Ch.29: Anti-Cancer Agents (Milner) Flashcards
agents that can affect DNA are called:
mutagenic
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
4 cell types that can be targeted
round cells
epithelial cells
mesenchymal cells
hematopoietic cells
Which cell type is MOST and LEAST susceptible to chemo at a given dose?
MOST: hematopoietic
LEAST: mesenchymal
what do “phase specific” drugs target
specific phases in the cell cycle
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)
5 Phase non-specific drugs
1) alkylating drugs
2) nitrosoureas
3) antitumor abx
4) procarbazine
5) platinum derivatives
3 Phase specific drugs that target DNA synthesis*
cytosine arabinoside
hydroxyurea
methotrexate
4 Phase specific drugs that target mitosis*
vincristine
vinblastine
paclitaxel
docetaxel
Classifications of chemo drugs
alkylating agents* antimetabolites tumor antibiotics vinca alkaloids platinum derived hormones targeted therapy
biggest group of anti-cancer drugs
alkylating agents
antimetabolite drugs Mech. of action (MOA)?
S phase specific drugs that affect DNA production
Hormone drugs MOA?
can induce apoptosis and exert effect on lymphocytes
name one thing that normal cells can usually repair but cancer cells can’t?
intra-strand cross-linking
Where are pro-drugs activated?*
in the liver via cytochrome P450
Is chlorambucil a pro-drug?
NO
Is cyclophosphamide a pro-drug?**
YES
How does targeted therapy work?
create a specific cocktail of drugs to target a specific kind of cancer
alkylating agents MOA
cause intra and inter-strand DNA cross-linking –> prevent replication/ protein synthesis
alkylating agents cell cycle specific/non-spec.?
non-specific
Is there cross-resistance among alkylating agents?
Yes
Name 4 alkylating agents
cyclophosphamide
chlorambucil
lomustine
procarbazine
tissue type most sensitive to chemo drug***
bone marrow. Therefore, MYELOSUPPRESSION is the most common side effect of chemotherapy (will by MC question!!)
Where is cyclophosphamide activated/excreted?
hepatic activation renal excretion (<-- reduce dose if p in renal failure!)
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?
NO
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?
No
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?*
no
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