Ch.29: Anti-Cancer Agents (Milner) Flashcards by Sara Prent

agents that can affect DNA are called:

mutagenic

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indications for chemotherapy

1) systemic neoplasia sensitive to chemo (i.e. lymphoma)
2) palliative for gross metastatic dz
3) adjuvant to eradication of micrometastatic dz (i.e. osteosarcoma, hemangiosarcoma)
4) radio-sensitization

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4 cell types that can be targeted

round cells
epithelial cells
mesenchymal cells
hematopoietic cells

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Which cell type is MOST and LEAST susceptible to chemo at a given dose?

MOST: hematopoietic
LEAST: mesenchymal

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what do “phase specific” drugs target

specific phases in the cell cycle

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How does the drug methotrexate work

affects pyrine and pyrimidine synthesis by having an affect on folate synthesis within the cell (folate needed for DNA synthesis)

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5 Phase non-specific drugs

1) alkylating drugs
2) nitrosoureas
3) antitumor abx
4) procarbazine
5) platinum derivatives

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3 Phase specific drugs that target DNA synthesis*

cytosine arabinoside
hydroxyurea
methotrexate

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4 Phase specific drugs that target mitosis*

vincristine
vinblastine
paclitaxel
docetaxel

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Classifications of chemo drugs

alkylating agents*
antimetabolites
tumor antibiotics
vinca alkaloids
platinum derived
hormones
targeted therapy

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biggest group of anti-cancer drugs

alkylating agents

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antimetabolite drugs Mech. of action (MOA)?

S phase specific drugs that affect DNA production

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Hormone drugs MOA?

can induce apoptosis and exert effect on lymphocytes

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name one thing that normal cells can usually repair but cancer cells can’t?

intra-strand cross-linking

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Where are pro-drugs activated?*

in the liver via cytochrome P450

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Is chlorambucil a pro-drug?

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Is cyclophosphamide a pro-drug?**

YES

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How does targeted therapy work?

create a specific cocktail of drugs to target a specific kind of cancer

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alkylating agents MOA

cause intra and inter-strand DNA cross-linking –> prevent replication/ protein synthesis

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alkylating agents cell cycle specific/non-spec.?

non-specific

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Is there cross-resistance among alkylating agents?

Yes

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Name 4 alkylating agents

cyclophosphamide
chlorambucil
lomustine
procarbazine

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tissue type most sensitive to chemo drug***

bone marrow. Therefore, MYELOSUPPRESSION is the most common side effect of chemotherapy (will by MC question!!)

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Where is cyclophosphamide activated/excreted?

hepatic activation
renal excretion (<-- reduce dose if p in renal failure!)

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Signs of cyclophosphamide toxicity

myelosuppression*** GI sterile hemorrhagic cystitis** transitional cell carcinoma

Acrolein

by-product of cyclophosphamide administration. Irritates the bladder lining and can cause cystitis, ulceration, edema, necrosis, etc. Prevention: do UA to check for blood in urine; stop cyclophosphamide therapy if there is blood

Tx for cyclophosphamide bladder toxicity

- Discontinue chlorambucil and replace with chlorambucil - Prednisolone to increase diuresis/inhibit activation of cyclophosphamide - Antibiotics - MESNA, DMSO If persistent: N-acetylcysteine

What is SIADHS

syndrome of inappropriate ADH secretion - results from cyclophosphamide - causes PU/PD and electrolyte changes - used for many tumor types

excretion of chlorambucil

renal

most common uses of chlorambucil

-substitute for cytoxan -chronic lymphocytic leukemia -feline GI (small cell) lymphoma (treats low grade forms of cancer)

signs of chlorambucil toxicity

mild myelosuppression, GI. Does NOT cause renal toxicity like cyclophosphamide does

Does chlorambucil target rapidly dividing cells well?

Which is more irreversible: inter or intra-strand DNA cross-linking?

inter

What is the substitute for cyclophosphamide?***

chlorambucil

CCNU aka:

lomustine

Lomustine has inc/dec. metagenesis compared to cyclophosphamide and chlorambucil? Why?***

Increased due to INTER-strand cross-linking.

lomustine class of drug

alkylating agent

Chars. of lomustin

- completely absorbed PO - INTER-linking - highly lipid soluble - crosses BBB! - "rescue drug" - use when others fail

metabolism/excretion of Lomustin***

- metabolites become active via 1st pass hepatic degradation | - mainly renal excretion, some hepatic via enterohepatic cycle

side effects of lomustin

myelosppression hepatotoxicity** myelosuppression

what class of drug is procarbazine?

alkylating agent

signs cisplatin toxicity

- nephrotoxic - nausea** - fatal pulmonary edema in cats**

cisplatin cell cycle specific or non-specific?

non-specific

cisplatin low/high protein bound?

high

excretion of cisplatin

renal

primary uses of cisplatin

osteosarcoma | squamous cell carcinoma

carboplatin specific or non-specific?

non-specific

excretion of carboplatin

renal

signs of carboplatin toxicity

myelosuppression | may affect platelets

can you use carboplatin in cats?

yes

advantages of carboplatin

fewer GI effects, can use in cats

antimetabolites are cell phase specific/non-spec.?***

S phase specific

chemical composition of antimetabolites

purine or pyrimidine analogues

Antimetabolite MOA

insert into DNA to make it non-functional

Name 2 antimetabolite drugs

methotrexate | cytosine arabinoside

methotrexate MOA

Is a dihydrofolate reductase antagonist. (stops folate synthesis in the body

Does methotrexate cross BBB?

yes

signs of methotrexate toxicity

myelosuppression GI (reversible with leucovorin)

uses of methotrexate

lymphoma | CNS tumors

when is 5-Fluorouracil contraindicated?**

in cats (SEIZURES)

cytosine arabinoside is removed from circulation by:

kidneys

cytosine arabinoside metabolized by:

liver

how is cytosine arabinoside ideally administered?

by continous infusion

Does cytosine arabinoside cross BBB?

Yes

most common uses of cytosine arabinoside

renal lymphoma lymphoma rescue CNS tumors

antibiotics are cell cycle phase specific/non-specific

non-specific

antibiotics usually have a trade-off between efficacy and toxicity

MOA of anthracyclines

free radical damage, inhibition of topoisomerase II (which unwinds DNA)

where is doxorubicin metabolized/excreted?

metabolized: liver excreted: kidney

side effects of doxorubicin***

``` may turn urine orange/red anaphylaxis*** vesicant*** cardiotoxicity*** *Do NOT want it to leak out of vein! ```

Protective agent you can give with doxorubicin

Dexrezoxane

where is mitoxantrone metabolized

liver

Signs of mitoxantrone toxicity

myelosuppression | GI

most common uses of mitoxantrone

LSA rescue transitional cell carcinoma thymomas

disadvantages of mitoxantrone

- very expensive* | - turns urine blue-green

how is actinomycin D excreted?

urine, feces

signs of actinomycin D toxicity

myelosuppression | GI

Does Actinomycin D cross BBB?

most common uses of Actinomycin D

lymphoma rescue | non-cardiotoxic substitute for Doxorubicin

Name 2 plant alkaloids

vincristin | vinblastine

plant alkaloids are cell cycle phase specific/non-specific?**

M phase (mitosis) specific

do plant alkaloids have cross resistance?*

plant alkaloid MOA

prevents assembly

how are vincristine and vinblastine excreted?

Liver (biliary)

signs of vincristine toxicity

- vesicant - myelosuppression - peripheral neuropathy

primary uses of vincristine

lymphoma transmissible venereal tumor thrombocytopenia

What are the 2 main drugs that act as vesicants if they get out of vein?

vincristine and doxorubicin

CHOP protocol includes which drugs

Cyclophosphamide, Doxorubicin, Vincristine, Prednisone

signs of vinblastine toxicity

vesicant | myelosuppression

primary uses of vinblastine

mast cell tumor | substitute for vincristine

prednisone (hormone) MOA

- bind to cytoplasmic receptors & inhibit DNA synthesis | - lympholytic

signs of prednisone toxicity

PU/PD polyphagia panting GI ulceration

primary uses of hormones (i.e. prednisone)

lymphoma mast cell tumor insulinoma intracranial neoplasia

major caution with hormones (i.e. pred)

DO NOT USE WITH NSAIDS

signs of L-asparaginase toxicity**

anaphylaxis* potentiate vincristine-induced myelosuppression (not myelosuppressive alone)* pancreatitis

1ary used of L-asparaginase

lymphoma

Name 2 Targeted Therapy Receptor-Kinase Inhibitors

Toceranib | Masitinib

Toceranib and Masitinib MOA

Target RT-Kinases KIT, PDGF. **Toceranib also targets VEGF Many cancers have intuitively activated CKIT, which is blocked by these drugs

Toceranib/masitinib side effects

related to effect on KIT: myelosuppression, GI, skin, renal

1aryuse of Toceranib/masitinib

mast cell tumor

Which anti-cancer drugs have urinary (renal) excretion?

``` actinomycin D carboplatin cisplatin cyclophosphamide Minimally: doxorubicin, vincristine, vinblastine ```

Which anti-cancer drugs have biliary (hepatic) excretion?

actinomycin D cisplatin doxorubicin vincristine/vinblastine