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Found. of Path. Processes - Block 1 > 19 - Cancer Chemotherapy II > Flashcards

19 - Cancer Chemotherapy II Flashcards

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1
Q

What are the five classes of chemotherapy drugs based on mechanism?

A
  1. Alykylating agents
  2. Antimetabolites
  3. Natural products
  4. Miscellaneous agents
  5. Hormonrs and hormone antagnists
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2
Q

What is the mechanism of action of alkylating agents? How effective are these?

A

Introduce an alkyl group into DNA, RNA, and/or proteins.

DNA is likely the most important target.

Causes DNA crosslinks, strand breaks, and misreading of code.

*least selective of the anti-neoplastic, tend to kill tumor and normal cells equally*

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3
Q

What is the specificity of alkylating agents? Whta are examples of each?

A

Cell-cycle nonspecific: also effects G0 cells

  • mechlorethamine (nitrogen mustard)
  • carmustine (BNCU) (Nitrosoureas)

Cell-cycle specific/ phase non-specific

  • cyclophosphamide (Nitrogen mustard)
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4
Q

What are the three alkylating agents and how do they differ in their side effects?

A

Mechlorethamine: nasuea/vomiting, myelosuppression, mild alopecia

Cyclophosphamide: Nausea/vomiting, limited myelosuppression, alopecia

Carmustine: nausea/vomiting, delayed myelosuppression

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5
Q

What are the “typical” side effects of alkylating agents?

A

Hematopoiesis suppression: often used as in indicator of therapeutic effectiveness and normal cell recovery

GI effects: damage to intestinal mucosa and oral mucosa, nausea and vomiting.

Alopecia

These effects are common to many anti-neoplastics due to the affect on rapidly dividing tissues.

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6
Q

What is nadir during treatment? What does it help us understand?

A

The lowest or deepest point; lowest WBC during treatment.

This shows the toxic effects of the drug, but can be used as a parameter to estimate the therapy’s effectiveness and guide future treatment.

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7
Q

What is Mechlorethamine? What types of cancer is it used to treat?

A

Cell-cycle nonspecific alkylating agent.

Bifunctional alkylating agent that produces DNA cross-links; highly reactive, disappears from blood in seconds to minutes.

Used in combo for hodgkin and non-hodgkin’s lymphoma.

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8
Q

What is cyclophosphamide? What is the associated toxicity? What is its spectrum of activity?

A

Prodrug activated by liver cytochrome P450s

Toxic byproduct called acrolein made in the process of activating the drug that causes bladder toxicity and sterile sterile hemorrhagic cystitis (but can be prevented with mesna)

Very braod spectrum of activity agains many cancers: lymphoma, leukemia, carcinoma of carcinoma or breast cancer and endometrium, lung cencer.

Most widely used in class (alkylating agets)

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9
Q

What is a nitrosoureas alkylating agent? What is a property of it that allows for specificity in treating cancer?

A

Carmustine

It can cross the blood-brain barrier.

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10
Q

What is the action of antimetabolites? What is the specificity?

A

Structural analog of compounds required for intermediary metabolism that falsely substituite for prescursors of nucleic acid synthesis or other related pathways.

Includes analogs of folate, purines, and pyrimidines.

Greatst effectiveness in tumors where cell prokiferation is rapid; S phase specific.

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11
Q

What is the function of Methotrexate (MTX)?

A

Binds to dihydrofolate reductase (DHFR) and prevents formation of tetrahydrofolate. This causes the accumulation of intracellular folates such as FH2.

*Generally dihydrofolate reductase maintains the pool of tetrahydrofolic acid (FH4), which serves as a source for the active folate cofactors required for synthesis of purines and pyrimidines.

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12
Q

What is leucovorin rescue?

A

You need a high dose of methotrexate necessary to bind all dihydrofolate reductase (DHFR) and inhibit it; should be followed with a “Rescue” of host cells with leucovorin.

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13
Q

What is Leucovorin?

A

A folonic acid, fully reduced folate that doesn’t require reduction by DHFR.

normal cells ofter have increased capacitity to bring in leucovorin relative to tumor cells.

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14
Q

What are side effects of methotrexate?

A
  1. Intestinal epithelium damage
  2. BM suppression
  3. Renal tubular necrosis - keep urine alkaline to limit this
  4. Displaces other drugs from serum albumin
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15
Q

In what cancers is methotrexate indicated?

A

Acute lymphocytic leukemia and choriocarcinoma?

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16
Q

What is fluotouracil (5-FU)?

A

A pyrimidine analog that’s activated in cells to FUTP which inhibits RNA synthesis and to fDUMP which interferes with thymidylate synthase and ultimately DNA synthesis.

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17
Q

What are side effects of fluorouracil? What are some uses?

A

Nausea, anorexia, riarrhea, and myelosuppression.

Broad sprectrum uses: somach, colon, pancreas, ovary, head and neck, breast, bladder, and basal cell carcinoma.

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18
Q

What is cytarabine?

A

A pyrimidine (cytidine) analog that competes for phosphorylation of cytidine.

Competes with naturally occuring nucleotides for incorporation into DNA and causes chain termination.

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19
Q

What are side effects of cytarabine? What are uses?

A

Side effects: myelosuppression (dose-limiting) and neurotoxicity.

Uses: acute leukemias (acute mylocytic leukemia)

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20
Q

What other pyridine analog is similar to cytarabine but also inhibits ribonucleotide reductase? What is this used to treat?

A

Gemcitabine: only drug used to treat pancreatic cancer

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21
Q

What is the MOA of mercaptopurine? What are side affects are uses?

A

Purine analog that’s converted in cells to ribonucleotide that inhibits RNA and DNA synthesis.

Side effects: BM depression, vomiting, nausea, anorexia, and jaundice.

Uses: acute leukemias

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22
Q

How do TPMT polymorphisms impact mercaptopurine?

A

TPMT converts 6-Mercaptopurine (6MP) into an inactive form.

When patients have 2 copies of nonfunctional TPMT, they cannot tolerate the drug because they are unable to inactivate it (<1% of patients)

When patients have only 1 copy of nonfunctional TPMT, they require markedly reduced doses to prevent serious BM suppression (~10% of patients)

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23
Q

What is the function of hydroxyurea?

A

Inhibits ribonucleotide reductase and blocks the conversion of ribonucleotides to dNTPs, thereby preventing DNA synthesis.

  • Arrests cells at G1-S phase.

Major use: granulocytic leukemia

Side effects: hematopoietic depression and GI disturbances

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24
Q

What are the differnt classes of natural products that are anti-neoplastics?

A
  1. Vinca alkaloids
  2. Taxanes
  3. Enzymes
  4. Epipodophyllotoxins
  5. Topoisomerase inhibitors
  6. Monoclonal antibodies
  7. Antibiotics
  8. Anti-angiogenic peptides
  9. Biological response modifiers
  10. VitA analogs
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25
What is the mechanism of action of vinca alkaloids? What are two examples of drugs in this class?
_Bind to tubulin, inhibiting proper formation of mt and mitotic spindle_. **Vincristine and vinblastine**
26
How do Vinblastine and Vincristine different in their side effects? What does each treat?
**Vinblastine:** _strongly myelosuppressive_ (dose-limiting), epithelial ulcerations. * lymphomas and breast cancer **Vincristine:** _significantly less bone marrow toxicity,_ alopecia, neuromuscular abnormalities like peripheral neuropathy. * acute lymphocytic leukemia, lymphomas, wilm's tumor, beuroblastoma.
27
What is the MOA of the taxane group of drugs?
Enhance assembly and stability of mts by binding to B-subunit of tubulin (different binding site than vinca alkaloids) * **blocks in late G2 phase**
28
What effect do paclitaxel and vinca alkaloids have on microtubules?
Vinca alkaloids like vincristine and vinblastine bind to individual mts to block polymerization while dissociation pathway continues. Paclitaxel (taxol) binds to the complex (polymerized molecules) to stabilize it so it cannot dissociate anymore. \*both have the affect of killing tumor cells\*
29
What is paclitaxel used for? What are the side effects?
Used for refractory ovarian cancer, breast cancer Side effects: **dose-limiting leukopenia, peripheral neuropathy, and myalgia/arthralgia** (Can interfere with DNA repairm intensifying the effects of DNA damage by cisplatin or cyclophosphamide.)
30
What is doxorubicin? How does it work and what is it's spectrum of activity?
Antitumor antibiotic: **cycle specific /phase nonspecific, some anti-angioenic properties** Among the most active of antitumor agents **Wide spectrum of activity:** lymphomas, breast, ovary, small cell lung (most widely prescribed agent of this class)
31
What are the MOA's of doxorubicin? Which is thought to be the major one?
1. Intercalates in DNA, distorting the DNA helix 2. Causes lipid peroxidation adn free radical generation 3. Binds to DNA + topoisomerase II and prevents resealing of DNA strands (major mechanism)
32
What are side effects of doxorubicin?
**Cardiomyopathy (very severe)** **Bone marrow depression** **Alopecia** **GI problems**
33
What is the MOA of bleomycin? What is critical in this mechanism?
Mixture of iron-containing glycopeptides that **bind to DNA and cause oxidative-like damage to DNA which leads to site specific DNA strand breaks.** _Iron is critica_l in this: other redox-active metals such as copper do not work.
34
Bleomycin is stage specific for which stage of the cell cycle? What types of cancers is bleomycin active against?
**Phase specific for G2 (and M phases)** Active against: germ cell tumors of the testes and ovaries, cancers of the head, neck, lunch, and lymphomas.
35
What are side effecs of bleomycin? Why do these side effects occur?
**Minimal myelosuppression** **_Pulmonary toxicity_** (eg pneumonitis fibrosis) that's dose-related, cumulative, and potentially fatal. _Skin vesiculation_ and _hyperpigmentation_ \*Lung and skin have the lowest levels of bleomycin hydrolase (which inactivates bleomycin) which means it builds up to toxic levels in these locations\*
36
What is the mechanism of Etoposide (VP16)? What phase does it inactivate?
**Irreversibly stabilizes DNA-topoisomerase II complexes,** resulting in dnSNA breaks that cannot be repaired. Blocks in late G2 phae (G2/M interface)
37
What are the uses of Etoposide (VP16)? What are typical side effects?
Lymphomas, acute leukemia, small cell lung, testis, and kaposi's sarcoma. Side effects: **leukopenia (dose-limiting), nausea, vimiting, diarrhea, and alopecia.**
38
What are biological response modifiers (BRM)? What is the benefit of them?
**Naturally occuring proteins or therapeutic molecules designed to mimic or impact natural proteins.** Benefit: alter's patients own biological response to a tumor or treatment regimen
39
What is the goal of filgrastim (G-CSF)? What are side effects?
**To limit chemotherapy-induced neutropenia by promoting progenitors of neutrophils.** Expands the absolute pop of neutrophils, providing for quicker recovery from bone marrow suppression (neutrophils). Bone pain in 33% of people. (Important in combination therapy)
40
What is the MOA of Trastuzumab? What is the use? What are the side effects?
**Monoclonal antibody that binds to HER2 receptor.** Use: _breast cancers that overexpress HER2_ (25-30% of metastatic breast cancers) Side effects: * _cardiomyopathy_ * _Hypersensitivity_ * _infusion reactions_
41
What is the MOA of cisplatin? What is the specificity?
**Platinum coordination complex;** hydrolysis yields _activated species which causes DNA crosslinks_ **Cycle-specific/phase-nonspecific**; wide antitumor spectrum that revolutionized the treatment of testicular cancer. Also treats ovarian cancer, head, neck, bladder, small cell lung, colon, and esophagus cancers.
42
What are side effects of cisplatin?
* Nephrotoxicity * Ototoxicity (30%) * Peripheral neuropathy * Electrolyte disturbances * Nausea, vomiting (100%) * Myelosuppression
43
What is the MOA of procarbazine? What is the use and what are side effects?
**Activated in vivo, by liver enzymes, to a methylating agent which causes chromosomal damage. Greatest effects in G1 and S)** * atypical alkylating agent (no cross-resistance with other alkylating agents) Used in **Hodgkin's Lymphoma** Side effects: **myelosuppresion, nausea, and vomiting**
44
What are hormones and hormone antagonists useful against?
Tumors that are steroid hormone dependent * ~33% of breast cencers respond to hormone therapy * ~66% of breast cancers with good estrogen receptor
45
Presence of both _____ and _____ in breast tumors increase the probability of response to hormone/hormone antagonists therapy.
Both estrogen (ER) and progesterone receptors (PR)
46
What are two possible strategies for hormone therapy? What are examples of each and consequences?
1. **"Opposite" steroidal compounds:** estrogens for prostate cancer, progestins for endometrial tumors 2. **Anti-hormonal compounds:** antiandrogens for prostate cancer and antiestrogens for breast cancer **Consequence of antagonist approaches:** decrese in growth factor of responding tumor (hormone-dependent), more cells in G0
47
What is the benefit of using hormonal therapy?
Responses can be dramatic, prolonged, and be very tumor specific.
48
What is the MOA of prednisone?
**Binds to steroid receptos:** * can arrest cells at G1 * Depress expression of many growth-related genes * Induces nucleases which modulate cell lysis
49
What can prednisone treat? What are its palliative effects?
Lympholytic for _lymphoma_ and lymphocytic _leukemia_ because lymphoid tumors have a high content of steroid receptors. Also used for _breast cancers._ Palliative effects: **anti-emetic, stimulates appetitde, anti-inflamm.**
50
What are the pros and cons of using prednisone?
**PROs:** at doses and duration generally used there's limited myelosuppresion, good for combo therapy. **CONs**: may cause weight gain, fluid retention, and psychologic effects
51
What are the two types of antiestrogenic classes?
**Estrogen receptor antagonists:** tamoxifen (TAM) and raloxifene **A****romataes inhibitors:** Ietrozole (nonsteroidal, better because it's oral with a rapid onset)
52
What is Tamoxifen?
**A non-steroidal antiestrogen that competitively blocks estrogen receptor activity in breast tissue** Generaly cytostatic so helps are held in G0/G1; tumots regrow when tamoxifen is removed. Basically stops cell growth without necessarily killing them.
53
What are uses of tamoxifen?
**Advanced _post_-menopausal breast cancer** **_Pre_-menopausal metastatic breast cancer** **Breast cancer prophylaxis** for women at high risk (can reduce risk by 45%)
54
What activates tamoxifen? What are side effects?
Activated by **CYP2D6** Side effects: nausea, hot flashes, fatigue, bone and other musculoskeletal pain. _May increase the risk of uterine/endometrial cancer_ (Raloxifene)
55
What is the MOA of letrozole?
**Blocks conversion of androgens to estrogens by inhibiting aromatase.** Prevents stimulation of growth of ER+ (antiestrogenic) cells
56
What is the use of letrozole?
**1st line** treatment of post-menopausal locally advanced or metastatic breast cancer (objective response rate of 32% after 9.4 months)
57
How do the side effects of letrozole compare to those of tamoxifen?
**More likely to have bone and other musculoskeletal pain and hot flashes with letrozole than tamoxifen.** _Tamoxifen does NOT decrease (and may increase) bone density,_ while aromatase inhibitors have been assoaited with decreased bone mineral density.
58
What are wtwo antiandrogenic approaches to prostate cancer? What is an example of each?
**GnRH analogs:** leuprolide **Non-steroidal androgen receptor blockers:** flutamide
59
What is the MOA of leuprolide?
Analog of GnRH. After 2-4 weeks, it desensitizes GnRH signaling, decreasing LH/FSH and decreasing testosterone to castration levels.
60
What is an approved use for Leuprolide? What are common side effects?
**Advanced hormonarlly responsive prostate cancer.** Common side effects: _hot flashes and impotence_
61
What is flutamide and what is it's MOA? What does it treat and what are side effects?
**Non-steroidal antiandrogen that blocks androgen receptors.** Treats metastatic prostate cancer. Side effects: _gynecomastia, diarrhea, and hepatotoxicity_.
62
How common is resistance to anti-neoplastics?
Can come from resting cells (G0) Most tumors will contain a small fraction (~1 in 10^6 cells) that are likely resistant to one drug (and related drugs).
63
Multi-drug resistance (MDR) can cause simultaneous resistance to many drugs, what are examples of classes that this occurs in? What is this mediated by?
* Vinca alkaloids (vincristine and vinblastine) * Antibiotics (doxorubicin, etoposide, and bleomycin) * Taxanes (paclitaxel) **Mediated by ATP-dependent drug efflux pump**
64
What are the basic principles of combination therapy?
* Different cell cycle specificities (cell cycle specific and non-specific) * Active as single agents * Non-overlapping toxicities * Different mechanisms of action
65
What are the six strategies for combination strategy?
1. Sequential blockade 2. Concurrent inhibition 3. Complementary inhibition 4. Rescue 5. Synchronization 6. Recruitment
66
What is sequential blockade? What are two examples?
Simultaneous action of two inhibitors acting on different steps of a linear metabolic pathway. 1. Hydroxyurea + cytarabine 2. Methotrexate + 5-FU
67
What is concurrent inhibition?
Inhibitors block two separate pathways that lead to the same end product.
68
What is complementary inhibition? What is an example?
**One drug affects the function of an end product, the other drug affects the synthesis of that end product.** _Exp: cytarabine + doxorubicin_ - Cytarabine inhibits DNA synthesis - Doxorubicin causes DNA damage
69
What is rescue? What are two examples?
**"rescuing" the patient's normal cells from the treatment.** 1. Leucovorin (folinic acid) to rescue cells after high-dose methotrexate 2. Autologous bone marrow or stem cell transplant
70
What is synchronization? What are two examples?
**Synchronize cells so they are in one phase and then use a drug that is specific for that phase.** Exp. low doses of fluorouracil to block in S phase then high dose cytarabine to kill in S phase. \*attemps to synchronize in vivo have not proven very successful\*
71
What is recruitment? What is an example?
**Bring cells out of G0 and back into the cell cycle.** **Exp:** therapy with cell cycle-nonspecific drugs such as alkylating agents (mechlorethamine) or nitrosoureas (carmustine/BCNU) slowly _recruit non-dividing cells into the cell cycle. Then hit them with cycle-specific drugs._

Found. of Path. Processes - Block 1 (18 decks)

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