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Drugs
Drug Overview
157
Anatomy
Pre-School
03/29/2013

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Term
by chance discovery; used platinum electrode and observed no growth in bacteria, same observation in mammalian cells, realized Platin Chloride kills mammalian cells in vitro and can shrink tumors in rats and mice in vivo (development of drug)
Definition
Cisplatin
Term
Targeted synthesis (development of drug)
Definition
antimetabolites (5-FU)
Term
Screening of chemicals and natural productions (development of drug)
Definition
vinca alkaloids, Adriamycin, taxol
Term
Analog development
Definition
Mitoxantrone, carboplatin
Term
analog of Adriamycin (Doxorubicin); used in patients who have HEART ISSUES because SE of Adriamycin is cardiotoxicity
Definition
Mitoxantrone
Term
analog of Cisplatin; used in patients with KIDNEY PROBLEMS because Cisplatin has nephrotoxicity
Definition
Carboplatin
Term
Cytotoxic Agents
Definition
Alkylating agents, antimetabolites, cytotoxic antibiotics, natural products
Term
Cancer Chemotherapeutic Agents
Definition
Cytotoxic Agents, Hormones, Targeted Chemotherapeutic Agents
Term
Cell cycle phase specific (need prolonged exposure or repeated doses)
Definition
antimetabolites, vinca alkaloids
Term
Cell cycle phase non-specific (most effective against actively dividing cells but also effective in Go)
Definition
alkylating agents, cisplatin
Term
Go phase
Definition
refractory to chemotherapy
Term
G1 phase
Definition
L-asparaginase
Term
S phase
Definition
Procarbazine, Antimetabolites, Hydroxyurea, Camptothecins
Term
G2 phase
Definition
Bleomycin, Vinca alkaloids, taxanes
Term
M phase
Definition
Vinca alkaloids, Taxanes
Term
Classic alkylating agents
Definition
Nitrogen mustards, Nitrosoureas
Term
Non classic alkylating agents
Definition
Procarbazine, Bendamustine
Term
Nitrogen mustards
Definition
mechlorethamine, Melphalan, Cyclophosphamide, Chlorambucil
Term
Nitrosureas
Definition
carmustine (BCNU), lomustine (CCNU)
Term
Platinum analogs
Definition
cisplatin, carboplatin, oxaliplatin
Term
Alkylating Agents
Definition
Classic, non-classic, and Platinum analogs
Term
nitrogen mustard with smallest side chain; most active out of the alkylating agents
Definition
Mechlorethamine
Term
nitrogen mustard with a cyclic group and longer side chain causing it to only be a moderate anticancer drug
Definition
Chlorambucil
Term
Only alkylating agents that can cross the blood brain barrier; this is due to the side chain being lipophillic
Definition
Nitrosoureas
Term
very common regimen for treatment of Hodgkin's disease sand non-Hogkin's lymphomas
Definition
Mechloroethamine, Vincristine (Oncovin), Procarbazine, Prednisone (MOPP)!!
Term
Must be given IV by rapidly flowing infusion of saline; care must be taken to avoid extravasation--- any splash on hands causes blistering
Definition
Mechloroethamine
Term
Side effects of this drug include Myelosuppression, nausea/vomiting, alopecia, and menstrual irregularities
Definition
Mechloroethamine (a prototype of the nitrogen mustards)
Term
Broad spectrum of activity; is a prodrug that is metabolized by CYP450
Definition
Cyclophosphamide
Term
Reactive species metabolite of Cyclophosphamide
Definition
Phosphoramide mustard
Term
Toxic metabolite of Cyclophosphamide
Definition
Acrolein
Term
Side effects of this drug include Nausea/vomiting, bone marrow suppression, hemorrhagic cystitis** (ameliorated w/ SH donors and large fluid intake)
Definition
Cyclophosphamide
Term
can pass blood brain barrier, useful in the treatment of CNS tumors
Definition
Carmustine (BCNU)
Term
side effects include nausea/vomiting, delayed hematopoietic depression, CNS toxicity, pulmonary fibrosis with chronic use
Definition
Nitrosoureas
Term
N-methylated by liver microsomal enzymes, then function as an alkylating agent
Definition
non-classical alkylating agents
Term
most active agent against malignant melanoma (silencing the gene-- inhibiting DNA and RNA synthesis)
Definition
non-classical alkylating agents (Temozolomide, Decacarbazine, Procarbazine)
Term
Chloride dissociates --> reactive complex that reacts with water and DNA--> intrastrand cross link --> denaturation DNA
Definition
Platinum Analogs (Cisplatin, Carboplatin)
Term
Nephrotoxic: should be administered with vigorous hydration + mannitol to avoid renal toxicity
Definition
Cisplatin
Term
severe n/v ameliorated w/ 5-HT3 antagonists (decrease gastric motility); common treatment of testicular cancer
Definition
Cisplatin
Term
Myelosuppression is the dose-limiting toxicity; these are phase specific and were developed by rational synthesis rather than empirical screening of anticancer drugs
Definition
Antimetabolites
Term
3 major classes of antimetabolites
Definition
Folic acid analogs (Methotrexate); Pyrimidine analogs (5-Fluorouracil); Purine analogs and related inhibitors (6-MP)
Term
competitively inhibits dihydrofolate reductase (inhibits 1 carbon transfer); leading to the blockade of the biosynthesis of thymidylate and purines required for DNA synthesis
Definition
Folic Acid Analogs (Methotrexate)
Term
Is S-phase specific; can be administered intravenously, intra-arterially, intra-thecally, or orally; is eliminated mainly by the kidneys
Definition
Methotrexate
Term
2 differences between Folic Acid and Methotrexate
Definition
N#10- FA = H
N#10 - MTX =CH3
Pteriding Ring FA = O
Pteriding Ring MTX= NH2
Term
inhibits Thymidylate synthetase by being converted to FDUMP so that DUMP cannot be converted to DTMP
Definition
Fluorouracil
Term
used in the treatment of choriocarcinoma; in combo with other agents in the treatment of acute lymphoblastic leukemia and carcinoma of the breast, cervix, lung, head, and neck (maintenance with 6-MP)
Definition
Methotrexate
Term
Tumor can decrease active transport then it will not respond well to MTX. Give high doses of MTX and then you will get diffusion of MTX into the tumor. "rescue" normal cells with:
Definition
Leukovorin
Term
Is MYELOSUPPRESSIVE producing severe leukopenia, bone marrow aplasia, and thrombocytopenia; Oral dose causes GI toxicity; prolonged low doses cause hepatic dysfunction; precipitation of 7-OH metabolites causes renal toxicity
Definition
Methotrexate
Term
Tumor cell resistance: tumor cells generate an increased concentration of this through gene amplification causing a major mechanism of tumor resistance to methotrexate
Definition
FH2 reductase
Term
Pyrimidine Analogs that are pro-drugs
Definition
5-Fluorouracil, Cytarabine
Term
Pyrimidine Analogs
Definition
5-FU, Cytarabine, Gemcitabine
Term
Inside tumor cells it is activated to a "fraudulent" nucleotide, fdUMP
Definition
5-fluorouracil
Term
is a phase NON-specific (unlike other antimetabolites!!) due to its RNA action
Definition
5-FU
Term
exclusively used to treat solid tumors, especially breast, colorectal, and gastric tumors and squamous cell tumors of the head and neck; can cause myelosuppression, NV, and oral/GI ulceration
Definition
5-FU
Term
Tumor Cell Resistance: 5-FU - due to increased synthesis of:
Definition
thymidylate synthetase
Term
Analog of cytidine in which the ribose moiety has been replaced with an arabinose
Definition
Cytarabine
Term
Phosphorylated in vivo --> cytosine arabinoside triphosphate (ara CTP) which competitively inhibits DNA polymerase --> blocks DNA synthesis and causes cell death
Definition
Cytarabine
Term
Ara-CTP competes with dCTP and inhibits DNA polymerase, incorporates into DNA produces strand breaks and triggers apoptosis
Definition
Cytarabine (cytosine arabinoside, ara-C)
Term
has a narrow clinical spectrum and is primarily used in combo with Daunorubicin or Thioguanine (6-TG) for the treatment of acute non-lymphocytic leukemia such as AML
Definition
Cytarabine
Term
high doses can damage the liver, heart, and other organs
Definition
Cytarabine
Term
Tumor cell resistance: depressed levels of kinase required for activation- leads to lack of phosphorylation and decreased inhibition of DNA synthesis; enhanced levels of deaminase that inactiveates the drug
Definition
Cytarabine
Term
Purine Antagonists
Definition
6-mercaptopurine, 6-thioguanine, Fludarabine
Term
are all pro-drug; must be converted to nucleotides, the active species; activation MUST occur in target cells
Definition
purines and purine analogs
Term
all are rapidly broken down to inactive products, mainly in extra-tumor tissues. However nucleotides have longer half life; All interfere with several biochemical targets but inhibition of DNA synthesis appears important for all
Definition
Purines and purine analogs
Term
only difference is -SH instead of -OH; "false" nucleotides-- inhibit synthesis
Definition
Thiopurines
Term
structural analog of hypoxanthine (natural purine)
Definition
6-mercaptopurine (6-MP)
Term
must be converted intracellularly to the nucleotide 6-mercaptopurine ribose phosphate by hypoxanthine-guanine phosphoribosyl transferase (HGPRT); can also be converted to 6-mercaptopurine ribonucleotide
Definition
6-MP
Term
converts 6-MP to an INVACTIVE form
Definition
xanthine oxidase
Term
if on this drug you want to reduce the dose of 6-MP by 1/4; 6-MP commonly leads to hyper-uricemia (gout)
Definition
allopurinol
Term
cytotoxic because they inhibit de novo purine biosynthesis
Definition
6-MP ribose phosphate and the methylated nucleoside
Term
used primarily for the maintenance of remission in patients with acute lymphocytic leukemia and is given in combo with MTX for this purpose
Definition
6-MP
Term
acute lymphocytic leukemia (ALL) treatment
Definition
6-MP + MTX
Term
Tumor cell resistance (2 ways): Decreased drug activation by HGRPT (converts it to active form inside the cell); an increased inactivation by alkaline phosphase (degrades the drug)
Definition
6-MP and 6-TG
Term
structural analog of guanine in which a sulfhydryl replaces a hydroxyl group
Definition
6-Thioguanine (6-TG)
Term
cytotoxicity is due to feedback inhibition of purine biosynthesis by 6-TG ribose phosphate
Definition
6-TG
Term
Used in the treatment of AML
Definition
6-Thioguanine
Term
when given with allopurinol you do NOT need to reduce the dose
Definition
6-TG
Term
is dephosphorylated to 2-fluoro-arabinofluranosyladenosine then phosphorylated intracellularly to triphosphate
Definition
Fludarabine phosphate
Term
The triphosphate metabolite interferes with DNA synthesis and DNA repair through inhibition of DNA polymerases alpha and beta
Definition
Fludarabine
Term
used in the treatment of non-Hodgkin's lymphoma and chronic leukemia (CLL)
Definition
Fludarabine
Term
main dose-limiting toxicity: myelosuppression and immunosuppression. Patients are at risk for opportunistic infections
Definition
Fludarabine
Term
major classes of natural products
Definition
antitumor antibiotics (anthracyclines, mitomycin, bleomycin); vinca alkaloids, taxanes and related drugs; camptothecins; epipodophyllotoxins
Term
prototype; isolated from Sreptomyces peucetius in 1958; it contains an amino sugar and an antrhacycline ring
Definition
Doxorubicin (Adriamycin)
Term
structurally similar to doxorubicin, lacking the hydroxyl ring
Definition
Daunorubicin (Daunomycin)
Term
synthesized to reduce cardiotoxic effects; a synthetic anthracene
Definition
Mitoxantrone
Term
3 different MOAs: 1- intercalate into the base pairs in DNA minor groove 2- inhibit Top II enzyme preventing the relaxation and supercoiled DNA, thus blocking DNA transcription and replication, causing ds breaks 3- free radical damage of cell membrane
Definition
Anthracyclines
Term
does not have to penetrate cell-- generates superoxide quinine ring-- lipid peroxidation **
Definition
Anthracyclines
Term
extensively bound to plasma proteins and tissues after IV administration! mainly metabolized by the liver; MUST BE ADMINISTERED IV!
Definition
Anthracyclines
Term
can cause severe tissue necrosis, can't be administered IM or SC; care must be taken to avoid extravasation during IV infusions or injections
Definition
Anthracyclines
Term
produces lower frequency of severe local reactions after inadvertent extravasation compared to doxorubicin and daunorubicin
Definition
Mitoxantrone
Term
one of the most effective agents against SOLID TUMORS- also effective against acute leukemia and malignant leukemia
Definition
Doxorubicin
Term
most effective against lymphocytic and granulocytic leukemia! has little activity against solid tumors
Definition
Daunorubicin
Term
as effective as daunorubicin with less toxicity; also effective in some patients with advanced breast cancer
Definition
Mitoxantrone
Term
Tumor cell resistance: due to reduced intracellular accumulation of the drug due to increased EFFLUX: amplification of the mdr1 gene/P170gp, known as MDR phenotype
Definition
Anthracyclines
Term
will block the multi-drug resistance pump (P-gp) and coule be used together with anti-tumor drugs
Definition
Verapamil
Term
can cause both acute and chronic cardiomyopathy; damage to cardiac cell mitochondria is IRREVERSIBLE
Definition
Doxorubicin, Daunorubicin and to a less extent Mitoxantrone
Term
Binds Fe and inhibit OH production; decreases lipid peroxidation (can administer with Anthracyclines to reduce heart issues)
Definition
Dexrazoxane (metal-chelating agent)
Term
antibiotic isolated from Streptomyces caespitosus; reduced and reacts with amino groups on guanine residues on adjacent base pairs in complementary DNA strands that result in cross linking inhibiting DNA synthesis
Definition
Mitomycin (mitomycin C)
Term
cell cycle non-specific but maximum kill in G1 and S phases; effective against recurrent breast and colon cancer, metastatic or recurrent osteogenic and soft tissue sarcomas and bladder cancer
Definition
Mitomycin
Term
Tumor cell resistance: reduced intracellular drug accumulation (like P170 MDR gp); activation or enhancement of DNA repair mechanisms; increased glutathione transferase (GST) activity
Definition
Mitomycin
Term
clinical usefulness is limited due to SEs: bone marrow suppression, mucocutaneous toxicity, pulmonary toxicity, hemolytic-uremic syndrome; extravasation
Definition
Mitomycin C
Term
treatment for hemolytic-uremic syndrome (can occur with Mitomycin C)
Definition
prednisone, captopril, and heparin
Term
group of glycopeptides extracted from bacterium Streptomycces verticillus. Each individual molecule has a planer and an amine end
Definition
Bleomycin
Term
The planer end of the molecule intercalates with DNA (Between GT and GC!) sequences, the other end binds to Fe++ and facilitates its oxidation to Fe+++ ---> generating oxygen free radicals that cleave DNA
Definition
Bleomycin
Term
Cells in Go and G2 are most sensitive; one of the few drugs that acts on Go!! is inactivated in most tissues except skin and lungs by an enzyme; toxicity in skin and lungs occurs because they lack that enzyme
Definition
Bleomycin
Term
used in combo therapy only!
Definition
Bleomycin
Term
BEP regimen (testicular cancer)
Definition
Bleomycin, Etoposide, Cisplatin
Term
ABVD regiment (Hodgkin's Lymphomas)
Definition
Doxorubicin, Bleomycin, Vinblastine, Decacarbazine
Term
Tumor cell resistance: high levels of bleomycin hydrolase activity; tumor cell mutation altering the sequence that is sensitive to bleomycin intercalation
Definition
Bleomycin
Term
age related side effects, cumulative dose-related PULMONARY TOXICITY
Definition
Bleomycin
Term
Tumor cell resistance: high levels of bleomycin hydrolase activity; tumor cell mutation altering the sequence that is sensitive to bleomycin intercalation
Definition
Bleomycin
Term
age related side effects, cumulative dose-related PULMONARY TOXICITY
Definition
Bleomycin
Term
M phase specific drugs; bind to tubulin dimers in cytoplasm --> inhibit assembly (polymerization) of microtubules --> arrest at metaphase (M phase)
Definition
Vinca Alkaloids (Vinblastine, Vincristine)
Term
Used in combo with Doxorubicin, Bleomycin, and Decacarbazine for Hodgkin's Lymphomas
Definition
Vinblastine
Term
used with Cyclophosphamide, hydroxydauoribicin, and prednisolone for non-hodgekin's lymphomas
Definition
Vincristine (Oncovin)
Term
used with Mechlorethamine, Proccarbazine, and Prednisolone for Hodgkin's lymphomas
Definition
Vincristine
Term
ABVD regimen for Hodgkin's Lymphomas
Definition
Doxorubicin, Bleomycin, Vinblastine, Decacarbazine
Term
CHOP regimen for non-Hodgkin's Lymphomas
Definition
Cyclophosphamide, Hydroxydauoribicin, Oncovin, Prednisolone
Term
MOPP regimen for non-Hodgkin's lymphomas
Definition
Mechlorethamine, oncovin, Procarbazine, Prednisolone
Term
Used in non-hodgekin's lymphomas, Hodgkin's lymphomas, treatment of solid tumors in children, tumors of the breast, cervix in adults. IN combo with prednisolone for the induction of remission of childhood leukemia
Definition
Vincristine
Term
Dose limiting neurotoxicity. Vesicant. Dose-dependent sensory impairment and then motor impairment at higher doses
Definition
Vincristine
Term
Myelosuppression (leukopenia within 4-10 days after treatment)
Definition
Vinblastine
Term
Phlebitis or cellulitis, if the drugs extravasate during the injection, as well as n/v, diarrhea, alopecia
Definition
Vincristine and Vinblastine
Term
disrupt the equilibrium between free tubulin and microtubules by shifting it in the direction of ASSEMBLY, inhibiting depolarization--- cause both stabilization of microtubules and the formation of abnormal bundles of microtubules
Definition
Taxanes
Term
used in solid tumors: NSCLC< ovarian and breast cancers; 90% hypersensitivity rxns (premedicate with antihistamines and steroids, neuropathy, alopecia, necrosis w/ extravasation,
Definition
Taxanes
Term
and albumin-bound paclitaxel formulation-- can use instead and do not need to premedicate for hypersensitivity reactions
Definition
Abraxane
Term
is not used clinically becauseos f toxicity; isolated from a Chinese tree
Definition
Camptothecin
Term
has a lactone ring susceptible to hydrolysis-- (hydroxyl deriviative of the compound cannot be taken up by the tumor cell, this derivative will cause severe myelosuppression, diarrhea, sever vomiting)
Definition
Camptothecin (CPT)
Term
more water soluble, can be taken up by active transport system into tumor cell, less toxicity (closed ring)
Definition
Topotecan (TPT)
Term
The A ring shields the D lactone ring; less susceptible to hydrolysis and can be taken up by the tumor cell although it is actively metabolized to another active molecule
Definition
irinotecan (CPT-11)
Term
both bind to Topoisomerase I!
Definition
TPT and CPT-11
Term
Binds to Top II
Definition
Doxorubican
Term
binds to DNA/top I --> cleavable complex. this prevents DNA re-ligation, causing DNA damage during the S-phase (collision of replication fork)
Definition
TPT
Term
prodrug converted in the liver by the carboxyestrase enzyme to the SN-38 metabolite which is 1000 FOLD MORE POTENT!
Definition
CPT-11
Term
CPT-11 is a prodrug that is converted in the livery by a carboxyestrase enzyme into:
Definition
SN-38 metabolite
Term
after forming SN-38 metabolite, 2nd phase is conjugation of metabolite to be eliminated. If there is no conjugation then:
Definition
build up SN-38--- myelosuppression, etc. Mutation in enzyme is what causes you to not fulfill 2nd phase of metabolism
Term
second line therapy for ovarian and small lung cancers (1st line for ovarian is Cisplatin!)
Definition
Topotecan
Term
First line therapy for metastatic colon cancer in combo with 5-FU and Leucovorin
Definition
Ironotecan
Term
For metastatic pancreatic cancer:
Definition
combo of 5-FU, leucovorin and oxaliplatin, Irinotecan
Term
increased risk for sever/life threatening neutropenia (sometimes need to do genotyping when taking Camptothecins)
Definition
UGT1A1 gene carriers
Term
camptothecins cause diarrhea (25%): early during infusion treat with ____; late (>24 hours) use____
Definition
atropine, immodium
Term
semisynthetic derivative of podophyllotoxins was isolated from American mayapple roote
Definition
etoposide (VP-16)
Term
forms a ternary complex with DNA and top II leading to the formation of a cleavable complex, which causes DNA damage and cell death; can be oral of IV
Definition
Epipodophyllotoxins (Etoposide or VP-16)
Term
used in small cell lung cancer, germ cell tumors, and in combo with bleomycin for testicular cancer
Definition
Epipodophyllotoxins
Term
used for NHL, some leukemia; kills by ADCC and fixing complement (targets CD20 on B cells)
Definition
Rituximab (Rituxan)
Term
targets HER2 on some breast cancers and gastric cancer
Definition
Trastuzumab (Herceptin)
Term
antibody-drug conjugate; binds CD30 and is conjugated to a cytotoxic drug auristatin
Definition
Bretuximab vedotin (Adcetris)
Term
Recombinant IL-2 (cytokine) conjugated to diphtheria toxin; binds CD25 and the diphtheria toxin kills the target cell; used for leukemia nad lymphomas
Definition
Denileukin diftitox (ontak)
Term
mAb against CTLA4; used for malignant melanoma by blocking CTLA4 and promoting T cell activation
Definition
Ipilimumab (Yervoy)
Term
autologous cellular immunotherapy cancer vaccine; used for prostate cancer
Definition
Sipuleucel-T (Provenge)
Term
cytokine that has severe side effects
Definition
IL-2 (Aldesleukin)
Term
cytokine that seems to promote activation of T cells and act on tumor cells to slow proliferation; used for variety of different cancers
Definition
IFN alpha
Term
used for chronic myelogenous leukemia (CML) and other leukemias that are Bcl-ABL+
Definition
Imatinib (Gleevec)
Term
binds/blocks intracellular site on epidermal growth factor receptor; blocks proliferation, inhibits angiogenesis
Definition
Erlotinib (Tarceva)
Term
bind and blocks growth factor itself, keeping ligand from being able to bind to the receptor and keep it from stimulating that pathway
Definition
Cetuximab (Erbitux)
Term
mAb against VEGF
Definition
Bevacizumab (Avastin)
Term
used for multiple melanoma; constipate plasma cell and myeloma cell, block activation of NFKB, proteasome inhibitor
Definition
Bortezomib (Velcade)
Term
used for multiple melanoma; constipate plasma cell and myeloma cell, block activation of NFKB, proteasome inhibitor
Definition
Carfilzomib (Kyprolis)
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