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279 Cards in this Set
- Front
- Back
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General Principle of Cancer Therapy
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attack is generally directed against metabolic sites essential to cell replication, for example, the availability of purine and pyrimidine precursors for DNA and RNA synthesis
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Why do all antitumor agents have a steep dose-response curve for both toxic and therapeutic effect?
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they interfere with both normal and abnormal proliferating cells.
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Treatment Strategies
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eradication of every possible neoplastic cell
palliation if you can't cure: treated as chronic disease |
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Indications for Treatment
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neoplasms are disseminated and not amenable to surgery
supplemental to attack micrometastases following radiation and surgery tumors most susceptible to chemotherapy are undifferentiated and have high growth fractions |
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Treatment Regimens
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follows 1st order kinetics: given dose of drug destroys a constant fraction of cells
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Log Kill
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example: diagnosis of leukemia is made when there is 10^9 leukemic cells
If treatment leads to 99.999% kill (a 5-log kill) induce clinical remission of the neoplasm there would be .0001% of 10^9 cells (10^4 tumor cells) remaining in the body. |
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Why might there be some cells still remaining?
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resistant to drug because of heterogeneity
pharmacologic sanctuaries (CNS, testes) |
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What log reduction is needed in bacterial infections and why?
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3-log because the body can eliminate the rest
tumor cells are not as readily eliminated and additional treatment is required |
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Treatment Protocols
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Combination Chemotherapy: if drugs don't have too much overlap in toxicity, they can't be used at almost full dosage
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True Synergism
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the effect of the two drug is greater than additive
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Drug Combinations Therapy
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provide maximal cell kill within range of tolerated toxicity
effective against a broader range of cell lines slow or prevent the development of resistant cell lines |
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For Hodgkin's Lymphoma
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ABVD
Adriamycin Bleomycin Vinblastine Dacarbazine |
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Hodkins Lymphoma or Medulloblastoma
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MOPP
Mechlorethamine Oncovin Procarbazine Prednisone |
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Small Cell Lung Cancer
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COPE
Cyclophosphamide Oncovin Platinol Etoposide |
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Colorectal Cancer
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F-CL
5-Flurocil Calcium Leucovorin |
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Why is therapy scheduled intermittently?
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to allow recovery of normal tissue such as the patient's immune system that have been effected by the drug, thereby reducing infection
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Growth Fraction
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fraction of tumor cells in the replicative cycle
influences susceptibility to cancer chemotherapeutic agents lare growth factor, the more susceptible slow growing tumors unresponsive |
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Tumor Susceptibility and Cell Cycle
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rapidly dividing cells are generally more sensitive to anticancer drugs than those in Go (nonproliferating)
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Normal Tissues that also may susceptible due to large growth fraction
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bone marrow
hair follicles intestinal epithelium |
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Cell Cycle-specific drugs
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cell cycle phase-specific drugs
drugs that exert their action only on cells traversing the cell cycle most effective in hematologic malignancies and in which large portion of cells are proliferating |
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Cell Nonspecific Drugs
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sterilize tumor cells that are cycling or resting in Go
useful in low-growth fraction solid tumors as well as high growth fraction solid tumors |
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Cell Specific Agents
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antimetabolites
bleomycins microtubule inhibitors epipodophyllotoxins camptothecins |
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Cell Cycle-nonspecific agents
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alkylating agents
platinum coordination complexes antitumor antibiotics |
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Tumor Stem Cells
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small fraction of cells within tumors.
effective agents sterilize or inactivate them |
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Primary Resistance
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absence of response on the first exposure
renal cell cancer, brain cancer, malignant melanoma |
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Acquired Resistance
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Single Drug Resistance
Multidrug Resistance |
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Single Drug Resistance
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specific to a single drug
due to a change in the tumor cell's genetic apparatus with amplification or increased expression of one or more specific genes |
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Multi Drug Resistance
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emerges to a variety of several anticancer drugs that are structurally and functionally different after exposure to a single agent
overexpression of membrane efflux pumps |
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Multidrug Transporters
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belong to a superfamily of ATP Binding Cassette proteins
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P-glycoprotein
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Pgp, MDR1, ABCB1
most important efflux pump responsible for multidrug resistance encoded by MDR1 gene ATP-dependent drug efflux pump for xenobiotic compounds with broad substrate specificity |
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Pgp can confer on MDR on:
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Doxorubicin
Daunorubicin Actinomycin Vincristine Vinblastine Etoposide Tenoposide |
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What does Pgp does not transport?
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alkylating agents, antimetabolites or cisplatin
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Other efflux pumps:
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MRP: multidrug resistance-associated proteins
LRP: lung resistance-related protein BCRP: breast cancer resistance protein |
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Toxicity:
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affects rapidly proliferating cells (normal)
buccal mucosa bone marrow GI mucosa hair cells |
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Common Adverse Effects
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narrow therapeutic window
severe vomiting, stomatitis, alopecia myelosuppression |
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Specific AE
1.Doxurubicin 2.Cyclophophamide 3.Ifosphamide 4.Bleomycin |
1. cardiotoxicity
2. hemorrhagic cystitis 3. hemorrhagic cystitis 4. pulmonary fibrosis |
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Minimizing Adverse Effects
1.Leucovorin 2.Mesna 3.Dexrazoxane 4.Filgrastim |
1. rescues bone marrow from methotrexate
2.reduces haemorrhagic cystitis 3.reduces cardiotoxicity 4.neutropenia: granulocyte colony stimulating factor |
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Treatment Induced Tumors
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most antineoplastic agents are mutagens, neoplasms may arise like acute nonlymphocytic leukemia may arise 10 or more years after original cancer
especially a problem with alkylating agents |
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Folate Analogs (antimetabolite)
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methotrexate
pemetrexed |
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Purine Analogs(antimetabolite)
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Mercaptopurine
Thioguanine Fludarabine Cladribine Pentostatin |
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Pyrimidine Analogs(antimetabolite)
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Fluorouracil
Capecitabine Cytarabine Gemcitabine 5-Azacytidine |
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Antimetabolite MOA
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related to nucleotide and nucleic acid synthesis
cycle-specific with maximal cytotoxic effect in S-phase |
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Methotrexate (MTX)
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folate analog
inhibits dihydrofolate reductase: cell is deprived of folate and therefore dTMP and purine nucleotides decrease and therefore decrease in DNA and RNA and proteins, leading to cell death |
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How does MTX enters cell?
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via reduced folate carrier, which also carries naturally occuring reduce folate
kills during S phase: when cells are in the logarithmic phase of growth |
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Resistance MTX
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nonproliferating is resistant to methotrexate
neoplastic cells: decreased influx due to transport system decreased polyglutamate formation amplification of dihydrofolate reductase altered DHFR with lower affinity for MTX |
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MTX PK
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absorbed from GI tract, can be given IV, IM, IT
does not penetrate BBB (therefore given IT) inside cell, it is polyglutamated by folylpolyglutamate synthase |
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Metabolism of MTX
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minimal
high doses: methotrexate undergoes hydroxylation at the 7 position this hydroxylated derivative is less hydrosoluble and may lead to crystalluria (important to keep urine alkaline and the patient well hydrated to avoid renal toxicity) |
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Excretion MTX, drug interactions and c/i
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renal excretion of MTX: glomerular filtration and active tubular secretion.
do not combine with NSAID (decreased renal blood flow) Ciplastin:nephrotoxic weak organic Acids: aspirin or piperacllin renal insufficiency avoid in pregnancy |
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MTX USES
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ALL
choriocarcinoma burkitt's lymphoma in children breast cancer head and neck carcinomas |
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MTX AE
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common ones listed before (leucovorin relieves): must be kept minimal to avoid interference with action of MTX
Renal Damage complication of high dose Hepatic Function: hepatic fibrosis and cirrhosis Pulmonary Toxicity: pneumonitis Neurologic Toxicities: IT admin: seizure, coma, death----> leucovorin does not reverse neurotoxicity defective oogenesis or spermatogenesis, abortion and teratogenesis |
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MTX other USES
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low dose MTX: psoriasis
immunosuppressive: organ transplantation and for treatment of dermatomyositis, rheumatoid arthritis and Crohn's disease Methotrexate is used with misoprostol as abortifacient |
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Leucovorin
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antidote to drugs that decrease levels of folic acid such as methotrexate to rescue the bone marrow
usually started 24hrs after the beginning of methotrexate infusion and is usually given IM or IV |
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Pemetrexed
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Folate Analogue
Polyglutamated pemetrexed is a potent inhibitor of thymidylate synthase and a much weaker inhibitor of DHFR; similar to 5-FU, its cytotoxic effect is likely due to inducitno of thymineless cell death |
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Pemetrexed Use
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second line agent of nonsmall cell carcinoma
+cisplatin: malignant pleural mesothelioma |
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Why do you give vitamin B12 and folic acid supplementation with Pemetrexed
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reduce toxicity to normal cells
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6-mercaptopurine (6-MP)
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purine analog: thiol analog of hypoxanthine
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6-MP MOA
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converted to 6-MP ribose phosphate (TIMP) by the salvage pathway enzyme HGPRT
TIMP inhibits first step of de novo purine ring biosynthesis (catalyzed by glutamine:phosphoribosyl pyrophosphate amidotransferase) TIMP also blocks formation of AMP and GMP from IMP dysfunctional RNA and DNA result from incorporation of guanylate analogs |
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6-MP Resistance
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inability to bio-transform 6-MP to TIMP because of low HGPRT (Lesch-Nyhan Syndrome)
increased dephosphorylation increased metabolism of the drug to thiouric acid by xanthine oxidase |
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6-MP PK
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given orally and distributed widely throughout body except CSF
metabolized in liver to 6-methylmercaptopurine or to thiouric acid by xanthine oxidase excreted by kidney |
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Allopurinol and 6-MP
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xanthine oxidase inhibitor, frequently administered to cancer patients receiving chemotherapy to reduce hyperuricemia
therefore decrease the amount of 6-MP to avoid accumulation of the drug |
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6-MP Uses
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indicated for remission induction and maintenance therapy of acute lymphatic leukemia
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6-MP AE
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common
bone marrow suppression hepatotoxicity |
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6-Thioguanine
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converted to nucleotide thioguanine monophosphate (TGMP) by HGPRT
TGMP inhibits synthesis of the purine ring and the phosphorylation of GMP to GDP can also be incorporated into RNA and DNA |
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6-Thioguanine USES
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treatment of Acute Nonlymphocytic Leukemias
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Does allopurinol potentiate 6-TG and why?
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NO because very little is metabolized to thiouric acid.
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6-Thioguanine AE
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same as 6-MP
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Fludarabine
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the triphosphate is incorporated into DNA and RNA--> decreases DNA and RNA synthesis adn alters their function
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Fludarabine USE
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2nd line for B-cell chronic lymphocytic Leukemia
Given IV because intestinal bacteria split off the sugar to yield the very toxic metabolite fluoroadenine |
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Fludarabine AE
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common
myelosuppression fever, edema, severe neurologic toxicity high doses: encephalopathy, blindness, death |
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Cladribine
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Chlorinated purine analogue structurally related to fludarabine
cladribine phosphate is incorporated into DNA causing strand breaks it also depletes intracellular pools of the essential purine metabolites NAD adn ATP Hair Cell Leukemia (replaced Cladribine) |
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Pentostatin
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selective inhibitor of adenine deaminase (ADA)
structural analogue of the intermediate catalyzed by ADA and binds to the enzyme with high affinity increase in Adenosine and 2'deoxyadenosine levels |
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What does an increase in 2'deoxyadenosine do?
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irreversibly inhibits S-adenosylhomocysteine hydrolase adn the resulting increase in intracellular S-adenosylhomocysteine is toxic to lymphocytes
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what is Pentostatin used in?
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hairy cell leukemia
but replaced by Cladribine |
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5-Fluorouracil and DNA synthesis
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pyrimidine analog
converted to the deoxyribonucleotide 5-FdUMP 5-FdUMP competes with dUMP for thymidylate synthase results in inhibition of DNA synthesis through thymineless death |
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5-Fluorouracil and RNA synthesis
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5-FU is also converted to 5FUTP and incorporated into RNA
incorporates into RNA, interfering with RNA processing and function |
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5-FU Resistance
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cells with no ability to convert 5-FU to active form
altered or increased thymidylate synthase increased rate of 5-FU catabolism |
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5-FU PK
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IV
topically for skin cancer good penetration, including CSF metabolized in the liver |
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5-FU USE
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carcinomas of the breast
carcinomas of GI tract topical treatment of premalignant keratoses of the skin and superficial basal-cell carcinomas Adjunvant therapy with Levamisole (antihelminth) improves survival of patients with colonic cancer |
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5-FU + Leucovorin Combination
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First line of Chemotherapy for colorectal cancer.
5-FU inhibits thymidylate synthase by forming a ternary complex involving the enzyme, the substrate (5-FdUMP), and the cofactor (N5, N10-methylene-THF)---> increases levels of N5, N10-methylene-THF and potentiates the activity of 5-FU |
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5-FU AE
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common
ulceration of oral adn GI mucosa bone marrow depression (with bolus injection) hand foot syndrome |
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Hand-foot-Syndrome
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a dermatopathy (erythematous desquamation of the palms and soles) seen after extended infusions 5-FU
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Capecitabine
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pyrimidine analog
fluoropyrimidine carbamate orally available prodrug of 5-FU |
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Capecitabine MOA
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converted in a series of enzymatic steps to 5-FU
cytotoxic activity is the same as 5-FU |
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Capecitabine PK
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oral admin, well absorbed
eventually biotransformed into alpha-fluoro-Beta-alanine metabolites eliminated in urine |
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Capecitabine USE
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Metastatic colorectal cancer
Second line therapy in metastatic breast cancer similar efficacy as IV 5-FU |
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Capecitabine AE
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similar to 5-FU occuring primarily in GI:
diarrhea, necrotizing enterocolitis, hyperbilirubinemia Dermatologic Toxicity: palmar plantar erythrodysesthesia use cautiously with patients with hepatic or renal impairment C/I in patients who are hypersensitive to 5-FU, pregnant or are lactating |
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Palmar Plantar Erythrodysesthesia
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numbness, painful swelling, dysesthesia/paresthesia and erythema of the palms of the hands and soles of the feet
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Cytarabine (ARA-C)
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pyrimidine analog: deoxycytidine
2'deoxycytidine in which the ribose is replaced by D-arabinose cytosine arabinoside sequentially phosphorylated to cytosine arabinoside triphosphate (ara-CTP) Incorporated into DNA. The incorporated residue inhibits DNA polymerase |
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ARA-C PK
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not effective orally because its deamination to noncytotoxic ara-U by cytidine deaminase in the intestinal mucosa
Given IV: distributes throughout the body does NOT enter CNS: may be injected IT extensive oxidative deamination to ara-U. both ara-C and ara-U are excreted by kidney |
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ARA-C USE
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Acute non-lymphatic leukemia: in combination with 6-TG and Daunorubicin
Acute Lymphocytic leukemia Blast phase of Chronic Myelocytic Leukemia |
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ARA-C AE
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common
myelosuppression hepatic dysfunction high doses or IT; seizures or altered mental states |
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Gemcitabine
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pyrimindine analog
analog of the nucleoside deoxycytidine phophorylated by nucleoside kinases to nucleoside di adn triphosphate--->inhibit DNA synthesis |
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What two actions cause inhibition by gemcitabine?
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1.inhibition of ribonucleotide reductase
2. incorporation of gemcitabine triposphate into DNA causing Chain Termination |
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Gemcitabine PK
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given by IV by infusion
deaminated to difluorodeoxyuridine, which is not cytotoxic and excreted in the urine |
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Gemcitabine USES
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Adenocarcinoma of the pancreas
Nonsmall cell lung cancer Breast cancer Ovarian Cancer |
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Gemcitabine AE
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common
myelosuppression transient elevations of serum transaminases, proteinuria, and hematuria |
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Gemcitabine Resistance
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resistance to the drug is probably due to its inability to be converted to a nucleotide
tumor cell produces increased levels of endogenous deoxycytidine that compete for the kinase |
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5-Azacytidine
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cytidine analogue (pyrimidine analog)
triphosphate metabolite is incorporated into DNA and RNA----> interferes with cytosine methylation, altering gene expression and promoting cell differentiation |
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5-Azacytidine USE
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Myelodysplasia
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Antitumour Antibiotics
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Produced by actinomycete Streptomyces
bind to DNA through intercalation between bases and block synthesis of new RNA or DNA or both, cause DNA strand scission, and interfere with cell replication |
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Antitumour Antibiotics (Types)
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Anthracyclines
Mitoxantrone Actinomycin Bleomycin Mitomycin Plicamycin |
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Anthracyclines
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among the most important antitumor agents
Doxorubicin Daunorubicin Idarubicin Epirubicin |
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Anthracycline Structure
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tetracyclic ring attached to an unusual sugar:duanosamine
Doxorubicin and Daunorubicin: isolated from Streptococcus peucetius (fungi) Doxorubicin hydroxylated analog of daunorubucin Idarubicin and Epirubicin are semi-synthetic derivatives |
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Anthracycline MOA
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exert their cytotoxic action through 4 mechanisms:
1. Inhibition of topoisomerase II 2. High-affinity binding to DNA through intercalation, with consequent blockade of the synthesis of DNA and RNA, strand scission 3. Binding to cell membranes to alter fluidity and ion transport 4.generation of seimquinone free radicals and oxygen free radicals through an iron-dependent, enzyme-mediated reductive process: cause of anthracycline's cardiac toxicity |
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Anthracycline Resistance
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1. increase efflux via the P-glycoprotein
2. Cells rich in glutathione peroxidase are resistant 3. decrease cytochrome p-450 reductase, topoisomerase II and DNA repair may play a role |
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Anthracycline PK
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1.IV since they are inactivated in GI tract
2.Extravasation is serious problem which may lead to tissue necrosis 3. No CNS penetration 4. Undergo extensive metabolism 5. Bile is route of excretion 6. Some renal excretion 7. RED COLOR TO URINE |
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Doxorubicin USE
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one of the most important and widely used anticancer drugs
lymphoblastic leukemia acute myeloblastic leukemia wilm's tumor neuroblastoma sarcomas breast carcinoma ovarian carcinoma transitional cell bladder carcinoma thyroid carcinoma gastric carcinoma hodgkin's disese malignant lymphoma bronchogenic carcinoma |
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Daunorubicin USE
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Acute nonlymphocytic leukemia of adults
Acute lymphocytic leukemia of children of children and adults |
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Idarubicin Use
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Acute Myeloid Leukemia in adults
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Epirubicin Use
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breast cancer
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Anthracyclines AE
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MYELOSUPPRESSION
mucosits is dose limiting Cardiotoxicity radiation recall reaction |
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Anthracycline Cardiotoxicity
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Acute Form: within 2-3 days
arrhythemias, ECG changes, pericarditis, myocarditis Transient Chronic Form:dose dependent dilated cardiomyopathy with heart failure: due to production of free radicals within myocardium lower weekly doses or continous infusions od doxorubicin appear to reduce incidence of cardiotoxicity use Iron-chelating agent dexrazoxane can be used to reduce cardiotoxicity |
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Cardiotoxicity is common with ?
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doxorubicin and daunorubucin
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Radiation Recall Reaction
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erythema and desquamation of skin observed at sites of prior radiation therapy
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Mitoxantrone
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anthracene compound: structurally related to anthracyclines
binds to DNA to produce strand breaks: mediated by topoisomerase II; it also intercalates with DNA IV |
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Mitoxantrone USE
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Acute Nonlymphocytic Leukemia in adults
advanced hormone-resistant prostate cancer |
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Mitoxantrone AE
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leukopenia is the dose-limiting toxicity
common cardiac toxicity manifested as arrhythmias |
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Dactinomycin (Actinomycin D)
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antitumor antibiotic isolated from Streptomyces organism
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Dactinomycin MOA
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intercalates into small groove of double helix between G-C base pairs, forming stable complex
interferes with RNA polymerase high doses: intereferes with DNA synthesis blocks protein synthesis and DNA strand breaks |
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Dactinomycin Resistance
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increased efflux via p-glycoprotein
DNA repair may also play a role |
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Dactinomycin PK
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IV
concentrates in liver: partially metabolized slowly excreted via bile some via urine doesn't enter CSF |
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Dactinomycin USES
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Wilm's Tumor
Gestational Choriocarcinoma |
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Dactinomycin AE
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bone marrow depression
Immunosuppresive; patients should not receive live virus vaccines common skin abnormalities associated with inflammation at sites of prior radiation therapy |
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Bleomycins
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produced by Streptomyces Verticillus
drug is a mixture of two peptides: bleomycin A2 and B2 cell cycle specific. arrest cells in G2 Phase |
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Bleomycin MOA
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DNA-bleomycin-Fe2+ complex undergoes oxidation to bleomycin-Fe3+
liberated electrons react with O2 to form free radicals which attack he phosphodiester bonds in DNA, resulting in strand breakage and chromosomal aberrations |
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Bleomycin Resistance
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unknown mechanism
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Bleomycin PK
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SC, IM, IV, intracavitary
bleomycin hydrolase: inactivates the drug is high in some tissues (liver and spleen) low in lungs and absent in skin, accounting for its toxicity in those tissues Most of the drug is excreted unchanged into the urine by glomerular filtration |
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Bleomycin USE
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Testicular Carcinoma
Squamous cell carcinoma Lymphomas |
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Bleomycins AE
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most serious adverse reaction is pulmonary toxicity (pneumonitis, fibrosis). Dose limiting
cutaneous reactions: hyperpigmentation, hyperkeratosis, erythema, ulceration Hyperthermia, headache, nausea, vomiting very little myelosuppression |
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Mitomycin
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antibiotic isolated from Streptomyces caespitosus
undergoes activation through an enzyme-mediated reduction to generate an alkylating agent that cross-links DNA targets hypoxic tumor cells such as those at the center of a solid tumor because it requires bioreductive activation which occurs more readily in low oxygen environments |
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Mitomycin USE
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disseminated adenocarcinoma of the stomach or pancreas
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Mitomycin AE
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myelosuppression
common hemolytic uremic syndrome believed to result from drug-induced endothelial damage |
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Plicamycin
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binds to DNA and interrupts RNA synthesis
decreases plasma calcium levels through action on osteoclasts that is independent of its action on tumor cells |
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Plicamycin Uses
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malignant tumors of the testis where treatment by surgery or radiation is impossible
treatment of hypercalcemia and hypercalciuria associated with advanced neoplasms |
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Plicamycin AE
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thrombocytopenia
leukopenia hypocalcemia bleeding disorders liver toxicity |
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Alkylating Agents
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exert cytotoxic effects via transfer of their alkyl groups to various cellular constituents
alkylation of DNA within the nucleus is probably the major interaction that leads to cell death react chemically with suphhydril, amino, hydroxyl, carboxyl, and phosphate groups of other cellular compounds as well |
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What is the major site of alkylation in DNA?
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7 nitrogen atom of guanine
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What can alkylation of guanine lead to?
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miscoding though abnormal base pairing with thymine or
in depurination by excision of guanine residues---> DNA strand breakage through scission of sugar phosphate backbone of DNA |
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What cells are most susceptible to Alkylating agents?
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replicating cells: not cell specific but cells are most susceptible to alkylation in late G1 and S phases of the cell cygle and arrest in G2
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Toxicities in Alkylating Agents
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dose related adn occur particularly in rapidly growing tissues like the bone marrow, GI tract adn gonads
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What causes the emetic effects from alkylating agents and how can you treat it?
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CNS in origin
pre-treatment with 5-HT3 receptor antagonists like ONDANSETRON or Granisetron |
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Alkylating Agents and blood cell count
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necessary to do repeated rbc counts
if severe leukopenia or thrombocytopenia develops, therapy has to be interrupted |
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Alkylating Agent Uses
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lymphatic and solid cancers with other agents
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Alkylating AE
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all are mutagenic adn carcinogenic
lead to second malignancy such as acute leukemia also may lead to acute nonlymphocytic leukemia |
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Classes of Alylating Drugs
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NITROGEN MUSTARDS
ETHYLENIMINES AND METHYLMELAMINES ALKYL SULFONATES NITROSOUREAS TRIAZENES METHYLHYDRAZINES |
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NITROGEN MUSTARDS
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Mechlorethamine
Cyclophophamide Ifosfamide Melphalan Chlorambucil |
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ETHYLENIMINES AND METHYLMELAMINES
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Thiotepa
Altretamine |
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ALKYL SULFONATES
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Busulfan
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NITROSOUREAS
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Carmustine
Lomustine Semustine Streptozocin |
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TRIAZENES
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Dacarbazine
Temozolomide |
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METHYLHYDRAZINES
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Procarbazine
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Mechlorethamine
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nitrogen mustard
bifunctional agent unstable powerful vesicant IV hardly any drug is excreted due to its reactivity |
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Mechlorethamine USE
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hodgkins disease
lymphosarcoma chronic myelocytic or chronic lymphocytic leukemia replaced by other more stable alkylating agents |
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Mechlorethamine AE
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bone marrow depression
immunosuppression extravasation is serious problem |
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Cyclophosphamide
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nitrogen mustard
most widely used alkylating agent not a vesicant orally or IV prodrug: activated by CY2B to 4 hydroxycyclophosphamide broad spectrum-used in combination |
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Vesicant
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A blister agent (also known as a vesicant) is a chemical compound that causes severe skin, eye and mucosal pain and irritation. They are named for their ability to cause severe chemical burns, resulting in large, painful water blisters on the bodies of those affected
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Cyclophosphamide PK
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oral
well absorbed minimal amounts excreted in feces or in urine |
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Cyclophosphamide Anticancer Uses
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lymphomas
leukemias mycosis fungoides neuroblastomas adenocarcinoma of the ovary retinoblastoma carcinoma of the breast |
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Cyclophosphamide Other Uses
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wegner's granulomatosis
nephrotic syndrome rheumatoid arthritis |
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Cyclophosphamide AE
|
bone marrow depression
hemorrhagic cystitis sterility inappropriate ADH secretion |
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What is responsible for the hemorrhagic cystitis?
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acrolein, a metabolite of cyclophsophamide
reduce in intensity or prevented by parenteral admin of Mesna (sulfhydryl compound that reacts with acrolein in the bladder) |
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Ifosfamide
|
analog of cyclophosphamide
prodrug: activated by hydroxylation in the liver by CYP3A4 infused IV |
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Ifosfamide Uses
|
use with other agents for third line chemotherapy of germ cell testicular cancer
used in combination with prophylactic agent for hemorrhagic cystitis such as mesna |
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Ifosfamide AE
|
common
nephrotoxicity bone marrow depression hemorrhagic cystitis inappropriate ADH secretion Renal Failure |
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What do you do to reduce AE
|
adequate hydration
Mesna |
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Melphalan
|
Nitrogen mustard
actions similar to other nitrogen mustards not vesicant orally or IV Multiple Myeloma AE similar to other alkylating agents nausea, vomiting, and alopecia are infrequent |
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Chlorambucil
|
slowest acting nitrogen mustard in use
Chronic lymphocytic leukemia Malignant Lymphomas |
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Chlorambucil AE
|
myelosuppressive is moderate, gradual and rapidly reversible
GI discomfort, azoospermia, amenorrhea, pulmonary fibrosis, seizures, dermatits and hepatotoxicity may be rarely encountered increase incidence of leukemia and other tumors |
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Thiotepa
|
ethylenimines and methylmelamines
thiotepa and it's metabolite TEPA form DNA cross-links AE : alkylating agents |
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Altretamine
|
ethylenimines adn mthylmelamines
advanced ovarian cancer after failure of first line therapies mechanism unknown |
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Busulfan
|
alkyl sulfonate
CML myelosuppression is main toxicity leukemogenic |
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Busulfan and Allipurinol
|
Intial phase: hyperuricemia, due to extensive purine catabolism and renal damage use Allopurinol
|
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|
Unusual complications of Busulfan
|
syndrome resembling Addisons disease (but without steriod deficiency)
cataracts, gynecomastia, cheilosis, glossitis, anhidrosis, and pulmonary fibrosis |
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Nitrosoureas
|
Brain tumors
lipophilic carmustine and lomustin and cross BBB profound and delayed myelosuppression except Streptozocin urinary excretion |
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|
What do all nitrosoureases require and how?
|
biotransformation
occurs by non-enzymatic decompostion to alkylating and carbamoylating derivatives |
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Carmustine
|
nitrosoureas
lipophilic IV excreted in kidney |
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Carmustine Uses
|
Brain tumors
Multiple Myeloma Hodgkins and Non-hodgkins Lymphomas |
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Carmustine AE
|
delayed hematopoietic depression
aplastic marrow on prolonged usage renal failure interstitial pulmonary fibrosis high dose: hepatic toxicity |
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Lomustine and Semustine
|
carmustine analog
reliable bioavailability by oral route Brain Tumors melanoma GI cancers same carmustine AE |
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Streptozocin
|
nitrosoureas
naturally occuring compound from Streptomyces Achromogenes methylnitrosourea moiety attached to carbon 2 of glucose minimal bone marrow toxicity |
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Streptozocin USE
|
high affinity for B cells of islets of Langerhans
causes diabetes in animals treatment of insulin-secreting islet cell carcinoma of the pancreas Non hodgkins lymphomas |
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Streptozocin AE
|
renal or hepatic toxicity
renal usually reversible but may be fatal hematological toxicity in 20% of patients |
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Dacarbazine
|
triazene
methylating agent after metabolic activation by CYP450 isoforms IV Malignant Melenoma Hodgkins Disease (2nd line therapy) |
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Decarbazine AE
|
nausea/vomiting
myelosuppression flulike syndrome hepatoxicity, alopecia, facial flushing, nuerotoxicity, dermatological reactions |
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Temoxolomide
|
triazene
metabolite acts as a methylating agent orally Glioblastoma Multiforme Astrocytoma |
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Procarbazine
|
Methylhdrazine
orally In combination MOPP : treatment of Hodgkin's disease |
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|
Why are alternative regimens used more now than MOPP?
|
less leukemogenic potential
|
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Procarbazine MOA
|
converted by CYP to highly reactive derivatives that methylate DNA
DNA, RNA and protein sythesis are inhibited---> produces chromosome breaks |
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Procarbazine AE
|
hemolytic anemia
pulmonary reactions disulfriam-like reactions leukomogenic, mutagenic, teratogenic one metabolit is a MAO inhibitor |
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Platinum Coordination Complexes
|
broad antineoplastic activity
foundation for treatment of testicular, ovarian and cancers of the head, neck, bladder, esophagus, lung and colon |
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Cisplastin
|
inorganic metal complex
IV Kills cells in all stages of cell cycle Inhibits DNA sythesis and binds DNA through formation of cross-links |
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|
Cisplastin USE
|
testicular
ovarian bladder use with vinblastine and bleomycin has major advance in development of curative therapy for nonseminomatous testicular cancers |
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Cisplastin AE
|
nephrotoxicity: avoided by hydration and diuresis
ototoxicity peripheral neuropathy |
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Amifostine
|
thiophosphate cytoprotective agent indicated to reduce cumulative renal toxicity associated with repeated administration of cisplastin
dephophorylated by alkaline phophatase to pharmacologically active free thiol metabolite thiol scavanges reactive cisplastin metabolites in normal tissues redue xerostomia in patients undergoing post operative radiation treatment for head and neck cancer, where the radiation part includes substantial portion of parotid glands |
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Carboplatin
|
platinum analog of cisplatin
ovarian carcinoma well tolerated with less nausea, neurotoxicity, ototoxicity and nephrotoxicity than cisplastin |
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|
Oxaliplatin
|
colorectal cancer in comb with 5-FU/leucovorin
neurotoxicity acute neurotoxicity (exacerbated by cold temp) |
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Microtubule Inhibitors
|
mitotic spindle is essential for equal partioning of DNA into the two daughter cells formed when a cell divides
Microtubule inhibitors include vinca alkaloids, taxanes and epothilones |
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Vinca Alkaloids
|
Vincristine
Vinblastine Vinorelbine |
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|
Vinblastine and Vincristine
|
natural products isolated from madagascar periwinkle plant, Catharanthus roseus
|
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|
Vinorelbine
|
semisynthetic vinca alkaloid
|
|
|
Vinca Alkaloid MOA
|
bind to Beta-tubulin on a portion of the molecule that overlaps with GTP-binding domain
ability of B-tubulin to polymerize with alpha tubulin into microtubules is inhibited mitotic arrest in metaphase and apoptosis |
|
|
Vinca alkaloid USE
|
combinatino with other drugs
Vincristine: Acute leukemia, Hodgkins and non-hodgkins lymphomas, rhabdomyosarcoma, neuroblastoma, wilm's tumor Vinblastine: metastatic testicular carcinoma, hodgkins and non-hodgkins lymphomas, mycosis fungoides, kaposi's sarcoma, choriocarcinoma, carcinoma of the breast Vinorelbine advanced nonsmall cell lung cancer |
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|
Vinca PK
|
IV injections leads to rapid cytotoxic effects and cell destruction--->hyperuricemia due to oxidation of purines
admin with allopurinol |
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|
Vinca AE
|
Vincristine: neurological: peripheral neuropathy and possible optic atrophy
Vinblastine: myelosuppression is dose limiting adverse effect of vinblastine Vinorelbine:myelosuppression, granulocytopenia is dose-limiting toxicity |
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Paclitaxel
|
taxanes
alkaloid derived from bark of pacific yew tree, Taxus brevifolia |
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|
Paclitaxel and Docetaxel MOA
|
binds beta-tubulin subunit of microtubles at site distinct from vinca alkaloid
promote microtubule polymerization and inhibit depolymerization stabilization of microtubules in a polymerized state arrests cells in mitosis and eventually leads to the activation of apoptosis |
|
|
Paclitaxel Use
|
advanced ovarian cancer
breast cancer non-small cell lung cancer second line for AIDS related Kaposi sarcoma |
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|
Paclitaxel AE
|
hypersensitivity
myelosuppression peripheral neuropathy alopecia arthralgias myalgias cardiac toxicity mucositis onycholysis |
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|
How must Paclitaxel be administered?
|
in a vehicle of 50% ethanol and 50% polyethoxylated castor oil because of limited solubility but may cause the hypersensitivity
premedicate with dexamethasone, diphenydramine and H2 blocker |
|
|
Abraxane
|
Albumin-bound form of paclitaxel which does not cause hypersensitivity, does not require premedication and causes less side effects
|
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|
Docetaxel
|
semisynthetic drug from yew, Taxus baccata
breast cancer NSCLC Prostate cancer gastric adenocarcinoma head and neck cancer |
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|
Docetaxel AE
|
myelosuppresion, peripheral neuropathy, vomiting, fluid retention, myalgia, alopecia, mucositis, onycholysis
more soluble than paclitaxel, administered in polysorbate 80 and causes lower incidence of hypersensitivity reactions pretreat with dexamethasone to prevent fluid retention |
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Taxanes PK
|
hepatic metabolism
biliary excretion |
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Ixabepilone
|
epothilones macrolides originally extracted from myxobacterium Sorangium Cellulosum
semisynthetic analog of epothilone B binds directly to B-tubulin thereby stabilizing microtubules and arresting cell proliferation has activity in taxane resistant cells |
|
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Ixabepilone Uses
|
metastatic or locally advanced breast cancer resistant to first line therapy.
|
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Etoposide
Teniposide |
epidodophyllotoxins
semisynthetic derivative of podophyllotoxin inhibit topoisomerase II resulting in DNA damage through strand breakage blocked in late S-G2 phase IV no CSF penetration Excreted in Urine and some bile |
|
|
Etoposide USE
Teniposide USE |
Etoposide: testicular cancer and SCLC
Teniposide: refractory childhood acute lymphoblastic leukemia |
|
|
Epipodophyllotoxins AE
|
Myelosuppression
Nausea, vomitting, alopecia |
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|
Camptothecins
|
Topotecan
Irinotecan Camptotheca Acuminata tree derivatives |
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|
Camptothecins MOA
|
inhibit topoisomerase I: inhibition results in DNA damage
S-phase specific drugs because ongoing DNA synthesis is needed for cytotoxicity Lead to cell arrest at G2 phase and then apoptosis |
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Topotecan
|
ovarian and SCLC and carcinoma of the cervix
neutropenia, thrombocytopenia, anemia, primary dose-limiting adverse effects |
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Irinotecan
|
prodrug that is metabolized to an active topoisomerase I inhibitor
indicated for metastatic carcinoma of the colon or rectum diahrea that can cause hypovolemia myelosuppresion is dose limiting |
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|
Hormonal Agents
|
Glucocorticoids
Estrogens Estrogen Inhibitors Progestins Androgens Androgen Inhibitors |
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|
Glucocorticoids
|
dexamethasone
prednisone hydrocortisone lympholytic effects adn their ability to supress mitosis in lymphocytes Acute Leukemia in children Malignant lymphoma in Children and adults management of autoimmune hemolytic anemia and thrombocytopenia associated with CLL--->increase the number of platelets and RBC |
|
|
Estrogens
|
Diethylstibestrol adn Ethinylestradiol
Prostatic Cancer supress pituitary LH secretion via negative feedback effects, thus inhibit testosterone production in testes, leading to inhibiting of growth of prostatic tissue |
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|
Estrogen Complications
|
thromboemboli, myocardial infarction, strokes, hypercalcemia
women: loss of libido, menstrual changes men: gynecomastia and impotence Gonadotropin releasing hormone analogs preferred due to lesser side effects for prostate cancer for men. |
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|
Estrogen Inhibitors
|
Selective Estrogen Receptor Modulators (SERMs)
Selective Estrogen-Receptor Downregulators (SERDs) Aromatase Inhibitors (AIs) |
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|
SERMs
|
Tamoxifen
first line for receptor positive Breast Cancer give orally Chemopreventive agent in women at risk for breast cancer activity against endometrial cancer competitive partial agonist inhibitor or estrogen need to have ablation of endogenous estrogen because it has 10 fold less affinity for estrogen receptors |
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|
Tamoxifen AE
|
hot flashes
nausea fluid retention |
|
|
Toremifine
|
SERM
derivative of tamoxifen breast cancer in women with tumors that are ER positive or unknown receptor type status |
|
|
SERDs
|
pure anti-estrogens
Fulvestrant unlike SERMs, SERDs are devoid of any estrogen agonist activity binds to estrogen receptor with 100 times more affinity than tamoxifen, inhibits dimerization adn increases its degradation reduces # of ER molecules: as consequence, ER mediated transcription is abolished |
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|
Felvestrant Use
|
hormone receptor positive metastatic breast cancer in post menopausal women with disease progression following antiestrogen therapy
|
|
|
Aromatase Inhibitors
|
Aminoglutethimide
Anastrozole and Letrozole Exemestane and Formestane |
|
|
Aminoglutethimide
|
inhibits aromatase
since estrogens promote growth of breast cacner, estrogen synthesis in extragonadal adipose tissue can be important in breast cancer growth in postmenaupausal women inhibits adrenal steroid synthesis at the first step (cholesterol to pregnenolone) |
|
|
Aromatase
|
converts androstenedione to estrone
aromatization can occur in body fat |
|
|
What is Aminoglutethimide usually administered with?
|
hydrocortisone to avoid symptoms of adrenal insufficiency
|
|
|
Aminoglutethimide AE
|
dizziness, lethargy, visual blurring, ataxia, rash, adrenal insufficiency, myelosuppression
|
|
|
Anastrozole and Letrozole
|
selective, nonsteroidal, reversible, competitive inhibitors of aromatase
advanced ER-positive breast cancer |
|
|
Anastrozole and Letrozole AE
|
nausea headache fatigue hot flashes arthralgias
|
|
|
Exemestane and Formestane
|
Steroidal Agents. irreversible inhibitors or aromatase
metastatic breast cancer and in prevention of recurrences in cancers primarily treated with surgery and radiation Side Effects: mild nausea, headache, fatigue, hot flashes |
|
|
Aromatase Inhibitors vs. Estrogen Receptor Antagonists
|
aromatase inhibitors more effective against breast cancer, but produce profound suppression of estrogen action and lead to increased risk of osteoporotic fractures
|
|
|
Progestins
|
Hydroxyprogesterone, Medroxyprogesterone, Megestrol
second line hormonal therapy for metastatic , hormone-dependent breast cancer adn in management of endometrial carcinoma previously treated by surgery and radiotherapy stimulate appetite and restore sense of well-being in cachetic patients with advanced stages of cancer and AIDS |
|
|
Androgens
|
Testosterone and Fluoxymesterone
palliative effect in some women with breast carcinoma don't play a major role in management of breast carcinoma because rates are higher with conventional chemotherapy |
|
|
Androgen Inhibitors
|
carcinoma of the prostate is uniquely dependent on hormonal stimulation with androgens
androgen deprivation therapy through surgical or medical castration is the mainstay of treatment for advanced prostate cancer |
|
|
Gonadotropin Releasing Hormone Agonists
|
leuprolide
goserelin nafarelin buserelin triptorelin |
|
|
GnRH Agonists
|
treatment of advanced prostatic carcinoma: chemical suppression of pituitary.
continously given as a depot preparation: initial surge in LH and FSH levels followed by inhibition of gonadotropin release----> reduced production of testosterone in testes. |
|
|
Treatment of Prostate Cancer
|
GnRH analogs are as effective as diethylstilbestrol (DES) and bilateral orchiectomy in the treatment of prostate cancer
GnRH agonists: less gynecomastia, nausea, vomiting, edema and thromboembolism occur sig. less frequent than with DES |
|
|
GnRH Agonist Treatment
|
initially increase in symptoms but use a blocker such as flutamide or use GnRH antagonists
|
|
|
GnRH Antagonists
|
Abarelix
palliative treatment of men with advanced symptomatic prostate cancer in whom GnRH agonist therapy is not appropriate and who refuse surgical castration reduces serum testosterone levels without transient increase observed with GnRH agonists |
|
|
Androgen Receptor Blockers
|
classified into 2 groups:
1. Steroidal: cyproterone and megestrol 2. Nonsteroidal: flutamide, nilutamide, and bicalutamide |
|
|
flutamide
|
metabolized to an active hydroxylated metabolite that binds to the androgen receptor
also blocks the inhibitory effects of testosterone on gonadotropin secretion, causing an increase of LH and testosterone levels |
|
|
Flutamide Uses
|
more commonly used in clincal practice
monotherapy not indicated as routine, first line treatment for patients with advanced prostate cancer in combinatino with GnRH analog |
|
|
Signal Transduction inhibitors
|
many listed on pg. 34 and 35, go over table
|
|
|
GnRH Antagonists
|
Abarelix
palliative treatment of men with advanced symptomatic prostate cancer in whom GnRH agonist therapy is not appropriate and who refuse surgical castration reduces serum testosterone levels without transient increase observed with GnRH agonists |
|
|
Androgen Receptor Blockers
|
classified into 2 groups:
1. Steroidal: cyproterone and megestrol 2. Nonsteroidal: flutamide, nilutamide, and bicalutamide |
|
|
flutamide
|
metabolized to an active hydroxylated metabolite that binds to the androgen receptor
also blocks the inhibitory effects of testosterone on gonadotropin secretion, causing an increase of LH and testosterone levels |
|
|
Flutamide Uses
|
more commonly used in clincal practice
monotherapy not indicated as routine, first line treatment for patients with advanced prostate cancer in combinatino with GnRH analog |
|
|
Signal Transduction inhibitors
|
many listed on pg. 34 and 35, 36 go over table
|
|
|
Imatinib
|
tyrosine kinase inhibitor
CML therapy |
|
|
Retinoid
|
Differentiating agent
trans-retinoic acid (tretinoin) produces remissions in patients with promyelocytic leukemia (APL) through induction of terminal differentiation--->leukemic promyelocytes lose their ability to proliferate |
|
|
Tretinoin Toxicity
|
mucocutaneous, skeletal, liver and teratogenic adverse effects
|
|
|
Arsenic Trioxide
|
induction of remission in patients with Acute Promyelocytic Leukemia with t(15:17) chromosomal translocation refractory to or relapsed following first line therapy with tretinoin and anthracyclines.
induces differentiation and apoptosis |
|
|
Arsenic Trioxide Toxicities
|
fatigue, QT prolongation, arrhythmias, and a syndrome characterized by fever dyspnea, skin rash, fluid retention adn weight gain
|
|
|
Imatinib
|
tyrosine kinase inhibitor
CML therapy |
|
|
Retinoid
|
Differentiating agent
trans-retinoic acid (tretinoin) produces remissions in patients with promyelocytic leukemia (APL) through induction of terminal differentiation--->leukemic promyelocytes lose their ability to proliferate |
|
|
Tretinoin Toxicity
|
mucocutaneous, skeletal, liver and teratogenic adverse effects
|
|
|
Arsenic Trioxide
|
induction of remission in patients with Acute Promyelocytic Leukemia with t(15:17) chromosomal translocation refractory to or relapsed following first line therapy with tretinoin and anthracyclines.
induces differentiation and apoptosis |
|
|
Arsenic Trioxide Toxicities
|
fatigue, QT prolongation, arrhythmias, and a syndrome characterized by fever dyspnea, skin rash, fluid retention adn weight gain
|
|
|
Hydroxyurea AE
|
myelosuppression
high doses: megaloblastosis unresponsive to B12 GI symptoms, including nausea, vomiting and diarrhea are common with high doses |
|
|
Mitotane
|
related to DDT and DDD (insecticides)
selective for adrenocortical cells, normal or neoplastic (normal or neoplastic) rapid reduction of adrenocorticosteroids |
|
|
Mitotane USE
|
palliation of inoperable adrenal cortical carcinoma
|
|
|
Mitotane AE
|
skin eruptions, diarrhea adn mental depression
anorexia, nausea, somnolence, dermatitis admin adrenocorticosteroid is indicated |
|
|
Interferon alpha-2a
|
hairy cell leukemia, AIDS-related Kaposi's sarcoma and Philadelphia chromosome (Ph) positive CML
|
|
|
Interferon Pharmacokinetics
|
given IM or SC
undergo glomerluar filtration and are degraded during reabsorption liver metabolsim is minimal |
|
|
Interferon AE
|
depression, fever with chills
leukopenia thrombocytopenia fatigue malaise anorexia weight loss alopecia transient elevation of liver enzymes |
|
|
Bone Marrow Growth Factors
|
can reduce frequency and severity of neutropenic sepsis and other complications
use in conjunctino with chemotherapy |
|
|
Filgrastim
|
granulocyte colony stimulating factor (G-CSF)
|
|
|
Sargramostim
|
Granulocyte macrophage stimulating Factor (GM-CSF)
|
|
|
What are the two recombinant colony stimulating growth factors for RBCs
|
erythropoietin
darbopeotin alfa (longer half life due to glycosylation) indicated for chemotherapy induced anemia in patients with nonmyeloid cancer and for anemia associated with chronic renal failure |
