Pharm: Chemotherapeutic Agents Flashcards
How do alkylating agents work? What class of chemo drugs do they fall under?
Alkylating agents are CCNS Drugs - cell cycle non-specific, meaning they can work on tumor cells in resting phase as well as dividing phase.
They work by forming reactive molecular species that alkylate DNA bases, specifically N-7 GUANINE.
This leads to cross-linking of bases, abnormal base pairing, and DNA strand breaks.
How do tumor cells develop resistance to alkylating agents?
Remember: alkylating agents alkylate the N-7 guanines of tumor DNA and x-link bases/break strands, etc…
Tumors develop resistance by INCREASING THEIR REPAIR MECHANISMS, decreasing drug permeability, and thiol trapping molecules like GLUTATHIONE.
Name the drugs that fall under the Alkylating Agent Category:
Cyclophosphamide
Mechlorethamine
Platinum Analogs (all end in PLATIN)
Procarbazine
What is the main toxic break down product of cyclophosphamide?
What enzyme is responsible for the breakdown of cyclophosphamide?
What do you take BEFORE cyclophosphamide to prevent toxicity of this toxic breakdown product?
Cyclophosphamide must be activated by a CYP in the liver (biotransformation of the drug) before it can have any effect on a tumor.
Breakdown product is ACROLEIN. - can cause bladder inflammation.
Take MESNA before cyclophosphamide - prevents acrolein accumulation.
Does Mechlorethamine have to be hepatically converted into its active form?
What toxic effect does it have?
No, unlike cyclophosphamide, mechlorethamine spontaneously converts to its reactive cytocoxic alkylating agent
GI distress (alopecia/myelosuppression as always)
STERILITY
VESICANT- causes blistering upon contact
What cancer is Mechlorethamine best used to treat? What’s another drug used to treat the same thing?
Hodgkins Lymphoma
Also use Procarbazine.
Cisplatin is what kind of drug? How can you remember the drugs that have this MOA?
An alkylating agent, specifically a PLATINUM ANALOG:
PLATIN: are platinum agents and alkylating agents.
How do you apply cisplatin, and other Platinum Analog alkylating agents?
IV - excreted through Kidney in UNCHANGED FORM
Which alkylating agent forms hydrogen peroxide and generates free radicals, causing DNA strand cutting?
Procarbazine
Procarbazine is administered how, distributed where and eliminated by what organ?
Administered Orally, penetrates all tissues AND BBB, then eliminated hepatically
How do ANTIMETABOLITE drugs work against cancer cells?
What other function of antimetabolites serve that can be good or bad, depending on the patient’s disease?
Antimetabolites are structurally similar to endogenous compounds and are ANTAGONISTS of FOLIC ACID, PURINES, and PYRIMIDINES.
In addition to chemotherapy, antimetabolites are IMMUNOSUPPRESSANTS
How does Methotrexate work?
DHFR inhibitor –> decreases amount of cell THYMIDILATE.
Need Dihydrofolate reductase for Purine synthesis.
Leads to accumulation of ADENOSINE, which is toxic to cells.
In what cell cycle stage does an antimetabolite drug work best?
DNA Synthesis stage (S Phase)
This makes it a CCS (Cell cycle specific drug)
The toxic effects of methotrexate on normal human cells can be reduced by giving the patient what? what is this called?
Exogenous Folinic Acid
LEUCOVORIN RESCUE
What is unusual about the clearance of methotrexate?
It is not metabolized in the body, and relies solely on kidney excretion for elimination from the body.
Need to stay hydrated cause crystals of it can accumulate in tubules.
What increases the toxicity of methotrexate?
NSAIDS
What are Mercaptopurine and Thioguanine? How do they work?
Purine antimetabolites. - are converted into toxic metabolites by the same enzyme, and in turn, inhibit several enzymes involved in purine metabolism.
What enzyme turns Mercaptopurine and Thioguanine into their active, toxic forms?
HGPRTases
What is a CCS drug?
Cell-cycle specific drug. Relies on the rapid proliferation of the tumor cell population for its effectiveness, due to the targets being present only when the cells are mitotically active.
What is a CCNS drug?
Cell cycle non-specific. Doesn’t really matter what stage the cell is in, it can still kill it, even in G0.
What does “growth fraction” mean?
The proportion of cells in a tumor population that are actively dividing.
What is the Log-kill hypothesis?
Anticancer drugs kill a FIXED PROPORTION of a tumor cell population, not a fixed number.
For example, a 1-log-kill will decrease a tumor cell population by one order of magnitude. (e.g…. 90% of the cells will be eradicated)
What is an oncogene?
a mutant form of a normal gene that is found in naturally occurring tumors. When expressed in non-cancerous cells, it causes them to behave like cancer cells.
What is a vesicant?
Give an example.
A drug that causes blisters on contact with tissues.
Example: Mechlorethamine (alkylating agent)
Tumor cells have many mechanisms of resistance to anticancer drugs. One method involves the formation of TRAPPING AGENTS. Describe this mechanism.
Tumor cells can increase their production of thiol trapping agents like GLUTATHIONE, which interact with anticancer drugs that form reactive electrophilic species.
Most common with ALKYLATING AGENTS bleomycin, cisplatin, and anthracyclines.
What method of resistance exists against drugs that have to be converted to their active form once inside the tumor cell?
Tumor cell decreases synthesis of the enzymes necessary for prodrug cleavage into their cytotoxic metabolites.
Example: PURINE AND PYRIMIDINE ANTIMETABOLITES
What is the mechanism of methotrexate resistance by tumor cells?
Methotrexate messes up DHFR, so increased synthesis of DHFR by the tumor cell, or enzyme mutations can decrease drug effectiveness.
What is the toxicity associated with cisplatin and carboplatin?
Aucoustic nerve damage and nephrotoxicity
What’s the dose-limiting toxicity of Oxaliplatin?
Neurotoxicity
How can you prevent the nephrotoxicity associated with cisplatin or carboplatin?
Administration of Mannitol and forced hydration.
What 2 categories of drugs are CCNS?
Alkylating agents and Antibiotics
What drug inhibits Thymidylate synthase?
5-FU
50FU is converted to FdUMP which directly inhibits Thymidylate Synthase
If you have a brain tumor, will 5-FU reach it?
YES - complete distribution.
What can you administer prior to 5-FU to make it more effective? How does this substance achieve this result?
Leucovorin. (exogenous folate)
Increases the growth fraction of the tumor. Remember: TUMORS ARE MOST SUSCEPTIBLE AT THEIR HIGHEST GROWTH FRACTION
What is the MOA of Cytarabine?
Antimetabolite.
Activated by kinases to AraCTP, which inhibits DNA Polymerase.
MOST SPECIFIC DRUG FOR S PHASE
Mnemonic for Cytarabine?
CytARAbine makes AraC.
What is the MOA of Gemcitabine?
Antimetabolite
Deoxycitidine analog that’s converted to active -PP or -PPP form.
Inhibits RIBONUCLEOTIDE REDUCTASE
and causes CHAIN TERMINATION of replicating DNA.
Mnemonic for Gemcitabine?
Put gems on a chain.
Gemcitabine causes chain termination
What stage of the cell cycle does Vinorelbine target?
MOA?
Vinca alkaloids are M-phase specific.
They prevent the polymerization of tubulin dimers (mitotic spindle inhibitors)
What are the names of the other vinca alkaloids? Which one has the worst reputation for causing peripheral neuropathy?
Vinblastine and Vincristine (causes peripheral neuropathy the worst)
How do you have to administer a vinca alkaloid?
Parenterally
What chemotherapeutic drugs inhibit TOPOISOMERASE II, thereby accumulating double strand DNA breaks?
What else do they do?
ETOPOSIDE and TENIPOSIDE
“the topo” drugs.
They also inhibit mitochondrial electron transport.
What are the 3 chemotherapeutic drugs that penetrate the BBB?
- Procarbazine (Alkylating agent)
-
Carmustine*
(VERY lipid soluble alkylating agent used
SPECIFICALLY for brain tumors) - 5-Fluorouracil (antimetabolite)
In what cell stage can you use Etoposide and Teniposide?
Late S, early G2
What 2 drugs inhibit Topoisomerase 1?
Topotecan Irinotecan
“otecans”
What is the MOA, administration route, and toxicity of PACLITAXEL and DOCETAXEL?
MOA: Inhibit the depolymerization of tubulin dimers (mitotic spindle inhibition)
Route: IV
Toxicity: Peripheral Neuropathy
What is the only Antibacterial Chemotherapeutic agent that is CCS?
What cell cycle stage?
Bleomycin - G2 specific
What is the MOA of Bleomycin?
Bleomycin is a glycopeptide mixture that generates free radicals.
Cause DNA damage, breaksm etc…
What is the dose-limting toxicity of Bleomycin?
Pulmonary Fibrosis
Starts out as pulmonary pneumonitis, but advances to fibrosis slowly.
Your patient’s cancer cells are stuck in late S - G2 phase. What drugs do you use?
Etoposide and Teniposide. They’re specific for Late S - Early G2
Which of the chemotherapeutic agents is an anthracycline? What does that even mean?
Doxorubicin and Daunorubicin
Derived from Streptomyces bacteria
What are the 3 MOAs of Doxorubicin and Daunorubicin?
They are anthracyclines.
- Intercalate between base pairs
- Inhibit Topo II
- Generate Free Radicals
What is the dose-limiting toxicity of Doxorubicin/Daunorubicin?
Cardiac toxicity:
EKG abnormalities
Arrhythmia
Cardimyopathy
Congestive heart failure
If you’re taking Allopurinol, what chemo drug won’t work?
6-Mercaptopurine (an anti-metabolite)
Allopurinol prevents it from being converted to its active toxic product.
What can be given in addition to Doxorubicin to prevent cardiotoxicity?
DETRAZOXANE - inhibits free radical generation
What is the MOA of DACTINOMYCIN?
Binds to dsDNA and prevents DNA-dependent RNA synthesis
What antibiotic chemo agent is metabolized by liver enzymes to an active alkylating agent that cross-links DNA?
MITOMYCIN
