Drugs that Disrupt DNA and/or Prevent DNA Replication - Fitz Flashcards
What are the three types/groupings of antineoplastics that Disrupt DNA?
- Drugs that crosslink DNA
- Drug that intercalate
- Drugs that cause strand breaks
What are three types/subgroups of crosslinking antineoplastic drugs that disrupt DNA?
- Alkylating agents
- Nitrogen Mustards
- Nitroureas
- Platinum-containing drugs (-platinum)
- Antibiotic (Mitomycin)
What are the two drugs that are Nitrosoureas?
- Carmustine (BCNU)
- Lomustine (CCNU)
What are five drugs that are derived from Nitrogen Mustard (mustard gas)?
- CHLORAMBUCIL
- CYCLOPHOSPHAMIDE
- IFOSFAMIDE
- MECHLORETHAMINE
- MELPHALAN
What are the three steps in the mechanism of action of crosslinking agents?
- Activation: converted to electrophiles
- Nucleophilic attack: on anything in the cell (especially N7-guanine)
- Attaches to DNA => DNA DAMAGE (crosslinking)
When does the primary toxicity of crosslinking agents occur?
late G1 and S phase
Why are crosslinking agents selectively toxic to cancer cells?
- 50% of human cancers have mutation in p53
- cells cannot repair the DNA alkylation
- accumulation of errors → undergo apoptosis
- normal cells stop the cell cycle and repair the damage
What are three common resistance mechanisms that cancer cells develop in response to crosslinking agents?
- increased production of nucleophilic substances (e.g. glutathione - trapping agent)
- increased DNA repair
- increased activity of repair enzymes (e.g. guanine O6-alkyl transferase)
- decreased activation (oral agents only)
How do you distinguish between crosslinking agents that can be given IV or can be given orally?
- based on how quickly they are activated (become electrophiles)
- Meclorethamine: immediate activation on exposure to H2O
- add something to molecule to slow down activation
What are the therapeutic uses of crosslinking agents?
- Most commonly used antineoplastic agents
- Subtyping cancer to identify the best drug
What are the common side effects/toxicities of crosslinking agents?
(Hint: 8 total)
Generally, less for oral agents and greatest for MECHLORETHAMINE
- moderate to severe myelosuppression
- severe nausea and vomiting (Mechlorethamine & Cisplatin)
- strong vesicant (blistering) properties (not for oral agents)
- immunosuppression
- gonadal failure (sterility)
- carcinogeneisis (leukemias, esp. AML)
- mutagenesis
- teratogenesis
What are the four Anthracycline Antibiotics that are Intercalating Agents?
- DOXORUBICIN
- one of the most widely used antineoplastic drugs
- DAUNORUBICIN
- EPIRUBICIN
- EPIRUBICIN
- MITOXANTONE
What type of cancer are Anthracycline Antibiotics (intercalating agents) very useful for treating?
Breast cancer
What are the primary mechanisms of action of Anthracycline Antibiotics (intercalating agents)?
- intercalation in major groove of DNA causing several cytotoxic actions:
- inhibition of topoisomerase II
- single- and double-strand breaks (mutagenic) or sister chromatid exchange (carcinogenic)
What are the secondary mechanisms of action of Anthracycline Antibiotics (intercalating agents)?
- interact with cell membranes to alter fluidity and ion transport
- in the presence of NADPH, they react with cytochrome P450 reductase to form superoxide anion radicals
Even though they are CCNS, when is the maximum toxicity of Anthracycline Antibiotics (intercalating agents)?
S phase
(at low concentrations will pass through S and die in G2)
What are the three main forms of resistance that cancer cells can form in response to Intercalating agents?
- *decreased accumulation via increased P-glycoprotein → multidrug resistance
- Natural products
- changes in target proteins
- decreased topoisomerase II activity (i.e. decreased DNA synthesis)
- increased inactivation
- increased glutathione peroxidase activity (i.e. protection against oxidative damage)
How are Intercalating agents administered? Metabolized?
- given IV (vesicant)
- eliminated by metabolic conversion and biliary excretion
- dependent on adequate liver function
What is the broadest spectrum/most common antineoplastic drug?
- Doxorubicin = Adriamycin
- first line treatment for breast cancer
What is the most serious toxic side effect of Intercalating Agents?
ANTHRACYCLINE ANTIBIOTICS cause an UNUSUAL CARDIOMYOPATHY that is often IRREVERSIBLE and related to the TOTAL DOSE of the drug.
- present years after treatment has stopped
- unresponsive to standard treatment (digitalis)
What are the 8 common toxic side effects of Intercalating Agents?
- Cardiomyopathy:
- Acute: increased heart rate, conduction abnormalities, arrhythmias
- Delayed: congestive heart failure that is unresponsive to digitalis (may occur years after treatment)
- Extravasation → necrosis (vesicant)
- Myelosuppression is major dose-limiting complication (individual course of treatment)
- Nausea and vomiting
- Alopecia
- Mutagenic, carcinogenic
- “Radiation recall reaction” - erythema and desquamation of the skin at sites of prior radiation therapy
- Hand-foot syndrome (palmar-plantar erythrodysesthesia)
What color is the urine of a patient that received treatment with an Intercalating Agent 24-48 hours after administration?
Red/Reddish-Orange
(the exception is MITOXANTONE which turns the urine — and the whites of the eyes — blue!)
What is special about the drug Procarbazine that Fitz listed as a drug that causes strand breaks and/or prevents DNA replication?
- It is actually an ALKYLATING AGENT
- has more effects on RNA & protein synthesis than other alkylating agents
- has more strand breaks than other alkylating agents
What two drugs are Plant Alkaloids that cause DNA strand breaks and/or prevent DNA replication?
- Epipodophyllotoxin: ETOPOSIDE
- Camptothecins: IRINOTECAN/TOPOTECAN
What are two mechanisistic similarities between all antineoplastic drugs that cause DNA strand breaks and/or prevent DNA replication?
- all are CCS
- all require functional apoptotic machinery (esp. p53) to complete the cell kill
- DNA breaks accumulate in G2
What is the MOA of Bleomycin?
- binds to DNA (not RNA) through its amino-terminal peptide
- generates free radicals that cut the DNA
- causes accumulation of cells in G2 that have chromosomal aberrations (chromatid breaks, gaps, fragments and translocations)
Bleomycin Blasts DNA
Why is Etoposide a better antineoplastic drug than IRINOTECAN and TOPOTECAN?
- Etoposide = Topo II inhibitor
- more specific for rapidly dividing cells
- harder to repair
- Irinotecan/Topotecan = Topo I inhibitor
Where are Irinotecan and Topotecan activated and metabolized in the body?
Liver
What two forms of resistance are possible with Bleomycin?
- increased inactivation
- increased hydrolase activity (also important for toxicity - not in skin/lungs)
- increased DNA repair
What two forms of resistance are possible with Etoposide?
- decreased accumulation via increased P-glycoprotein (multidrug resistance)
- changes in target proteins
- mutation or decreased expression of topoisomerase II
- decreased apoptosis due to mutation of p53
What two forms of resistance are possible with Irinotecan/Topotecan?
- decreased activation
- decreased accumulation via increased P-glycoprotein (multidrug resistance)
Why is Bleomycin used in combination with other antineoplastic therapies?
Unique MOA
What type of cancer is Irinotecan/Topotecan used for?
Metastatic Colon Cancer
What are common toxicity side effects of Bleomycin?
- hypersensitivity
- GI
- lungs (pulmonary fibrosis) and skin lack the hydrolase that degrades BLEOMYCIN
- alopecia
- edema of the hands
What are common toxicity side effects of Etoposide?
- nausea and vomiting
- cardiovascular: hypotension, EKG changes
- alopecia
- leukopenia
What are common toxicity side effects of Irinotecan/Topotecan?
- myelosuppression
- diarrhea (both forms may be severe):
- early:
- accompanied by other cholinergic symptoms (rhinitis, increased salivation, miosis, lacrimation)
- treatable with ATROPINE
- late:
- prolonged
- causes dehydration, electrolyte imbalances and sepsis that may be life-threatening
- treated with LOPERAMIDE (opiate)
- early:
When it comes to selectivity of alkylating agents, why are cancer cells fools?
- most cancer cells have defective/dysfunctional p53
- cannot repair damage by alkylating agents
- normal cells are not hurt because they have functional p53 and repair mechanisms
