7 - Cell Cycle Non-Spec Drugs Flashcards
what are the classes of cancer drugs?
(which is “picking the lock”, and which is “smashing the lock”)
- cell cycle specific drugs (CCS)
- “pick the lock”
- side effects: more mild/ not as bad
- cell cycle NON-SPECIFIC drugs (CCNS)
- “destory the lock”
- side effects: more severe –> affects normal cells too
types of toxicity of cancer chemotherapeutic agents
- acute toxicity - occurs w/in hours
- delayed toxicity - chronic toxicity; occurs w/in days/weeks
cell cycle specific drugs (CCS):
types and toxicity
- antimetabolites: no acute toxicity
- antimitotics: acute and delayed toxicity
cell cycle non-specific drugs (CCNS):
types and toxicity
- acute and chronic toxicity
- side effects are more severe
what is the mechanism of action of cell cycle non-specific drugs?
- many act as DNA modifying agents producing DNA lesions and DNA damage
- will affect both non-cycling and cycling cells
cell cycle non-specific drugs:
side effects
- CCNS results in MORE SEVERE side effects than th especific drugs
- exhibits both acute and chronic toxicity
alkylating agents:
list them
- Cisplatin
- Cyclophosphamide
- Dacarbazine
- Mechlorethamine
- Melphalan
- Nitrosureas
- Procarbazine
what are the classes of alkylating agents?
- nitrogen mustard
- alkyl sulfonates
- ethylenimines
- triazines
- tetrazines
- nitrosureas
alkylating agents:
differences?
- distinct structural differences affect DNA in different ways
- many require host metabolism to activate drug – Prodrug
alkylating agents
mechanism, toxic side effects
- mech:
- these agents alkylate macromolecules, notably DNA;
- and/or by forming covalently-bound cross-links in DNA
- side effects:
- acute and chronic
- nausea and vomiting
- bone-marrow suppression
- alopecia
- teratogenicity and carcinogenicity (alkylating agents can THEY THEMSELVES be carcinogens, but we use them anyway because they work
DNA alkylation:
mechanism of action
- bulky lesions in DNA –> mutagenic and affect the base pairing –> cause mis-coding –> killing of the daughter cell
- affect virtually all metabolic processes which use DNA as a template
- Replication
- Transcription
- Singla transduction (impedes hormone receptor binding)
alkylating agents in cancer chemotherapy
- *cyclophosphamide (cytoxan) is responsible for many of the cancer cures that we have
- used to tx: CHOP, CMF, CAF; lymphoma, leukemia, breast cancer
cyclophosphamide (cytoxan):
characteristics
- one of the most widely used alkylating agents
- high oral bioavailability
- admin: oral or intravenous routes w/ equal clinical efficacy
- inactive in its parent form –> activated to cytotoxic forms by liver microsomal enzymes
- *therefore, needs NORMAL LIVER FUNCTION
cyclophosphamide -
used to tx what?, what is it co-administered with?
- breast CA, ovarian CA, non-hodgkins lymphoma, CLL, soft tissue sarcoma, neuroblastoma, Wilm’s tumor, rhabdomyosarcoma
- Co-administered w/ CHOP
- C - cyclophosphamide
- H - hydroxyDaunorubicine
- O - oncovin (vincristine)
- P - prednisone
Used in many tx - non-Hodgkins’ lymphoma
what is the history of CYCLOPHOSPHAMIDE?
- it is a NITROGEN MUSTARD (which was used in WWI: chemical warfare
- countries stockpiled mustard gas during WWII –> and studied the effects to protect soliders
- learned they could be used as effective CA chemotherapy drugs
Nitrosoureas:
examples, characteristics, metabolism, excretion, tx
- examples:
- Carmustine (BCNU)
- Lomustine (CCNU)
- Streptozotocin
- characteristics
- highly lipid-soluble –> readily crosses BBB
- oral admin is possible
- metabolism
- requires biotransformation - nonenzymatic decomposition
- excretion
- urinary excretion (major route of elim; needs normal kidney fxn)
- tx: brain tumors
antibiotic drugs used as cancer chemotherapeutic agents, and where do they work in the cycle?
- anthracyclines –> intercalation of DNA, and free radical formation
- mitomycin C –> alkylating agent that cross-links DNA
- bleomycin –> act on strand breaks of DNA
Anthracyclines:
mechanism of action
- Inhibits topoisomerase II
- will perturb DNA tertiary and quaternary structure
-
Intercalates into DNA
- high-affinity binding
- block DNA and RNA synthesis
- induce DNA strand scission (DNA damage)
-
Generates ROS (Reactive oxygen species)
- DNA damage
- Membrane binding
- affects fluidity and ion transport
which anthracycline is one of the most important anti-cancer drugs in clinical practice?
doxorubicin (Adriamycin)
indicated in tx of many cancers (multiplicity of uses)
cancer types attached
what effect does competitive antagonism have on the logarithmic scale?
- w/ admin of a competitve antagonist –> the curve shifts to the right
- (indicating that a higher conc of substrate is needed to reach 50% effect)
Bleomycin:
biochem, mech
- biochem: small peptide that contains a DNA-binding region and an iron-binding domain at opposite ends of the molecule
- mechanism:
- binds to DNA
- causes single- and double-strand breaks following free radical formation
- breaks due to oxidation of DNA-bleomycin-Fe II complex
- chromosomal aberrations
- inhibits DNA biosynthesis
- **Cell cycle specific drug; cells accumulate in the G2 phase of the cell cycle (damaging DNA)
