L18-19 Antineoplastics Flashcards
What characteristics of tumor cells will increase the likelihood of a successful treatment?
Fast growing tumors
High % of cells in growth stage
Small tumors–better penetration
Early detection
What are some ways that tumors become resistant to drug treatment?
Change levels/affinity of target enzymes Decrease drug activation Increase DNA repair Increase salvage pathways for purines and pyrimidines Decrease drug uptake Increase efflux through P-glycoprotein
What does P-glycoprotein do?
Increases drug efflux causing tumor resistance to treatment
Cancer drugs target fast reproducing cells. What cells in the body will also be damaged?
Bone marrow leading to increased bleeding and depressed immunity Gi tract–N/V Hair follicles Renal Reproduction Teratogenesis
What was one of the first cytotoxic agents used to treat cancer?
Mustard gas used to treat lymphoma
How do alkylating agents work?
Very reactive agent that alkylates the DNA and causes miscoding, breaking, and crosslinking
Not cell-cycle specific
Most effective on rapidly growing cells
Alkylating agent toxicity
Vesicant: tissue damage at injection site (mustard gas damages tissue)
Affects rapidly proliferating cells–hair, marrow, sperm, GI
Traditional toxicities
Cisplatin (Platinol)
Platinum alkylating agent Cross-links DNA Sensitizes cells to radiation Broad spectrum Used in testicular cancer Toxicity: renal (amifostin prtects), acoustic nerve damage, anaphylaxis, nausea and vomiting bad Carboplatin and Oxalaplatin similar
What alkylating agent causes acoustic nerve damage leading to tinnitus?
Cisplatin (Platinol)
Carboplatin
Same function and effects as Cisplatin
Oxalaplatin
Same function and effects as Cisplatin
Mechlorethamine (Mustargen)
Nitrogen Mustard alkylating agent One of the first drugs Most effective in G1 and M phase Used often in Hodgkin's Disease Toxicity: vesicant!, hyperuricemia from massive tumor cell lysis, renal damage, N/V, sterility & teratogenicity
Cyclophosphamide (Cytoxan)
Nitrogen mustard alkylating agent
Must know this drug!
Oral–unique
Pro-drug that is activated by P-450
Metabolized into Acrolein that causes hemorrhagic cystits–to protect against this give MESNA
Broad spectrum, used for immun suppression
Toxicities: not a vesicant, alopecia bad, SIADH, N/V, anorexia
What drug causes hemorrhagic cystitis and how is this prevented?
Cyclophosphamide (Cytoxan)
Co-administer MESNA
What drug causes SIADH?
Cyclophosphamide (Cytotoxan)
Ifosfamide
Similar to Cyclophosphamide, combined with MESNA, also causes hemorrhagic cystitis
Chloranbucil
Alkylating agent Oral, slow action Used for CLL Very non-toxic Used for years–a long-term drug
Thiotepa
Alkylating agent
Used for bladder cancer
Not oral
Bendamustine
Alkylating agent
Used for CLL and non-hodgkins lymphoma
What drug is often used to counter the hyperuricemia in cancer patients?
Allopurinol with hydration
Busulfan–Myleran
Alkylating agent
CML
Known for hyperuricemia
What are Nitrosoureas?
Alkylating agents that have ability to form 2 rings to attack DNA/RNA synthesis
Carmustine (BCNU)
Nitrosourea drug
Known for high lipid solubility making it effective for brain tumors
Vesicant–burns on admin.
Lomustine (CCNU)
Nitrosourea drug
Known for high lipid solubility making it effective for brain tumors
Vesicant–burns on admin.
If you need to treat a brain tumor, what are 2 drugs to think of?
Carmustine (BCNU)
Lomustine (CCNU)
Darcarbazine
DNA cross-linker
Activated by P450
IV
Hodgkin’s disease, malignant melanoma, sarcomas
Temozolomide and Procarbazine are similar
Temozolomide
DNA cross-linker
Activated by P450
IV
Used for glioma and astrocytoma
Procarbazine
DNA cross-linker
Activated by P450
IV
Used for Hodgkin’s and non-hodgkin’s lymphomas, brain tumors
Metabolite is an MAO inhibitor–careful with antidepressants and linezolid
What drug is known for having a metabolite that inhibits MOA?
Procarbazine
Methotrexate
Inhibits dihydrofolate reductase to inhibit production of folic acid and thereby inhibit production of thymidylate which eventually prevents DNA synthesis and damages DNA
Can be used for immune suppression in low doses
For cancer: high doses but only few times
Leucovorin: given after to rescue the normal cells from damage
Toxicity: precipitates in kidney–hydration important, hepatotoxicity
Leucovorin
Given after methotrexate to rescue normal cells from damage from dihydrofolate reductase inhibition
Also used with 5-FU to increase its effectiveness
Pemetrexed
Similar to Methotrexate
Inhibits thymidilate synthase
Used with Cusplatin for mesothelioma and non-small cell lung cancer
Causes hand-foot disease and myelosuppression
What drug is assoc. c hand-foot disease?
Pemetrexed
5-FU
What does rifampin do to P450?
Induces
What drug is converted by P450 to its active form?
Cyclophosphamide
How do purine analogues work?
Converted to nucleotides by HGPRT that then prevent synthesis of purines and stop DNA/RNA synthesis
Not cell cycle specific
Myelosuppressive
Mercaptopurine (Purinethol)
Purine analogue that inhibits purine synthesis
Metabolized by xanthine oxidase–important drug interaction with Allopurinol and other drugs that affect XO
Used for leukemia
What drug interacts with Mercaptopurine and how?
Allopurinol
Inhibits xanthine oxidase which metabolizes Mercaptopurine and therefore would cause toxicity
What is Xanthine oxidase?
Enzyme used in the production of uric acid
It is the target of Allopurinol to treat hyperuricemia
Thioguanine
Similar to Mercaptopurine but not metabolized by xanthine oxidase
Treats AML
Pentostatin, Cladribine, Fludarabine
Purine analogues like Mercaptopurine
What drug is metabolized by xanthine oxidase?
Mercaptopurine
What is Thymidylate Synthase?
Enzyme involved with production of Thymidine
Blocking it causes deficiency in Thymidine and buildup of precursor molecules that both damage DNA
5-Fluorouracil (5-FU, Adrucil)
Inhibits thymidylate synthase–blocks DNA synthesis Purine group Needs folic acid to work so adding Leucovorin added to help with this Cell cycle specific–G1 and S phases Broad spectrum of use Colorectal cancer Topical for basal cell carcinoma Causes hand-foot disease
Capesitabine
5-FU prodrug more selective for tumor and less side effects
Purine group
Cytarabine
Antimetabolite Purine drug Competes with Cytosine for DNA incorporation stopping DNA synthesis Used in leukemias Severe marrow suppression
What drug causes radiation recall?
Hydroxyurea
Doxorubicin, Daunorubicin
Antibiotic
Logdes itself in the DNA and breaks it and causes dysfunction
Generates free-radicals leading to cardiomyopathy especially with Herceptin which is also cardiotoxic
Cardio effects increased by Iron–decreased by iron chelator Dexrazoxane
Used for Thyroid and Breast cancers and many others
Daunorubicin can also cause red urine and is used for some leukemias
What drug causes cardiomyopathy?
Doxorubicin
What drug causes red urine?
Daunorubicin
Dexrazoxane
Iron chelator used to decrease cardiotoxicity of Doxorubicin
Bleomycin (Blenoxane)
Antibiotic Binds DNA and breaks it Most active in G2 and M phase Good for testicular and ovarian cancer and many others Little myelosuppression Does cause pulmonry fibrosis Can cause anaphylactoid Sx
What drug did Lance Armstrong not want to take for testicular cancer because it can cause pulmonary fibrosis?
Bleomycin
Dactinomycin (Actinomycin D)
Antibiotic binds DNA and breaks it
Strong vesicant
Radiation recall
Vincristine/ Vinblastine
Plant alkaloid
Bind tubulin to prevent microtubule aligning in mitosis of M phase
Vincristine: leukemia, Hodgkin’s, high neurotoxicity because axonal transport requires microtubules, low myelosuppression
Vinblastine: testicular carcinoma,Hidgkin’s, more myelosuppression but less neurotoxicity
Paclitaxel (Taxol)
Plant Alkaloid
Binds microtubulin stabilizing it and preventing disassembly after mitosis
Very toxic
Broad spectrum
Causes peripheral neuropathy, myelosuppression, myalgia, arthralgia, hypersensitivity–decreased by binding to albumin
Topoisomerase Inhibitors
Prevents the uncoiling of DNA
Etoposide (Teniposide)
Topoisomerase II inhibitor
DNA strand breaks
Testicular cancer
Causes leukopenia
Topotecan, Ironotecan
Topoisomerase I inhibitor
Cell cycle arrest
Topotecan: ovarian cancer
Ironotecan: broad spectrum
Myelosuppression!
Asparaginase (Elspar)
Breaks down asparagine that is required by leukemia cells
Hypersensitivity reactions
Drugs that end in -tinib are?
Tyrosine Kinase inhibitors
All metabolized by CYP3A4
Imatinib (Gleevec)
Inhibits Bcr-Abl fusion protein (Philadelphia chromosome) that is unique to cancer cells especially CML but also gastrointestinal stromal tumor
No severe SE’s
Can be some immunosuppression
Erlotinib
Blocks ATP binding to HER1/EGFR tyrosine kinase
Non-small cell lung cancer (2nd line) and pancreatic cancer
Gefitinib
Inhibits EGFR tyrosine kinase
Diarrhea
Cetuximab
EGF receptor antibody blocks cell growth
Anaphylactoid reactions
Bevacizumab
Angiogenesis Inhibitor
VEGF blocker?
Decreases blood supply to slow tumor growth
Bleeding and thromboembolism risk increased with systemic use
Blood vessels don’t heal well so avoid surgery
PD-1 inhibitors
PD-1 secreted by tumors to prevent immune system from seeing them
Blocking it allows immune system to attack them
Nivolumab, Pembrolizumab
Inhibit PD-1
Allow T-cells to see tumors
Prednisone
Lymphomas and Leukemias
Tamoxifen
Block estrogen receptor in breast
Can cause uterine hyperplasia
Must be activated by CYP2D6
What drugs inhibit CYP2D6? What cancer drug might this affect?
Fluoxetine, Paroxetine
Prevents activation of Tamoxifen
Trastuzumab (Herceptin)
Antibody to HER2 receptor
Cardiotoxic, do not combine with doxorubicin
Flutamide
Anti-androgen for prostate cancer
What drugs cause Radiation Recall?
Dactinomycin
Hydroxyurea
Doxorubicin
Daunorubicin
What drugs cause Pulmonary fibrosis?
Bleomycin
Busulfan
What drugs cause peripheral neuropathy?
Vincristine
Vinlablastine
Paclitaxel
What drugs cause hyperuricemia?
6-Mercaptopurine (remeber Allopurinol affects metabolism)
Busulfan
What drugs cause acoustic nerve damage?
Cisplatin
What drugs cause red urine?
Daunorubicin
What drugs cause hepatotoxicity?
Methotrexate
6-Mercaptopurine
BCNU
CCNU
What drugs cause hemorrhagic cystitis?
Cyclophosphamide
Ifofsphamide (MESNA) reverses it
What drugs cause Cardiomyopathy?
Doxorubicin, Daunorubicin, Trastuzumab
Reversed with Dezrazoxane
