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FPP Block 1 > Cancer Chemotherapy II > Flashcards

Cancer Chemotherapy II Flashcards

1
Q

What are the different classes of chemotherapy based on mechanism of action? and examples

A
  1. alykylating agents
    1. nitrogen mustards, alkyl sulfonates, nitrosoures, triazenes
  2. antimetabolites
  3. natural products
  4. miscellaneous agent
  5. hormones and hormone antagonists
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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
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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

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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

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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
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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
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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

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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
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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
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10
Q

Methotrexate

A
  • binds to dihydrofolate reductase (DHFR) and prevents formation of tetrahydrofolate which is necessary for purine and pyrimidine synthesis
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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
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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
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13
Q

WHen is methotrexate indicated?

A

Actue lymphocytic leukemia

Choriocarcinoma

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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

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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

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16
Q

Gemcitabine

*

A
  • similarcytarbine, but also inhibits ribonucleotide reductase
  • pancreatic CA
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17
Q

other than cytarabine there is another pyrimidine analog. what is it?

A

Gemcitabine

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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
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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
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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

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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
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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
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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
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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
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25
Q

how does taxane work? and a use

A

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
Q

what is the difference in effect on microtubules of vincristine vs taxol

A

vincristine binds individual microtubule peices and taxol binds built microtubules and stops growth

27
Q

when do we use paclitaxel? and side effects?

A
  • 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
Q

What type of drug is Doxorubicin and describe its activity?

A
  • 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

**one of few drugs with some anti-angiogenic properties

29
Q

what is the mechanism of action of Doxorubicin

A
  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
Q

What are the side effects of Doxorubicin?

A
  • cardiomyopathy (ROS)
  • bone barrow depression
  • alopecia
  • GI problems
31
Q

What is the mechanism for Bleomycin? WHat type of cancer is it used for?

A
  • 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
Q

what are the side effects of bleomycin?

A
  • 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
Q

What is the mechanism of action of Etoposide? WHat are the uses? side effects?

A
  • 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
Q

WHat are biological response modifiers and how do they work?

A

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
Q

What is Filgrastim and how does it worK? side effects?

A

(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
Q

What is the mechanism of Trastuzumab (Herceptin)

A
  • humanized monoclonal antibody that binds to HER2 receptor
    • block proliferation of cells and may illicit response against HER2+ cells
37
Q

What is the use of Trastuzumab?

A
  • 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
Q

What are the side effects of Trastuzumab?

A

cardiomyopathy

hypersensitivity: including anaphylaxis

infusion reactions

39
Q

What is the mechanism, use and side effects of Trastuzumab

A
  • mechanism: monoclonal antibody that binds HER2 receptor
  • use: breast cancers that overexpress HER2
  • side effects: cardiomyopathy, hypersensitivity, infusion reactions
40
Q

WHat is the MOA of cisplatin? use?

A
  • 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
Q

side effects of cisplatin?

A

nephrotoxicity

ototoxiticy

peripher neuropathy

electrolyte disturbances

nausea vomiting, (100%)

myelosuppresion

42
Q

WHat is the mechanism of Procarbazine? use? SEs?

A
  • 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
Q

How are hormones and hormone antagonists used in cancer treatment?

A

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
Q

presence of ______________ in breast tumors increases the probability of a response to hormone therapy

A

estrogen and progesterone receptors (ER and PR)

45
Q

what are 2 possible strategies of hormonal therapy for cancer treatment and what what some consequences

A
  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
Q

what is the beneficial side effects of other hormonal therapies

A

adrenocorticoids as antiemetics/reduce nausea, vomiting

androgens as anabolic aganets

progestins as appetite stimulant

47
Q

How is prednisone used to treat cancer?

A
  • 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
Q

what are some side effects for prednisone?

A
  • 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
Q

WHat are the 3 types of antiestrogenic (ER+) chemo drugs?

A
  1. estrogen receptor antagonists
  2. aromatase inhibitors
  3. non-steroidal
50
Q

what are the 2 estrogen receptor antagonists?

WHat is the non-steroidal?

A
  • estrogen receptor antagonists:
    • Tamoxifen
    • Raloxifene
  • Non-steroidal
    • letrozole
51
Q

WHat kind of drug is tamoxifen? How does it work?

A
  • 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
Q

what are the uses of tamoxifen?

A
  • 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
Q

What are the possible side effects for Tamoxifen?

A
  • 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
Q

What is the mechanism fo action of Letrozole? what are the uses?

A
  • 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
Q

What is the difference in side effects between Letrozole and Tamoxifen?

A

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
Q

What is the mechanism of Leuprolide? use? side effects?

A

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
Q

mechanism of Flutamide? use? side effects?

A

nonsteroidal antiandrogen that block androgen receptors

use: treatment of metastatic prostate cancer

side effects: gynecomastia, diarrhea, hepatotoxicity

58
Q

Why is selection and overgrowth a major cause of chemotherapeutic failure?

A

most tumors will contain a small fraction of cell that are likely resistant to one drug (and related drugs)

59
Q

How is multidrug resisatcne related to cancer treatment? (MDR)

how is resistance often mediated

A
  • 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
Q

what are the principles to combination chemotherapy?

A
  • different cell cycle specificities
  • active as single agents
  • non-overlapping toxicities
  • different mechanisms of action
61
Q

What are 6 mechanisms to preventing resistance?

A
  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)
62
Q
A

FPP Block 1 (18 decks)

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