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FPP Weeks 1 & 2 > Anti-Neoplastics Pt. 2 > Flashcards

Anti-Neoplastics Pt. 2 Flashcards

1
Q

What are the different classifications of Anti-Neoplastics (Based on mechanism of action)?

A
  • Alkylating agents
  • Antimetabolites
  • Natural Products
  • Miscellaneous agents
  • Hormones and hormone antagonists
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2
Q

What mechanism do Alkylating agents use and what is the outcome of this interaction?

A

Alkylating agents introduce alkyl groups into DNA causing DNA crosslinks, strand breaks, and misreading of code

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3
Q

Describe cell-cycle specificity in terms of alkylating agents

A

Alkylating agents can be either

  • Cell-cycle-nonspecific
    • Affect all parts of cell cycle including G0
    • mechlorethamine, carmustine
  • Cycle-specific phase nonspecific
    • Don’t include G0
    • cyclophosphamide
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4
Q

Describe the 3 major side effects of alkylating agents

A
  1. Hematopoiesis suppression - Often used as an indicator of therapeutic effectiveness and normal cell recovery - bleeding and infection
  2. GI effects - damage to intestinal mucosa; nasuea/vomiting
  3. Alopecia (hair loss)
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5
Q

Nausea, Myelosuppression and Alopecia for

  • Mechlorethamine:
  • Cyclophosphamide:
  • Carmustine:
A
  • Mechlorethamine: Nausea, Myelosuppression and mild alopecia
  • Cyclophosphamide: Nausea, limited Myelosuppression and alopecia
  • Carmustine: nasuea, delayed myelosuppression and no alopecia
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6
Q

What is the meaning of a nadir in antineoplastics? Which drug reaches its nadir fastest?

A

The lowest or deepest point (lowest count of WBC after medication)

Cyclophosphamide reaches it’s nadir in 10 days

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7
Q

What are the classes of alkylating agents

A
  • Nitrogen mustards (Mechlorethamine; Cyclophosphamide)
  • Nitrosoureas (Carmustine)
  • Alkyl Sulfonates
  • Ethylenimines/Methyl-melamines
  • Triazenes
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8
Q

Why is mechlorethamine considered a bifunctional alkylating agent?

A
  1. It produces DNA cross-links
  2. Highly reactive, disappears from blood in seconds to minutes (does not enter CNS)
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9
Q

Mechlorethamine is used in combination therapy for…

A

Hodgkin’s and non-Hodgkin’s lymphoma

Breast, lung, and ovarian cancer

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10
Q

What is the mechanism of action of cyclophosphamide?

A

Prodrug activated by liver cytochrome P450s

The phosphoramide mustard acts as an alkylating agent

Acrolein is a toxic decomposition product that causes sterile hemoorhagic cystitis

Cyclophophamide has a broad spectrum of activity - used against a wide variety of cancers

Most commonly used Alkylating Agent

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11
Q

How can you prevent the bladder toxicity associated with acreolein

A

Mesna

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12
Q

What are the properties of nutrosoureas? (Carmustine)

A
  • Cycle nonspecific
  • Cross the blood brain barrier very well (brain neoplasms)
  • Treatment of brain tumors, multiple myeloma, melanoma
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13
Q

What are common properties among antimetabolites?

A
  • Structural analogs of compounds required for intermediary metabolism
    • Most effect in rapidly proliferating tumors
  • S phase specific
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14
Q

What is the mechanism of action for methotrexate?

A

Binds to dihydrofolate reductase and prevents formation of tetrahydrofolate

Cancer cells polymerize MTX to MTX-polyglutamate more than normal cells (MTX-polyG is a more potent inhibitor of DHFR)

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15
Q

High doses of methotrexate are necessary to bind all DHFR - how do you rescue the host cells from damage?

A

Leucovorin = folinic acid, a fully reduced folate that does not require reduction by DHFR

Normal cells have increased capacity to bring in leucovorin relative to tumor cells

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16
Q

What are the side effects of methotrexate?

A
  • Intestinal epithelium damage
  • Bone marrow suppression
  • Renal tubular necrosis (keep urine alkaline to limit this)
  • Displaces other drugs from serum albumin
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17
Q

Indications for Methotrexate

A

Choriocarcinoma (NUMBER ONE TREATMENT)

Acute lymphocytic leukemia

Osteosarcoma

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18
Q

Mechanism of action of Fluorouracil (5-FU)

A

Pyrimidine analog that is activated in cells to FUTP which inhibits RNA synthesis and to FdUMP which interfferes with thymidylate synthase and ultimately DNA synthesis

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19
Q

Fluorouracil - Side Effects

A

Nausea, anorexia, diarrhea

Myelosuppression

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20
Q

Fluorouracil Uses

A

Broad spectrum of uses

  • Stomach, colon, pancrease, breast, ovary cancer (mostly GI)
  • Basal cell carcinoma
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21
Q

What is Cytarabine (Ara-C) and what is its mechanism?

A

Cytarabine is a pyrimidine analog that competes for phophorylation of cytidine - Competes for incorporationinto DNA and causes chain termination

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22
Q

Cytarabine

Side effects:

Administration and clearance:

A

Side effects: Marked myelosuppression (dose limiting) and neurotoxicity

Administration:

  • Long continuous infusion (2x daily for 5 days)
  • Increases probablilty of killing tumor cells not initially in S phase
  • Very rapid metabolism - clears quickly
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23
Q

Use of Cytarabine?

A

Acute leukemias - Acute myelocytic leukemia (super effective)

Lymphomas

Head and neck cancer

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24
Q

Uses of…

Gemicitabine:

Cepecitabine:

A

Gemicitabine: Lung, Pancreatic, breast cancer

Cepecitabine: Breast, colon cancer

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25
Q

Mercaptopurine

Mechanism:

Side Effects:

Uses:

A

Mechanism: Purine analog - converted in cells to ribonucleotide that inhibits RNA and DNA synthesis

Side Effects: Bone marrow depression; vominiting, nausea, anorexia, Jaundice

Uses: Acute leukemias

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26
Q

When can administration of mercaptopurine be toxic

A

If patient has two copies of non functional TPMT (thiopurine methyltransferase), drug may reach toxic levels

10% of patients ahve 1 copy of nonfunctional TPMT and require reduced doses to prevent toxicity

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27
Q

Hydroxyurea - mechanism of action

A
  • Inhibits ribonucleotide reductase
    • Blocks conversion of ribonucleotides to dNTPs - prevents DNA synthesis
  • Arrests cells at G1 - S interface - useful in conjunction with radiation
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28
Q

Hydroxyurea

Major uses:

Side Effects:

A

Major uses: Graulocytic leukemia

Side Effects: Hematopoietic depression, GI disturbances

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29
Q

Natural products (neoplastic drugs)

A
  • Vinca alkaloids
  • Taxanes
  • Enzymes
  • Epipodophyllotoxins
  • Topoisomerase inhibitors
  • Monoclonal antibodies
  • Antibiotics
  • Anti-angiogenic peptides/Biological response modifiers
  • Vitamin A analogs
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30
Q

Vinca alkaloids

Mechanism:

Examples:

A

Mechanism: Binds to tubulin, inhibiting proper formation of microtubules and mitotic spindle

Example: Vincristine vs. vinblastine

  • Different toxicities
  • Different antitumor spectrum
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31
Q

Differences in side effects and treatments of Vinblastine vs. Vincristine

A
  • Vinblastine
    • Strongly myelosuppressive
    • Epithelial ulcerations
    • Treatment: Lymphomas/ Breast cancer
  • Vincristine
    • Significantly less bone marrow toxicity
    • Alopecia
    • Neuromuscular abnormalities
    • Treatment: ALL, lymphomas, WIlm’s tumor, neuroblastoma
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32
Q

Taxanes (Paclitaxel)

Mechanism:

A

Enhances assembly and stability of microtubules by binding to β-subunit of tubulin (differnt binding site than vinca alkaloids)

Blocks late in G2 phase - this phase is more sensitive to radiation

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33
Q

What is the difference between Paclitaxel and Vinca alkaloids as far as actions on microtubules?

A

Polymerization is blocked by vincristine or vinblastine and stabilized by paclitaxel (prevent disassembly)

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34
Q

_______ + _______ has become the standard therapy for ovarian cancer

A

Paclitaxel + cisplatin

35
Q

How does paclitaxel assist cisplatin or cyclophosphamide?

Side effects?

A

Paclitaxel can interfere with DNA repair, intensifying the effects of DNA damage by cisplatin or cyclophosphamide

  • Side effects
    • Dose limiting leukopenia
    • Peripheral neuropathy
    • Myalgia/arthralgia
36
Q

Doxorubicin Characteristics

A
  • Cycle-specific phase non-specific
  • Among the most active of antitumore agents
  • Wide spectrum of activity - Lymphomas, breast, ovary, small cell lung
37
Q

What is one of the few drugs with some anti-angiogenic properties

A

Doxorubicin

38
Q

Doxorubicin - mechanism (multi-faceted)

A
  1. Intercalates in DNA, distorting DNA helix
  2. Causes lipid peroxidation and free radical generation
  3. Binds to DNA + topoisomerase II - prevents resealing of DNA strand breaks
39
Q

Doxorubicin side effects

A

Cardiomyopathy

Bone Marrow depression

Alopecia

GI problems

40
Q

Bleomycin - Mechanism

A
  • Mixture of iron-containing glycopeptides that bind to DNA
  • Cause oxidative-like damage to DNA which leads to DNA strand breaks - only active with chelated Fe
    • Both single and double stranded breaks
41
Q

Bleomycin is phase-specific for _________

Active against:

A

Bleomycin is phase-specific for G2 (and M phases)

Active against: Germ cell tumors of testes and ovaries

  • Head, neck, lung, lymphomas
42
Q

Bleomycin side effects

A
  • Minimal myelosuppression
  • Pulmonary toxicity
  • Skin vesiculation, hyperpigmentation
  • Lung and skin have lowest levels of bleomycin hydrolase which inactivated bleomycin
43
Q

Etopside (mandrake plant) mechanism:

A

Irreversibly stabilizes DNA topoisomerase II complexes

Results in dsDNA breaks that cannot be repaired

Blocks in late G2 phase (G2/M interface)

44
Q

Etopside uses:

Side effects:

A

Etopside uses: Lymphomas, acute leukemia, small cell lung, testis, kaposi’s sarcoma

Side effects: Leukopenia, nausea, vomiting, diarrhea, alopecia

45
Q

What are biological response modifiers (BRM)?

A

Naturally occuring proteins or therapeutic molecules designed to mimic or impact antural proteins

Many effects on cell cycle, oncogene expression

46
Q

BRMs

Beneficial intent:

Limitations:

A
  • Beneficial intent:
    • Alter patient’s own biological response to a tumor or to treatment regimens
    • Intent is to add potential benefit but less possibility for serious toxicity
  • Limitations:
    • Response can be variable
    • Some have limited spectrum of action
47
Q

What is the purpose of Filgrastim (G-CSF)?

A

It is a granulocyte colony stimulating factor meant to limit chemotherapy induced neutropenia

Promotes progenitors of neutrophils (expands population) and provides for quicker recovery from bone marrow suppression

48
Q

Main side effect of filgastim?

A

Bone pain (33%)

49
Q

Trastuzumab

Mechanism:

Use:

Side Effects:

A

Mechanism: Humanized monoclonal antibody that binds to HER2 receptor - blocks proliferation of cells

Use: Metastatic breast cancers that overexpress HER2

  • Tend to be less responsive to anti-estrogen strategies and to many drugs except for anthracyclines and paclitaxel

Side Effects: Cardiomyopathy; hypersensitivity; infusion rxns

50
Q

Cisplatin Mechanism:

A

Platinum coordination complex - hydrolysis yields activated species which causes DNA crosslinks

Also covalently binds and inhibits thioredoxin reductase - directly promotes apoptosis

51
Q

Cisplatin

Specificity:

Use/Spectrum:

A
  • Specificity: Cycle-specific phase-nonspecific
  • Use/Spectrum: Wide antitumor spectrum
    • Testicular cancer
    • Ovarian cancer (with paclitaxel)
    • Head, neck, bladder…
52
Q

Cisplatin Side Effects

A
  • Nephrotoxicity
  • Ototoxicity
  • Peripheral neuropathy
  • Electrolyte disturbances
  • Nausea, vomiting
  • Myelosuppression
53
Q

Cisplatin vs. carboplatin and oxaliplatin

_______ and _______ have narrower spectrum of action

______ is the best of the platinum agents at coorectal cancer

A

Carboplatin and oxaliplatin have narrower spectrum of action

Oxaliplatin is the best of the platinum agents at coorectal cancer

54
Q

Procarbazine Mechanism:

A

Activated in vivo by liver to a methylating agent which causes chromosomal damage - atypical alkylating agent with not cross-resistance with other alkylating agents

55
Q

Procarbazine Uses:

Side effects:

A

Procarbazine Uses: Hodgkin’s lymphoma (greatest effects in G1 and S phase)

Side effects: Myelosuppression, nausea, vomiting

56
Q

Hormones and hormone antagonists in cancer therapy

A
  • Useful against tumors that are steroid hormone dependent
  • 33% of all breast cancers respond to hormonal therapy
  • 66% of breast cancers with good estrogen receptor content respond to hormonal therapy
57
Q

Possible strategies for hormone therapy (2)

Consequence?

A
  1. Opposite steroidal compounds - normal hormones promote tumor growth to administer “opposite” hormones
  2. Anti-hormonal compounds - block hormones

Consequence: decrease in growth fraction of responding tumor (more in G0 phase)

58
Q

Prednisone mechanism of action

A

Binds to steroid receptors which act to modulate aspects of cell growth

  • May arrest cells at G1
  • Depress expression of many growth related genes
  • Induce nucleases which may modulate cell lysis
59
Q

Prednisone palliative effects

A
  • Anti-emetic, stimulates appetite
  • Anti-inflammatory
60
Q

Potential complication of Prednisone:

Possible side effects:

A

Potential complication is immunosuppresion

May cause weight gain, fluid retention, and psychologic effects

61
Q

Antiestrogenics

Estrogen receptor antagonists:

Aromatase inhibitors:

A

Estrogen receptor antagonists: Tamoxifen; Raloxifene

Aromatase inhibitors: Letrozole (non-steroidal)

62
Q

Tamoxifen mechanism

A

Nonsteroidal antiestrogen that competitively blocks estrogen receptors in breast tissue - may prevent post menopausal osteoporosis

63
Q

Downsides of Tamoxifen

A
  • Generally cytostatic
  • Tumor regrows when tamoxifen is removed
  • Stops cell growth withot necessarily killing the cells
64
Q

Tamoxifen uses:

A

Advanced post-menopausal breast cancer

Pre-menopausal metastatic breast cancer

Breast caner prophylaxis for women at high risk

65
Q

Tamoxifen is activated by _______

A

CYP2D6

66
Q

Tamoxifen side effects:

A
  • Nausea
  • Fatigue
  • Hot flashes (menopause like symptoms)
  • Bone and other musculoskeletal pain
67
Q

The major way of generating estrogen in post-menopausal women is….

A

Aromatase

68
Q

Letrozole - mechanism

A

Blocks conversion of androgens to estrogens by inhibiting aromatase - prevents stimulation of growth of ER+ cells

69
Q

Aromatase inhibitors bind irreversibly to the heme of _____ (aromatase) which inhibits conversion of androgens to estrogens

A

CYP19

70
Q

Uses of Letrozole

A

1st line treatment of post-menopausal locally advanced or metastatic breast cancer

71
Q

Side effects of Letrozole AND tamoxifen

A

Hot flashes

Nausea

fatigue

bone and other musculoskeletal pain

72
Q

Tamoxifen does not decrease ______ _______ whereas aromatase inhibitors have been associated with decreased ______ _______ (same word)

A

bone density

73
Q

Antiandrogenic approaces to prostate cancer:

GnRH analogs:

Non-steroidal androgen receptor blockers:

A

GnRH analogs: Leuprolide

Non-steroidal androgen receptor blockers: flutamide

74
Q

Leuprolide - mechanism of action

A
  • Analog of GnRH
  • Initially stimualtes LH and FSH release causing testosterone surge and disease flare
  • After 2-4 weeks, it desensitizes GnRH signaling, decreasing LH/FSH and testosterone to castration levels
75
Q

Leuprolide - approved use

Side effects:

A

Advanced hormonally responsive prostate cancer - Most common 1st line drug therapy

Side Effects: Hot flashes; impotence

76
Q

Flutamide

Mechanism:

Treatment:

Side Effects:

A

Mechanism: nonsteroidal antiandrogen that blocks androgen receptors

Treatment: metastatic prostate cancer

Side Effects: gynecomastia, diarrhea, hepatotoxicity

77
Q

What is a major cause of chemotherapeutic failure?

A

Selection and overgrowth - most tumors will contain a small fraction of cells that are likely resistant to one drug

78
Q

_______ _________ is a key strategy in overcoming resistance

A

combination therapy

79
Q

Multi-Drug resistance (MDR) - how is it mediated?

What drugs is MDR especially prominent for?

A

Mediated by ATP-dependent drug efflux pumps

Especially prominent for:

  1. Vincristine; vinblastine
  2. Doxorubicin, bleomycin
  3. Etopside
  4. Paclitaxel
80
Q

Principles of combination chemotherapy

A
  • Different cell cycle specificities
  • Active as single agents
  • Non-overlapping toxicities
  • DIfferent mechanisms of action
81
Q

Strategies to delivery of combination chemotherapy:

Sequential blockade

Concurrent inhibition

Complementary inhibition

Rescue

Synchronization

Recruitment

A
  • Sequential blockade
    • simultaneous action of two inhibitors acting on different steps of linear pathway
  • Concurrent inhibition
    • Inhibitors block two separate pathways leading to same product
  • Complementary inhibition
    • One drug affects function of an end product and other affects synthesis of that product
  • Rescue
    • Rescue the patients normal cells from treatment
  • Synchronization
    • Push cells into one phase and then use drug specific for that phase
  • Recruitment
    • Bring cells out of G0 and back into cell cycle
82
Q

(DO NOT HAVE TO MEMORIZED) - Examples of

Sequential blockade

Concurrent inhibition

Complementary inhibition

Rescue

Synchronization

Recruitment

A

Sequential blockade: Hydroxyurea + cytarabine

Concurrent inhibition: no clear cut examples

Complementary inhibition: cytarabine inhibits DNA synth; Doxorubicin causes DNA damage

Rescue: Leucovorin to rescue cells after methotrexate exposure

Synchronization: Low dose fluorouracil to block in S phase; high dose cytarabine to kill in S phase

Recruitment: alkylating agents (mechlorethamine) or nitrosureas (carmustine) then hit with cycle-specific drugs

83
Q
A

FPP Weeks 1 & 2 (18 decks)

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