Antineoplastics Part Ii

Front 1

Folic acid analog:

Back 1

Methotrexate

Front 2

Pyrimidine analogs:

Back 2

5-Fluorouracil and
5-Fluorodeoxyuridine
Gemcitabine

Front 3

Purine analogs:

Back 3

6-Mercaptopurine, Azathioprine
6-Thioguanine

Front 4

Treatment of many types of cancers
Trapped as polyglutamate: leucovorin rescue
Kidney & liver damage, severe mucositis

Back 4

Methotrexate

Front 5

Explain leucovorin rescue w/ respect to methotrexate.

Back 5

Leucovorin is a THF which our cells can use as methotrexate and methotrexate's polyglutmated form inhibit DHFR which is needed to make THF. Administer leucovorin until levels of methotrexate go down. Poly-glutmated form will go back to methotrexate which can exit the cell. Leucovorin also saves cancer cells (bummer)

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MECHANISMS FOR DEVELOPMENT OF RESISTANCE TO METHOTREXATE

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1.)Decreased uptake, decreased folate carrier system.
2.)Increased DHFR content or mutated DHFR that does not bind methotrexate well.

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Only used for direct infusion into hepatic artery to treat metastases from bowel cancer.

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5-Flurodeoxyuridine (5-FUdR)

Front 8

Administered w/ 5-Fluorouracil to inhibit thimidylate synthase?

Back 8

Leucovorin

Front 9

Thimidylate synthase is used to synthesize what precursor in production of DNA?

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TMP

Front 10

Inhibits ribonucleotide reductase, and is incorporated into DNA leading to chain termination
First line drug for pancreatic cancer; also used in treatment of lung and bladder cancers.

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GEMCITABINE

Front 11

Azathioprine is a pro-drug that is reduced by ____ to form _____

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Glutathione
6-Mercaptopurine

Front 12

People taking allopurinol need to have the level of _____ monitored if it is given

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Mercaptopurine
(allpurinol inhibits xanthine oxidase which breaks mercaptopurine down into thio uric acid. Allopurinol tries to limit the amount of uric acid in people with gout)

Front 13

Intercalates with DNA bases and inhibits DNA and RNA polymerases
Wide spectrum: included in almost half of drug combinations
TOXICITIES: CARDIOTOXICITY
ACUTE: Arrhythmias
CHRONIC: Digitalis-resistant congestive heart failure; lifetime dose dependent - 20% of patients receiving 550 mg/m2
Produces severe alopecia
A potent vesicant

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DOXORUBICIN
(antibiotic)

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Important side effect of DOXORUBICIN

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TOXICITIES: CARDIOTOXICITY
ACUTE: Arrhythmias
CHRONIC: Digitalis-resistant congestive heart failure; lifetime dose dependent - 20% of patients receiving 550 mg/m2

Produces severe alopecia
A potent vesicant

Front 15

Binds to topoisomerase I and produces cuts in DNA
Used in combination with 5-FU and leucovorin in metastatic colorectal cancer
Immediate and delayed diarrhea – the latter can be severe and may lead to electrolyte imbalance and dehydration
Eliminated by biliary secretion – dosage adjustment is required in hepatic insufficiency

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IRINOTECAN
(camptothecan)

Front 16

What drug is co-administered w/ doxorubicin to allow a few extra treatments with doxorubicin and how does it work?

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Dexrazoxane
Binds w/ iron and makes it unavaiable. Iron normally would combine w/ doxorubicin to create oxygen radicals that damage the heart

Front 17

Vincristine. What kind of drug? What is its toxicity?

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prevent assembly of mitotic microtubules
neurotoxicity

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prevents disassembly of microtubules, used in cisplatin-resistant ovarian cancer

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Paclitaxel
prevents disassembly of microtubules, used in cisplatin-resistant ovarian cancer

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vinblastine and paclitaxel toxicity?

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bone marrow suppression

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hypersensitivity in 1-2% of patients: pre-treat with antihistamines and steroids

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Paclitaxel
prevents disassembly of microtubules, used in cisplatin-resistant ovarian cancer

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Mechanism of action: DNA scission (Topoisomerase II inhibitors)

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ETOPOSIDE AND TENIPOSIDE

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Dose of ___ must be decreased in kidney failure. _____ is extensively metabolized.

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Etoposide
Teniposide

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ETOPOSIDE AND TENIPOSIDE drug toxicities

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Relatively high incidence of secondary leukemias beginning about 2 years after treatment. Drug allergy.

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Binds to topoisomerase I and produces cuts in DNA

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IRINOTECAN – A CAMPTOTHECIN

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Used in combination with 5-FU and leucovorin in metastatic colorectal cancer

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IRINOTECAN – A CAMPTOTHECIN

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Immediate and delayed diarrhea – the latter can be severe and may lead to electrolyte imbalance and dehydration
Eliminated by biliary secretion – dosage adjustment is required in hepatic insufficiency

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IRINOTECAN – A CAMPTOTHECIN

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DEVELOPMENT OF MULTIPLE DRUG RESISTANCE (4 steps)

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1.)Uptake of drug
2.)Signal transduction to nucleus
3.)Expression and processing of drug pump
4.)Mature MDR-1 pump eliminates a broad spectrum of antineoplastics

Front 28

An estrogen receptor (ER) antagonist
Only useful in cancers expressing ER or progesterone receptor (PR)
New indication: reducing the incidence of breast cancer in women at risk:

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Tamoxifen (Nolvadex®):

Front 29

inhibits estrogen synthesis

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Aminoglutethimide

Front 30

an antiandrogen

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Flutamide

Front 31

GnRH and LHRH agonist
Initially stimulates secretion of testosterone, but later prevents it
Combined with flutamide to treat prostate cancer

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Leuprolide

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Inhibitor of BCR/ABL - the constitutively activated tyrosine kinase produced by chromosome translocation in CML
Blocks white blood cell proliferation
Inhibits Cyp3A4 cytochrome P450 isozyme

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Imatinib Mesylate (Gleevec®)

Front 33

binds to EGF receptor (EGFR) and inhibits it
for Non-Small Cell Lung Cancer (NSCLC)

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Gefitinib (Iressa®)

Front 34

An inhibitor of the proteasome: the major protein metabolizing enzyme in cells
Proteasome regulates cell cycle progression by controlling entry into the major phases of the cell cycle.
Build-up of damaged proteins because of proteasome inhibition results in cell death.
FDA approved for treatment of multiple myeloma

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BORTEZOMIB (Velcade®)

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______ binds to HER2 receptor and inhibits its growth signaling properties. Used for breast cancers.

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Trastuzumab (Herceptin®):
1. Severe allergic reactions. 2. Cardiomyopathy when co-administered with doxorubicin or cyclophosphamide:

Front 36

Treatment of non-Hodgkins lymphoma
Targets CD20 in B-lymphocytes
Severe reactions may occur including anaphylaxis.

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Rituximab (Rituxan®):
a monoclonal antibody

Front 37

EGFR-expressing metastatic colorectal carcinoma
Can cause hypotension and pharyngeal edema on infusion
Pulmonary inflammation and scarring
Skin rashes, especially when exposed to sunlight

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Cetuximab (Erbitux®):
a monoclonal antibody

Front 38

FDA approved as first line treatment for metastatic colorectal cancer – February 2004
Combined with irinotecan, 5-FU and leucovorin
Humanized mouse monoclonal antibody that binds to vascular endothelial growth factor (VEGF) and prevents vascularization of tumors.
Problems with wound healing.
Gastrointestinal fistula formation.

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BEVACIZUMAB (AVASTIN®)An Angiogenesis Inhibitor