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