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)
