Cancer Chemotherapy II Flashcards
1
Q
What are the different classes of chemotherapy based on mechanism of action? and examples
A
- alykylating agents
- nitrogen mustards, alkyl sulfonates, nitrosoures, triazenes
- antimetabolites
- natural products
- miscellaneous agent
- hormones and hormone antagonists
2
Q
WHat is the mechansim for alkylating agensts?
A
- introduce alkyl groups into DNA, RNA and/or proteins
- DNA is likely the most important target
- cause DNA crosslinks, strand breaks, misreading of code
3
Q
describe the cell cycle specificity of alkylating agents
A
- cell cycle non-specific
- also affect Go cells
- eg mechlorethamine, carmustine (BCNU)
- Cell-cycle specific/phase non-specific
- cyclophosphamide
alkylating agents are the least selective of the antineoplastics. they tend to kill normal cells and tumor cells equally
4
Q
What are the toxic effects of
mechlorethamine
cyclophosphamide
carmustine
A
mechlorethamine-nausea/vomiting, myelo-suppression, mild alopecia
cyclophosphamide- nausea/vomiting, a little myelo-suppression, alopecia
carmustine- nausea/vomiting, delayed myelo-suppression
5
Q
what are the 3 typical effects of alkylating agents
A
-
hematopoiesis suppression
- indicator of effectiveness nd normal cell recovery
- bleeding and infection
-
GI effects
- damage to intestinal mucosa, oral mucosal ulceration
- nausea vomiintg
- CTZ
- stimulation of neuroreceptors in GI tract
- Alopecia
6
Q
What class is Mechlorethamine? how does it work and what is it used for?
A
- prototype cell-cycle nonspecific agent with limited use given via IV
- combo therapy for Hodkin’s and non-Hodkin’s lymphoma, breast, lung and ovarian cancers
-
bifunctional alkylating agent
- produces DNA cross-links
- highly reactive, dissapears from blood in seconds to minutes
7
Q
How does cyclophosphamide work? what is the associated toxicity
A
- cycle specific phase, non-specific
- prodrug activated by liver cytochrome P450s. Active form is phosphoramide mustard and it acts as an alkylating agent
- toxicity: bladder. sterile hemorrhagic cystitis that can be partially prevented with mensa
***broad spectrum of activity against wide variety of cancer: lymphoma, leukemia, carcinoma of breast, and endometrium, lung cancer etc,)
MOST widely used agent in this class
8
Q
Carmustine
A
- is a nitrosourea
- cycle nonspecific
- crosses theblood brain barier well so used for brain neoplasms
- used for: brain tumors, multiple myeloma, mlanoma
- toxicity: similar to other alkylating agents
9
Q
What are antimetabolites?
A
-
structural analogs of compounds required for intermediary metabolism
- falsely substitute for precursors of nucleic acid synthesis or other related pathways
- effective when cell proliferation is rapid
- S-phase specific
10
Q
Methotrexate
A
- binds to dihydrofolate reductase (DHFR) and prevents formation of tetrahydrofolate which is necessary for purine and pyrimidine synthesis
11
Q
what is Leucovorin and what is its use?
A
- high doses of methotrexate is necessary to bind all dihydrofolate reductase (DHFR) to inhibit its activity
- followed by “rescue” of host cells with leucovorin
- Leucovorin is folinic acid. a fully reduced folate that does not require reduction by DHFR. normal cells often have increased capacity to bing in leucorvin relative to tumor cells. so leucovorin protects normal cells from methotrexate side effects
12
Q
side effects of methotrexate
A
- intestinal epithelium damage: mild diarrhea to sever bleeding
- bone marrow suppression
- renal tubular necrosis: keep urine alkaline to limit this
- displaces other drugs from serum albumin
13
Q
WHen is methotrexate indicated?
A
Actue lymphocytic leukemia
Choriocarcinoma
14
Q
what is Fluorouracil? what are its side effects, uses?
A
pyrimidine analog that interfers with DNA synthesis
activated in cells to FUTP which inhibits RNA synthesis and to FdUMP which interferes wth thymidylate synthase, and ultimately DNA synthesis
SE: nausea, anorexia, diarrhea, myelosuppresion
broad spectrum use : stomach, colon, pancreas, ovary, head and neck, breast, bladder, basal cell carcinoma
15
Q
How does Cytarabine and what are the side effects? what are the uses?
A
- pyrimidine (cytidine) analog that competes for phosphorylation of cytidine
- competes for incorporation into DNA and causes chain termination
side effects: myelosuppresion (dose-limiting) and neurotoxicity
use: acute leukemia
16
Q
Gemcitabine
*
A
- similarcytarbine, but also inhibits ribonucleotide reductase
- pancreatic CA
17
Q
other than cytarabine there is another pyrimidine analog. what is it?
A
Gemcitabine
18
Q
WHat is the mechanism, side effects ad uses of mercaptopurine?
A
- Mechanism:
- purine analog
- converted in cells to ribonucleotide that inhibits RNA and DNA synthesis
- Side effects:
- bone marrow depression
- vomiting, nausea, anorexia
- jaundice
- uses:
- acute leukemias
19
Q
describe how genetics may be involved in mercaptopurine toxicity
A
Thiopurine Methytransferase is an enzyme that breaks down (inactivates) 6-MP.
- (less than 1%) have 2 nonfunctional copies TMPT and therefore can’t break down mercaptopurine and therefore get a buildup which leads to toxicity
- 10% of pts only have one funcitonal copy of TPMT and therefore require significantly decreased doses of Mercaptopurine
20
Q
what is Nadir?
A
alkylatin agents often cause loss of white blood cells. this can help us assess treatment level. we can check and see, if white blood cells arent decreasing then we probably arent yet at a therapeutic dose
21
Q
How does hydroxyurea work? what are its uses and side effect?
A
- inhibits ribonucleutide reductase and blocks conversion of ribonucleotides to dNTPs, thereby preventing DNA synthesisi
- this arrests cells at G1-S inerface
- often used in combination with radiation
- use: granulocytic leukemia
- side effects: hematopoietic depression, GI disturbances
22
Q
WHat are the classes of natural products
A
- Vinca alkaloids
- vincristine
- vinblastine
- taxanes
- enzymes
- epipodophyllotoxins
- etoposide
- topoisomerase inhibitors
- monoclonal antibodies
- trastuzumab
- antibiotics
- doxorubicin
- bleomycin
- anti angiogenic peptides biological response mediators
- vit a analogs
23
Q
How does vinca alkaloids work? what are 2 examples
A
- bind to tubulin, inhibiting proper formation of microtubules and mitotic spindle
- (cells stuck in metaphase)
- Vincristine and vinblastine
- different toxicities and antitumor spectrum
24
Q
what are the sside effects of vinblastine
A
- Vinblastine
- strongly myelosuppressive (dose-limiting)
- epithelial ulceration
- used for lymphomas, breast cancer
- Vincristine
- significantly less bone marrow toxicity
- alopecia, neuromuscular abnormalitlies (inc peripherl neuropathy)
- treat: actue hocytic leukemia, lymphoma, wilms tumor, neuroblastoma, many other
25
how does taxane work? and a use
enhances assembly and stability of microtubules by binding to B-subunit of tubulin. different binding site than vinca alkaloids
blocks in late G2, phase that is more sensitive to radiation so paclitaxel may have some use as a radiosensitizer
26
what is the difference in effect on microtubules of vincristine vs taxol
vincristine binds individual microtubule peices and taxol binds built microtubules and stops growth
27
when do we use paclitaxel? and side effects?
* **use:** refractory ovarian cancer, breast cancer
* can interfere with DNA repair, intensifying the effects of DNA damage by cisplatin or cyclophosphamide
* **side effect:** dose-limiting leokpenia, peripheral neuopathy, myalgia, arthralgia
28
What type of drug is Doxorubicin and describe its activity?
* anti-tumor antibiotic that is cycle specific/phase-nonspecific
* among the **most active antitumor agents**
* wide spectrum of activity:
* the most widely prescribed agent of this class
* lymphomas, breast, ovary, small cell lung other
## Footnote
**\*\*one of few drugs with some anti-angiogenic properties**
29
what is the mechanism of action of Doxorubicin
1. intercalates in DNA, distoring DNA helix
2. causes lipid peroxidation and free radical generation
3. **_Binds to DNA topoisomerase II and prevents resealing of DNA strand breaks_**
30
What are the side effects of Doxorubicin?
* cardiomyopathy (ROS)
* bone barrow depression
* alopecia
* GI problems
31
What is the mechanism for Bleomycin? WHat type of cancer is it used for?
* mixture of iron containing glycopeptides that bind to DNA
* acuses oxidative like damage to DNA which leads to DNA strand breaks. Iron is critical to its mechnism
* so causes VERY specific DNA breaks
* phase speific for G2 (and M phases)
* use: germ cell tumors of testes and ovaries. head, neck, lung, lymphomas
32
what are the side effects of bleomycin?
* the main one is ***_pulmonary toxicity (eg pneumonitis fibrosis)_***
* dose related
* cumulative and potentially fatal
* minimal myelosuppression
* skin vesiculation, hyperpigmentation
* lung and skin have lowest levels of bleomycin hydrolase (which inactivates bleomycin)
33
What is the mechanism of action of Etoposide? WHat are the uses? side effects?
* irreversibly stabilizes DNA topoisomers II complexes which results in dsDNA breaks that cannot be repaired
* blocks in late G2 phase (G2/M interface)
* use: lymphomas, actue leukemia, small cell lung, testis, Kaposi's sarcoma
* side effects: leukopenia (dose-limiting), nausea, vomiting, diarrhea, alopecia
34
WHat are biological response modifiers and how do they work?
the alter the patients own bioogical response to a tumor or treatment regimen. hopefully add benefit without toxicity
they are naturally occuring proteins or therapeutic molecules designed to mimic or impact natural proteins
35
What is Filgrastim and how does it worK? side effects?
(G-CSF)
* goal is limit chemotherapy induced neutropenia
* promotes progenitors of neutrophils
* expands absolute population of neutrophils, providing quicker recovery from bone marrow suppression (neutropenia)
side effects: bone pain
36
What is the mechanism of Trastuzumab (Herceptin)
* humanized monoclonal antibody that binds to HER2 receptor
* block proliferation of cells and may illicit response against HER2+ cells
37
What is the use of Trastuzumab?
* 25-30% of metastatic breast cancers that overexpress HER2
* thse tumors are less responsive to anti-estrogen strategies to many drugs except for anthracyclines (eg doxorubicin) and paclitaxel
38
What are the side effects of Trastuzumab?
cardiomyopathy
hypersensitivity: including anaphylaxis
infusion reactions
39
What is the mechanism, use and side effects of Trastuzumab
* mechanism: monoclonal antibody that binds HER2 receptor
* use: breast cancers that overexpress HER2
* side effects: cardiomyopathy, hypersensitivity, infusion reactions
40
WHat is the MOA of cisplatin? use?
* it is a platinum coordination complex. hydrolysis yields activated species which cause DNA crosslinks
* cycle specific/phas nonspecific
* **use**: wide antitumor spectrum
* testicular cancer
* ovarian cacner in combo with paclitaxel
* head, neck, bladder, small cell lung, colon, esophagus
41
side effects of cisplatin?
**_nephrotoxicity_**
ototoxiticy
peripher neuropathy
electrolyte disturbances
nausea vomiting, (100%)
myelosuppresion
42
WHat is the mechanism of Procarbazine? use? SEs?
* actiavted in vivo to a methylating agent which causes chromosomal damage
* an atpical alkylating agent
* no cross-resistance ith other alkylating agents (eg nitrogen mustards)
* use: _Hodkin's lymphoma_
* side effects: myelosuppression, nausea, vomiting
43
How are hormones and hormone antagonists used in cancer treatment?
Useful against tumors that are steroid hormone-depenedent
33% of breast cancers respond to hormonal therapy
66% of breast cancers with good estrogen receptor
presence of both estrogen and progesterone receptors in breast tumor increases the probablility of a response
44
presence of ______________ in breast tumors increases the probability of a response to hormone therapy
estrogen and progesterone receptors (ER and PR)
45
what are 2 possible strategies of hormonal therapy for cancer treatment and what what some consequences
1. "opposite" steroidal compounds
1. ex: estrogen for prostate cancer
2. anti-hormonal compounds
3. consequence of antagonistic approaches
1. decrease in growth fraction of responding tumor and more cells in Go phase
46
what is the beneficial side effects of other hormonal therapies
adrenocorticoids as antiemetics/reduce nausea, vomiting
androgens as anabolic aganets
progestins as appetite stimulant
47
How is prednisone used to treat cancer?
* binds to steroid receptors which act to modulate several aspects of cell growth
* may arrest cells at G1
* depress expression of many growth-related genes
* induce nucleases which may modulate cell lysis
* lympholytic for lymphoma and lymphocytic leukemia
* lymphoid tumors have high content of sterois receptors
* also used for breast cancer
48
what are some side effects for prednisone?
* potential complication is immunosuppression
* at doses and duration generally used, there is limited myelosuppression
* good for combination therapy
* may cause weight gain, fluid retention, and psychologic effects
49
WHat are the 3 types of antiestrogenic (ER+) chemo drugs?
1. estrogen receptor antagonists
2. aromatase inhibitors
3. non-steroidal
50
what are the 2 estrogen receptor antagonists?
WHat is the non-steroidal?
* estrogen receptor antagonists:
* Tamoxifen
* Raloxifene
* Non-steroidal
* letrozole
51
WHat kind of drug is tamoxifen? How does it work?
* nonsteroidal antiestrogen that competitively blocks estrogen receptor activity in breast tissue
* estrogen agonist in bone tissue; may "prevent" post menopausal osteoporosis (not licensed use)
* generally cytostatic (hold in Go/G1)
* tumor regroth when tamoxifen removed
* stopping cell growth without necessarily killing the cells
* is activated by CYP2D6
52
what are the uses of tamoxifen?
* advanced post-menopausal breast cancer
* pre-menopausal breast cancer
* breast cancer prophylaxis for women at high risk
* can reduce breast cancer risk by 45%
53
What are the possible side effects for Tamoxifen?
* nausea
* hot-flashes
* fatigue
* bone and other musculoskeletal pain
* may increase rates of uterin/endometrial cancer (blocks estrogen receptors in breast so more estrogen in endometrium so growht so cancer)
54
What is the mechanism fo action of Letrozole? what are the uses?
* blocks the conversion of androgens to estrogens by inhibiting aromatase
* 1st line treatment of post-menopausal advanced or metastatic breast cancer
* better than tamoxifen
55
What is the difference in side effects between Letrozole and Tamoxifen?
Tamoxifen does not decrease bone density bu letrozole might
also slightly more likely to get hot flashes with letrozole.
(so slightly worse side efects with letrozole)
56
What is the mechanism of Leuprolide? use? side effects?
GnRH analog
initially stimulates LH and FSH causing testosterone surge but after 2-4 weeks it desensitizes GnRH signaling, decreasing LH/FSH and decreasing testosterone to castration levels
approved use for advanced hormonally responsive prostate cancer
hot flashes, impotence
57
mechanism of Flutamide? use? side effects?
nonsteroidal antiandrogen that block androgen receptors
use: treatment of metastatic prostate cancer
side effects: gynecomastia, diarrhea, hepatotoxicity
58
Why is selection and overgrowth a major cause of chemotherapeutic failure?
most tumors will contain a small fraction of cell that are likely resistant to one drug (and related drugs)
59
How is multidrug resisatcne related to cancer treatment? (MDR)
how is resistance often mediated
* cancer may be resistant to multiple drugs. even in different classs
ex: vinca alkaloid: vincristine, vinblastine
antibiotics: doxorubicin, bleomycin
etoposides
taxane: paclitaxel
* mediated by ATP-dependent drug efflux pumps
60
what are the principles to combination chemotherapy?
* different cell cycle specificities
* active as single agents
* non-overlapping toxicities
* different mechanisms of action
61
What are 6 mechanisms to preventing resistance?
1. **Sequential blockade:** simulatneous action of 2 inhibitors acting on different steps of a linear metabolic pathway ex: hydroxyurea+cytarabine, methotrexate+5-FU
2. **Concurrent Inhibition**: inhibitors block 2 separate pthways that lead to the same end product
3. **Complementary Inhibition:** one drug affects the function of an end product, the other drug affects the synthesis of that end product ex: _cytarabine_ (inhibits DNA synthesis) + _doxorubicin_ (causes DNA damage via intercalation and free radical generation)
4. **Rescue:**"rescue" the patient's normal cells from the treatment ex: leucovorin (folinic acid) to rescue cells after high-dose methotrexate exposure, or ex: autologous stem cell trasplant
5. **Synchronization:** synchronize cells so they re in one phase and then use a drug that is specific fr that phase ex: low dose of flurouracil (5-FU) to block in S phase, then high dose cytarabine to kill in S phase (although attempts havent been that successful
6. **Recruitment:** bring cells out of Go and back into cell cycle. therapy w cell-cycle nonspeciifc drugs (mechlorethamine or carmustine/BCNU)
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