuppression
Nephrotoxicity (may manifest as Fanconi syndrome)
Neurotoxicity (including peripheral neuropathies)
Ototoxicity
Chemotherapy induced nausea and vomiting
Prevent nephrotoxicity (may manifest as Fanconi syndrome) with:
- Amifostine (free radical scavenger)
- IV saline (induces chloride diuresis → ↑ urine chloride concentration → ↓ cisplatin reactivity)
Carboplatin
Alkylating agent
Platinum-based agent
Mechanism:
Cross-links between DNA strands → ↓ DNA replication
Clinical Use: Lymphomas Solid tumors -Ovarian cancer (cisplatin, carboplatin) -Lung cancer (cisplatin, carboplatin)
Adverse Effects:
Myelosuppression
Nephrotoxicity (may manifest as Fanconi syndrome)
Neurotoxicity (including peripheral neuropathies)
Ototoxicity
Chemotherapy induced nausea and vomiting
Prevent nephrotoxicity (may manifest as Fanconi syndrome) with:
- Amifostine (free radical scavenger)
- IV saline (induces chloride diuresis → ↑ urine chloride concentration → ↓ cisplatin reactivity)
Oxaliplatin
Alkylating agent
Platinum-based agent
Mechanism:
Cross-links between DNA strands → ↓ DNA replication
Clinical Use:
Lymphomas
Solid tumors
-Colorectal cancer (oxaliplatin)
Adverse Effects:
Myelosuppression
Nephrotoxicity (may manifest as Fanconi syndrome)
Neurotoxicity (including peripheral neuropathies)
Ototoxicity
Chemotherapy induced nausea and vomiting
Prevent nephrotoxicity (may manifest as Fanconi syndrome) with:
- Amifostine (free radical scavenger)
- IV saline (induces chloride diuresis → ↑ urine chloride concentration → ↓ cisplatin reactivity)
Irinotecan
Topoisomerase inhibitor
Mechanism:
Inhibition of topoisomerase I → ↓ DNA unwinding → ↓ DNA replication and DNA degradation (because of ssDNA breaks)
Clinical Use:
Colorectal cancer
Small-cell lung cancer
Pancreatic cancer
Adverse Effects: Myelosuppression GI symptoms (e.g., diarrhea) Cholinergic syndrome Alopecia Pulmonary toxicity (irinotecan)
Topotecan
Topoisomerase inhibitor
Mechanism:
Inhibition of topoisomerase I → ↓ DNA unwinding → ↓ DNA replication and DNA degradation (because of ssDNA breaks)
Clinical Use:
Cervical cancer
Ovarian cancer
Small-cell lung cancer
Adverse Effects: Myelosuppression GI symptoms (e.g., diarrhea) Cholinergic syndrome Alopecia
Etoposide
Topoisomerase inhibitor
Mechanism:
Inhibition of topoisomerase II → ↑ DNA degradation (dsDNA breaks) and ↓ DNA replication (cell cycle arrest in S and G2 phase)
Clinical Use: Solid tumors Testicular cancer Small-cell lung cancer Leukemias Lymphomas
Adverse Effects: Myelosuppression Alopecia Hypotension Mucositis (teniposide)
Vincristine
Mitotic Inhibitor
Vinca alkaloid
Mechanism:
Binding of β-tubulin → inhibition of β-tubulin polymerization into microtubules → prevention of mitotic spindle formation → mitotic arrest of the cell in metaphase (M-phase)
Clinical Use: Solid tumors -Neuroblastoma -Rhabdomyosarcoma -Wilms tumor Other -Acute lymphocytic leukemia -Hodgkin lymphoma -NHL
Adverse Effects:
Neurotoxicity (e.g., areflexia, peripheral neuropathy)
Paralytic ileus, constipation
Extravasation can cause significant irritation and/or ulceration of local tissue
Acute bronchospasm
Uric acid nephropathy
Vinblastine
Mitotic Inhibitor
Vinca alkaloid
Mechanism:
Binding of β-tubulin → inhibition of β-tubulin polymerization into microtubules→ prevention of mitotic spindle formation → mitotic arrest of the cell in metaphase (M-phase)
Clinical Use: Solid tumors Kaposi sarcoma Langerhans cell histiocytosis Testicular cancer Other Hodgkin lymphoma NHL
Adverse Effects:
Myelosuppression
Extravasation can cause significant irritation of local tissue
Pulmonary toxicity
Vinorelbine
Mitotic Inhibitor
Vinca alkaloid
Mechanism:
Binding of β-tubulin → inhibition of β-tubulin polymerization into microtubules→ prevention of mitotic spindle formation → mitotic arrest of the cell in metaphase (M-phase)
Clinical Use:
Non-small cell lung cancer
Breast cancer
Adverse Effects:
Myelosuppression
Hypersensitivity reactions
Docetaxel
Mitotic Inhibitor
Taxanes
Mechanism:
Hyperstabilization of polymerized microtubules → ↓ mitotic spindles breakdown → mitotic arrest in metaphase (not proceeding to anaphase)
Clinical Use: Breast cancer Ovarian cancer Prostate cancer Gastric cancer Kaposi sarcoma Non-small cell lung cancer
Adverse Effects: Myelosuppression Neuropathy Hepatotoxicity Hypersensitivity reactions Fluid retention Nail changes (e.g., nail bed purpura, onycholysis, nail pigmentation, splinter hemorrhage, subungual abscess)
Paclitaxel
Mitotic Inhibitor
Taxanes
Mechanism:
Hyperstabilization of polymerized microtubules → ↓ mitotic spindles breakdown → mitotic arrest in metaphase (not proceeding to anaphase)
Clinical Use: Breast cancer Ovarian cancer Prostate cancer Gastric cancer Kaposi sarcoma Non-small cell lung cancer
Adverse Effects: Myelosuppression Neuropathy Hepatotoxicity Hypersensitivity reactions Fluid retention Nail changes (e.g., nail bed purpura, onycholysis, nail pigmentation, splinter hemorrhage, subungual abscess)
Eribulin
Mitotic Inhibitor
Nontaxane microtubule inhibitor
Mechanism:
Inhibition of mitotic spindle formation → mitotic blockage → cell cycle arrest at the G2/M phase
Clinical Use:
Breast cancer
Liposarcoma
Adverse Effects:
Myelosuppression
Peripheral neuropathy
QT prolongation
Ixabepilone
Mitotic Inhibitor
Nontaxane microtubule inhibitor
Mechanism:
Binding to β-tubulin → hyperstabilization of the microtubules → ↓ breakdown of mitotic spindles breakdown → mitotic arrest in metaphase
Clinical Use:
Breast cancer
Adverse Effects:
Hypersensitivity
Myelosuppression
Peripheral neuropathy
Epothilone
Mitotic Inhibitor
Nontaxane microtubule inhibitor
Mechanism:
Binding to β-tubulin → hyperstabilization of the microtubules → ↓ breakdown of mitotic spindles breakdown → mitotic arrest in metaphase
Clinical Use:
Breast cancer
Adverse Effects:
Hypersensitivity
Myelosuppression
Peripheral neuropathy
Bleomycin
Mechanism:
Induces formation of free radicals → breakage of DNA strand → cell cycle arrest at G2 phase
Clinical Use: Squamous cell carcinomas of the head and neck Testicular cancer Hodgkin lymphoma Malignant pleural effusion
Adverse Effects: Pulmonary fibrosis Hyperpigmentation of the skin Mucositis Alopecia Minimal myelosuppression Idiosyncratic reaction
Actinomycin D (dactinomycin)
Mechanism:
DNA intercalation → interference with DNA transcription → ↓ RNA synthesis
Clinical Use: Childhood tumors -Wilms tumor -Ewing sarcoma -Rhabdomyosarcoma Gestational trophoblastic neoplasia
Adverse Effects: Myelosuppression Mucocutaneous toxicity Nephrotoxicity Hepatotoxicity
Doxorubicin
Anthracyclines are classically classified as cytotoxic antibiotics, but in terms of their chemotherapeutic action, they could also be classed as topoisomerase inhibitors.
Mechanism:
Inhibition of topoisomerase II → ↑ DNA degradation (dsDNA breaks) and ↓ DNA replication
Formation of free radicals → breakage of DNA strands
DNA intercalation → breakage of DNA strands and ↓ DNA replication
Clinical Use: Breast cancer (doxorubicin) Metastatic solid tumors (doxorubicin) Lymphomas (doxorubicin) Kaposi sarcoma (doxorubicin) Osteosarcoma
Adverse Effects: Cardiotoxicity (dilated cardiomyopathy with systolic CHF) Myelosuppression Alopecia Extravasation Infertility Urine discoloration
Prevent cardiotoxicity with dexrazoxane (iron chelating agent)
Mitomycin
Mechanism:
Cross-linking between DNA strands → ↓ DNA and RNA synthesis
Clinical Use:
Palliative chemotherapy of gastric and pancreatic cancer
Bladder cancer
Adverse Effects: Myelosuppression Hemolytic uremic syndrome Heart failure Thrombotic thrombocytopenic purpura Bladder fibrosis (with intravesical administration) ARDS
Imatinib
BCR-ABL and c-KIT tyrosine kinase inhibitors
Mechanism:
Inhibition of autophosphorylation and activation of multiple proteins by tyrosine kinases (e.g.,BCR-ABL, c-KIT)
Clinical Use:
Chronic myeloid leukemia
BCR-ABL positive ALL
Kit (CD117)-positive gastrointestinal stromal tumors
Aggressive systemic mastocytosis (imatinib)
Dermatofibrosarcoma protuberans (imatinib)
Hypereosinophilic syndrome (imatinib)
Chronic eosinophilic leukemia (imatinib)
Myelodysplastic/Myeloproliferative diseases (imatinib)
Adverse Effects: Fluid retention and edema Myelosuppression Hepatotoxicity (e.g., ↑ LFTs) Myalgia Neurotoxicity Bullous dermatologic reactions Hemorrhage Nephrotoxicity
Dasatinib
BCR-ABL and c-KIT tyrosine kinase inhibitors
Mechanism:
Inhibition of autophosphorylation and activation of multiple proteins by tyrosine kinases (e.g.,BCR-ABL, c-KIT)
Clinical Use:
Chronic myeloid leukemia
BCR-ABL positive ALL
Kit (CD117)-positive gastrointestinal stromal tumors
Adverse Effects: Fluid retention and edema Myelosuppression Hepatotoxicity (e.g., ↑ LFTs) Myalgia Cardiotoxicity Skin rash Hemorrhage Pulmonary arterial hypertension QT prolongation
Nilotinib
BCR-ABL and c-KIT tyrosine kinase inhibitors
Mechanism:
Inhibition of autophosphorylation and activation of multiple proteins by tyrosine kinases (e.g.,BCR-ABL, c-KIT)
Clinical Use:
Chronic myeloid leukemia
BCR-ABL positive ALL
Kit (CD117)-positive gastrointestinal stromal tumors
Adverse Effects: Fluid retention and edema Myelosuppression Hepatotoxicity (e.g., ↑ LFTs) Myalgia
Erlotinib
EGFR tyrosine kinase inhibitors
Mechanism:
Inhibition of HER1/EGFR tyrosine kinase → blockage of intracellular phosphorylation → cell death
Clinical Use:
Non-small cell lung cancer
Pancreatic cancer
Adverse Effects: Dermatologic toxicity (e.g., rash, bullous, blistering, and exfoliating skin conditions) Fatigue GI toxicity (e.g., diarrhea) Hepatotoxicity Ocular toxicity Nephrotoxicity
Gefitinib
EGFR tyrosine kinase inhibitors
Mechanism:
Inhibition of HER1/EGFR tyrosine kinase → blockage of intracellular phosphorylation → cell death
Clinical Use:
Non-small cell lung cancer
Pancreatic cancer
Adverse Effects: Dermatologic toxicity (e.g., rash, bullous, blistering, and exfoliating skin conditions) Fatigue GI toxicity (e.g., diarrhea) Hepatotoxicity Ocular toxicity Nephrotoxicity
Afatinib
EGFR tyrosine kinase inhibitors
Mechanism:
Inhibition of HER1/EGFR tyrosine kinase → blockage of intracellular phosphorylation → cell death
Clinical Use:
Non-small cell lung cancer
Pancreatic cancer
Adverse Effects: Dermatologic toxicity (e.g., rash, bullous, blistering, and exfoliating skin conditions) Fatigue GI toxicity (e.g., diarrhea) Hepatotoxicity Ocular toxicity Nephrotoxicity
Osimertinib
EGFR tyrosine kinase inhibitors
Mechanism:
Inhibition of HER1/EGFR tyrosine kinase → blockage of intracellular phosphorylation → cell death
Clinical Use:
Non-small cell lung cancer
Pancreatic cancer
Adverse Effects: Dermatologic toxicity (e.g., rash, bullous, blistering, and exfoliating skin conditions) Fatigue GI toxicity (e.g., diarrhea) Hepatotoxicity Ocular toxicity Nephrotoxicity
Alectinib
ALK tyrosine kinase inhibitors
Mechanism:
Inhibition of the anaplastic lymphoma kinase
Clinical Use:
Non-small cell lung cancer
Adverse Effects: GI toxicity (e.g., diarrhea) Fluid retention and edema Dermatologic toxicity (e.g., rash) Ocular toxicity Neurotoxicity Hepatotoxicity
Crizotinib
ALK tyrosine kinase inhibitors
Mechanism:
Inhibition of the anaplastic lymphoma kinase
Clinical Use:
Non-small cell lung cancer
Adverse Effects: GI toxicity (e.g., diarrhea) Fluid retention and edema Dermatologic toxicity (e.g., rash) Ocular toxicity Neurotoxicity Hepatotoxicity
Vemurafenib
V600E mutated-BRAF oncogene inhibitors
Mechanism:
Selective inhibition of BRAF oncogene with V600E mutation → inhibition of cancer cell growth
Often administered with MEK inhibitors (e.g., trametinib)
Clinical Use:
Metastatic melanoma
Erdheim-Chester disease
Adverse Effects: Dermatologic toxicity (e.g., rash) GI toxicity (e.g., nausea, diarrhea) Fatigue QT prolongation Dupuytren contracture and plantar fascial fibromatosis Pancreatitis
Trametinib
MEK inhibitor
Mechanism:
Inhibition of MAP kinase signaling pathway → inhibition of cancer cell growth and induction of apoptosis
Clinical Use:
Non-small cell lung cancer
Melanoma
Adverse Effects:
Hepatotoxicity
Dermatologic toxicity
GI toxicity
Ibrutinib
Bruton kinase inhibitor
Mechanism:
Inhibition of Bruton tyrosine kinase (BTK) → growth inhibition of malignant B cells
Clinical Use: Chronic lymphocytic leukemia (CLL) Mantle cell lymphoma Waldenstrom macroglobulinemia Graft-versus-host disease
Adverse Effects:
GI toxicity
Cardiotoxicity (e.g., atrial fibrillation)
Hepatotoxicity
Ruxolitinib
Janus kinase inhibitor
Mechanism:
Inhibition of JAK1 and JAK2 kinase → reduced activation of hematopoietic progenitor cells
Clinical Use:
Polycythemia vera
Myelofibrosis
Adverse Effects:
Hepatotoxicity (e.g., ↑ LFTs)
Hematologic toxicity (e.g., thrombocytopenia, anemia)
Palbociclib
CDK inhibitor
Mechanism:
Inhibition of cyclin-dependent kinase 4 and 6 → inhibition of cancer cell growth and induction of apoptosis
Clinical Use:
Metastatic breast cancer
Adverse Effects:
Myelosuppression
Pulmonary toxicity (e.g., pneumonitis)
L-asparaginase
Mechanism:
Cleavage of the amino acid L-asparagine by L-asparaginase → ↓ asparagine source for leukemic cells → cytotoxicity specific to leukemic cells
Cells in acute lymphoblastic leukemia and certain other cancer cells (e.g., lymphoblastic lymphoma, AML) are unable to synthesize asparagine on their own. This agent breaks down circulating asparagine, thus depriving cells of it.
Clinical Use:
Acute lymphoblastic leukemia
Adverse Effects: Hepatotoxicity Pancreatitis Hypofibrinogenemia and bleeding Thrombosis Hyperglycemia Allergic reactions
Bortezomib
Proteasome inhibitor
Mechanism:
Inhibition of ubiquitinated apoptotic protein degradation (e.g., of p53) → arrest in G2/M → programmed cell death (apoptosis)
Clinical Use:
Mantle cell lymphoma (bortezomib)
Multiple myeloma
Adverse Effects: Peripheral neuropathy Herpes zoster reactivation Hepatotoxicity Thrombocytopenia Neutropenia Pulmonary toxicity Heart failure
Carfilzomib
Proteasome inhibitor
Mechanism:
Inhibition of ubiquitinated apoptotic protein degradation (e.g., of p53) → arrest in G2/M → programmed cell death (apoptosis)
Clinical Use:
Multiple myeloma
Adverse Effects: Peripheral neuropathy Herpes zoster reactivation Hepatotoxicity Thrombocytopenia Neutropenia Pulmonary toxicity Heart failure
Ixazomib
Proteasome inhibitor
Mechanism:
Inhibition of ubiquitinated apoptotic protein degradation (e.g., of p53) → arrest in G2/M → programmed cell death (apoptosis)
Clinical Use:
Multiple myeloma
Adverse Effects: Peripheral neuropathy Herpes zoster reactivation Hepatotoxicity Thrombocytopenia Neutropenia Pulmonary toxicity Heart failure
Olaparib
PARP Inhibitor
Mechanism:
Inhibition of poly (ADP-ribose) polymerase → ↓ repair of single-strand DNA breaks
Clinical Use: Breast cancer Ovarian cancer Prostate cancer Pancreatic cancer
Adverse Effects:
Myelosuppression
Fluid retention and edema
GI toxicity (e.g., diarrhea)
Daunorubicin
Anthracyclines are classically classified as cytotoxic antibiotics, but in terms of their chemotherapeutic action, they could also be classed as topoisomerase inhibitors.
Mechanism:
Inhibition of topoisomerase II → ↑ DNA degradation (dsDNA breaks) and ↓ DNA replication
Formation of free radicals → breakage of DNA strands
DNA intercalation → breakage of DNA strands and ↓ DNA replication
Clinical Use:
Leukemias (daunorubicin, idarubicin)
Osteosarcoma
Adverse Effects: Cardiotoxicity (dilated cardiomyopathy with systolic CHF) Myelosuppression Alopecia Extravasation Infertility Urine discoloration
Idarubicin
Anthracyclines are classically classified as cytotoxic antibiotics, but in terms of their chemotherapeutic action, they could also be classed as topoisomerase inhibitors.
Mechanism:
Inhibition of topoisomerase II → ↑ DNA degradation (dsDNA breaks) and ↓ DNA replication
Formation of free radicals → breakage of DNA strands
DNA intercalation → breakage of DNA strands and ↓ DNA replication
Clinical Use:
Leukemias (daunorubicin, idarubicin)
Osteosarcoma
Adverse Effects: Cardiotoxicity (dilated cardiomyopathy with systolic CHF) Myelosuppression Alopecia Extravasation Infertility Urine discoloration
Dabrafenib
V600E mutated-BRAF oncogene inhibitors
Mechanism:
Selective inhibition of BRAF oncogene with V600E mutation → inhibition of cancer cell growth
Often administered with MEK inhibitors (e.g., trametinib)
Clinical Use:
Metastatic melanoma
Non-small cell lung cancer
Thyroid cancer
Adverse Effects: Dermatologic toxicity (e.g., rash) GI toxicity (e.g., nausea, diarrhea) Fatigue QT prolongation For dabrafenib and encorafenib Cardiomyopathy Febrile reactions Hyperglycemia Venous thromboembolism
Encorafenib
V600E mutated-BRAF oncogene inhibitors
Mechanism:
Selective inhibition of BRAF oncogene with V600E mutation → inhibition of cancer cell growth
Often administered with MEK inhibitors (e.g., trametinib)
Clinical Use:
Metastatic melanoma
Non-small cell lung cancer
Thyroid cancer
Adverse Effects: Dermatologic toxicity (e.g., rash) GI toxicity (e.g., nausea, diarrhea) Fatigue QT prolongation Cardiomyopathy Febrile reactions Hyperglycemia Venous thromboembolism
Treatment of Acute Chemotherapy-Induced Nausea and Vomiting (< 24 hours after chemotherapy; usually occurring 1–2 hours after chemotherapy)
- 5-HT3 antagonists (ondansetron, granisetron) (are most effective when used prophylactically to prevent vomiting)
- Dopamine receptor antagonists (prochlorperazine, metoclopramide)
Treatment of Delayed Chemotherapy-Induced Nausea and Vomiting (> 24 hours after chemotherapy)
NK1 antagonists (aprepitant, fosaprepitant)
Lenalidomide
Derivative of thalidomide
Mechanism:
- Antiemetic get used in pregnancy until significant teratogenic effects were identified
- Increases the binding of the E3 ubiquitin ligase complex to specific transcription factors that are over expressed in myeloma cells. Binding attaches ubiquitin to the transcription factors, which leads to their subsequent destruction by proteasome. Because these transcription factors are required for myeloma cell survival, diminished intracellular concentrations cause cell death.
Clinical Use:
Mantle cell lymphoma
Myelodysplastic syndrome (some cases are caused by B cell proliferation)
Amifostine
Mechanism:
Free radical scavenger
Clinical Use:
Nephrotoxicity from platinum compounds
Dexrazoxane
Mechanism:
Iron chelator
Clinical Use:
Cardiotoxicity from anthracyclines
Leucovorin (Folinic Acid)
Mechanism:
Tetrahydrofolate precursor
Clinical Use:
Myelosuppression from methotrexate (leucovorin “rescue”); also enhances the effects of 5-FU
Mesna
Mechanism:
Sulfhydryl compound that binds acrolein (toxic metabolite of cyclophosphamide/ifosfamide)
Clinical Use:
Hemorrhagic cystitis from cyclophosphamide/ ifosfamide
Rasburicase
Mechanism:
Recombinant uricase that catalyzes metabolism of uric acid to allantoin
Clinical Use:
Tumor lysis syndrome
Ondansetron
Mechanism:
5-HT3 receptor antagonists
Clinical Use:
Acute nausea and vomiting (usually within 1-2 hr after chemotherapy)
Prochlorperazine
Mechanism:
D2 receptor antagonists
Clinical Use:
Acute nausea and vomiting (usually within 1-2 hr after chemotherapy)
Aprepitant
Mechanism:
NK1 receptor antagonists
Clinical Use:
Delayed nausea and vomiting (>24 hr after chemotherapy)
Filgrastim
Mechanism: Recombinant G(M)-CSF
Clinical Use:
Neutropenia
Epoetin alfa
Mechanism:
Recombinant erythropoietin
Clinical Use:
Anemia
Granisetron
Mechanism:
5-HT3 receptor antagonists
Clinical Use:
Acute nausea and vomiting (usually within 1-2 hr after chemotherapy)
Metoclopramide
Mechanism:
D2 receptor antagonists
Clinical Use:
Acute nausea and vomiting (usually within 1-2 hr after chemotherapy)
Fosaprepitant
Mechanism:
NK1 receptor antagonists
Clinical Use:
Delayed nausea and vomiting (>24 hr after chemotherapy)
Sargramostim
Mechanism: Recombinant G(M)-CSF
Clinical Use:
Neutropenia
