7 - Cell Cycle Non-Spec Drugs Flashcards
1
Q
what are the classes of cancer drugs?
(which is “picking the lock”, and which is “smashing the lock”)
A
- 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
2
Q
types of toxicity of cancer chemotherapeutic agents
A
- acute toxicity - occurs w/in hours
- delayed toxicity - chronic toxicity; occurs w/in days/weeks
3
Q
cell cycle specific drugs (CCS):
types and toxicity
A
- antimetabolites: no acute toxicity
- antimitotics: acute and delayed toxicity
4
Q
cell cycle non-specific drugs (CCNS):
types and toxicity
A
- acute and chronic toxicity
- side effects are more severe
5
Q
what is the mechanism of action of cell cycle non-specific drugs?
A
- many act as DNA modifying agents producing DNA lesions and DNA damage
- will affect both non-cycling and cycling cells
6
Q
cell cycle non-specific drugs:
side effects
A
- CCNS results in MORE SEVERE side effects than th especific drugs
- exhibits both acute and chronic toxicity
7
Q
alkylating agents:
list them
A
- Cisplatin
- Cyclophosphamide
- Dacarbazine
- Mechlorethamine
- Melphalan
- Nitrosureas
- Procarbazine
8
Q
what are the classes of alkylating agents?
A
- nitrogen mustard
- alkyl sulfonates
- ethylenimines
- triazines
- tetrazines
- nitrosureas
9
Q
alkylating agents:
differences?
A
- distinct structural differences affect DNA in different ways
- many require host metabolism to activate drug – Prodrug
10
Q
alkylating agents
mechanism, toxic side effects
A
- 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
11
Q
DNA alkylation:
mechanism of action
A
- 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)
12
Q
alkylating agents in cancer chemotherapy
A
- *cyclophosphamide (cytoxan) is responsible for many of the cancer cures that we have
- used to tx: CHOP, CMF, CAF; lymphoma, leukemia, breast cancer
13
Q
cyclophosphamide (cytoxan):
characteristics
A
- 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
14
Q
cyclophosphamide -
used to tx what?, what is it co-administered with?
A
- 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
15
Q
what is the history of CYCLOPHOSPHAMIDE?
A
- 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
16
Q
Nitrosoureas:
examples, characteristics, metabolism, excretion, tx
A
- 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
17
Q
Carmustine:
biochem, mech, admin, indications
A
- highly reactive compound due to electronegativity –> will alkylate
- mech
- DNA modification: single base modification –> interstrand crosslink b/w N1 of guanine and the N3 of cytosine
- admin: NOT ORALLY because of first-pass metabolism
- indicated for:
- brain cancers: glioma, medulloblastoma, astrocytoma
- multiple myeloma
18
Q
Lomustine:
biochem, mech, admin, indications, AEs
A
- biochem: highly lipid-soluble drug –> crosses BBB
- mech: monofunctional alkylating agent, cross-links DNA
- admin: oral, once every 6 weeks
- indications: brain tumors (primary use)
- AEs:
- acute: nausea, vomiting
- chronic: alopecia, loss of appetite, bone marrow depression (this is an example of why cancer chemotherapy takes time)
19
Q
Streptozocin:
biochem, mech, indications
A
- biochem: glucosamine nitrosourea (diff’t structure –> different effects)
- mech: DNA damage
- indication: metastatic cancer of pancreatic islet cells (specialized use)
20
Q
Procarbazine:
biochem, mech, indications, side effects
A
- biochem: orally active methylhydrazine derivative; **weak MAO inhibitor
- mech: DNA alkylation – oxidative stress
- indicated for combination chemo:
- Hodgkin’s lymphoma,
- non-hodgkins
- brain tumors
- side effects:
- inc risk of secondary cancers (acute leukemia)
- drug-drug interactions –> adverse effects w/ other MAO inhibitors, sympathomimetic agents, tricyclic antidepressants, antihistamines, CNS depressants, antidiabetic agents, alcohol, and tyramine-containing foods
21
Q
antibiotic drugs used as cancer chemotherapeutic agents, and where do they work in the cycle?
A
- anthracyclines –> intercalation of DNA, and free radical formation
- mitomycin C –> alkylating agent that cross-links DNA
- bleomycin –> act on strand breaks of DNA
22
Q
list the anthracyclines?
A
- daunorubicin
- doxorubicin
- idarubicin
- epirubicin
- mitoxantrone
23
Q
Anthracyclines:
mechanism of action
A
- 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
24
Q
Anthracyclines:
biochem, admin, metabolism, elim, tx
A
- biochem: bioactive metabolite – hydroxylated molecule metabolite
- admin:
- Intravenously
- **admin every-3 week (takes a long time/ difficult for compliance)
- metabolism
- extensively in the liver; with reduction and hydrolysis of the ring substitutes
- elim:
- 50% of drug elimination in the feces
- tx:
- dose reduction is required in patients w/ liver dysfunction
25
**Anthracyclines**:
## Footnote
*toxicity*
* Myelosuppression: *main dose-limiting toxicity of all anthracyclines*
* **Cardiotoxicity**:
* Acute: *first 2-3 days; presents as arrythmias/ other abnormalities*
* *usually transient and asymptomatic*
* Chronic: *dose-dependent; dilated cardiomyopathy*
* *assoc. w/ heart failure*
* *may result from inc. production of free radicals w/in myocardium*
26
what consult do we need before starting pt on an **anthracycline?**
Cardiac consult
(due to risk of acute/chronic **CARDIOTOXICITY** due to production of free radicals w/in myocardium)
27
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*
28
**Doxorubicin:**
*admin, use, toxicity*
* admin:
* used in combination w/ other anti-cancer agents (cyclophosphamide, cisplatin, and 5-fluorouracil)
* Used for **CAF (cyclophosphamide, adriamycin, 5-fluorouracil)**
* Adjunt tx in breast CA after surgery/radiation
* acute toxicity
* nausea
* **red urine**
* **severe local vesicant action can occur**
* _adriamycin flare (erythematous streaking near site of infusion)_
* chronic toxicity
* cardiotoxicity
* alopecia
* myelosuppression
* stomatitis
29
how does St John's Wort affect anti-cancer therapy?
(mechanism)
* (herbal medicine used to tx depression); ex of why it's CRITICAL TO GET A THOROUGH CASE HX
* binds to topoisomerase II
* Competitive antagonist to **daunorubicin and doxorubicin**
* \*therefore, contraindicated during CA tx w/ either drug
30
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)
31
why can't you compete out St. John's Wort in Cancer tx?
the dose required may be **highly toxic**
32
should a pt take **megadoses of Vitamin C during CA chemo?**
why or why not?
* definitely **UNADVISABLE**
* bc Vitamin C is an **antioxidant --\>** whereas anti-cancer drugs kill tumor cells by **oxidative stress --\>**
* drugs produce ROS (reactive oxygen species)
* BUT VITAMIN C DESTROYS THE ROS --\> NEUTRALIZING CA THERAPY
* Therefore, recommend minimal doses of Vitamin c
33
which was the first **anthracycline agent** isolated?
Daunorubicin
34
**Daunorubicin:**
*characteristics, tx, toxicity*
* char: efficacy in solid tumors is **limited**
* tx: **acute myeloid leukemia**
* toxcititis: *similar to doxorubicin*
* Bone marrow depression
* Stomatitis *(inflammation of mouth and lips)*
* Alopecia
* GI disturbances
* Dermatological manifestations
* **CARDIAC TOXICITY**
35
**Idarubicin:**
*biochem, tx*
* biochem: semisynthetic anthracycline glycoside
* analog of Daunorubicin
* Tx
* used in **combination chemo**
* cytarabine - for acute myelodid leukemia
* \*when used w/ cytarabine -- more active than daunorubicin in producing complete remissions and in improving survival
36
**Epirubicin:**
## Footnote
*biochem, mech, tx*
* biochem: anthracycline analog
* mech: identical to the other anthracyclines
* tx: approved for use as component of adjuvant therapy in early-stage, node-positive breast CA
* metastatic breast CA
* gastroesophageal CA
37
**Mitoxantrone**:
## Footnote
*biochem, mech, tx, toxicity*
* biochem: anthracycline
* mech: binds to DNA to produce **strand breakage, & inhibits both DNA and RNA synthesis**
* tx: tx of advanced, hormone-refractory prostate cancer and low-grade non-Hodgkins lymphoma
* \*used as "backup drug" in cases of refractory cancer
* toxicity: (it's a nasty drug)
* **myelosuppression** w/ leukopenia (dose-lmting toxiticity)
* mild nausea/vomiting
* mucositis
* acute/and chronic **CARDIAC** toxicities
* **\*\*blue discoloration of the fingernails, sclera, and urine** (1-2 days after drug admin)
38
**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)
39
**Bleomycin:**
*admin, elim, indications, toxicity*
* admin: *variety of ways*
* subcutaneous
* intramuscular
* intravenous
* elim: **renal \<--** needs dose modification in patients w/ renal dysfunction
* indications:
* Hodgkin's and non-hodgkin's lymphoma
* germ cell tumor
* head and neck cancer
* squamous cell CA of skin, cervix, and vulva
* toxicity
* pulmonary: *dose-limiting*
* *presenting as pneumonitis w/ cough and dyspnea*
* *incidence inc in pts \> 70 y/o*
40
**Mitomycin C:**
*biochem, mech, indications, toxicity*
* biochem: alkylating agent that cross-links DNA;
* mech: requires enzyme modification
* indications:
* hypoxic tumor stem cells are hypersensitive
* squamous cell cancer of the anus (in comb. w/ 5-Fluorouracil and radiation therapy
* comb. chemo for squamous cell carcinoma of cervix, and for breast, gastric, and pancreatic cancer
* toxicity:
* acute: *nausea and vomiting*
* chronic:
* myelosuppression
* mycositis
* anorexia and fatigue
* hemolytic-uremic syndrome
* microangiopathic hemolytic anemia
* thrombocytopenia
* renal failure
41
**Mitomycin C:**
special use
Intravesical tx of superficial bladder cancer
(the advantage of this is that none of the agent is absorbed;
little to no systemic toxicity when used in this way)
