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FPP: pre-midterm > Cancer Chemotherapy II > Flashcards

Cancer Chemotherapy II Flashcards

1
Q

What are the main classes of chemotherapy drugs?

A

Alkylating agents, antimetabolites, natural products, miscellaneous agents, and hormones/anti-hormones

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2
Q

What is the MOA of alkylating agents?

A
  • Introduce alklyl groups into DNA, RNA and/or proteins
  • Causes DNA crosslinks, strand breaks, and misreading of code
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3
Q

Give examples of cell-cycle specific and nonspecific alkylating agents

A
  • cycle nonspecific= mechlorethamine, carmustine (BCNU)
  • cycle specific (phase nonspecfici)= cyclophosphamide

**alkylating agents are the LEAST selective of all antineoplastics (tend to kill tumor and normal cells ~equally)

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4
Q

What are some toxic effects of alkylating agents?

A
  • Nausea/vomiting
  • Myelosuppression -> BM toxicity
    • present for mechlorethamine
    • limited for cyclophosphamide
    • delayed for carmustine
  • Hematopoiesis (WBC production) suppression
  • GI effects
  • Alopecia/hair loss (cyclophosphamide)
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5
Q

Define nadir

A

The lowest point (useful in cancer to determine low WBC count and adjust therapy accordingly)

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6
Q

What are the classes of alkylating agents?

A
  • Nitrogen mustards= mechlorethamine, cyclophosphamide
  • Nitrosoureas= carmustine (BCNU)
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7
Q

What is the MOA for mechlorethamine?

A
  • cell cycle nonspecific
  • bifunctional alkylating agent
    • produces DNA crosslinks
    • highly reactive, diappears from blood in sec-min

**used in combo therapy for hodgkin’s and non-hodgkin’s lymphoma

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8
Q

What are characateristics of cyclophosphamide? What is it used for?

A
  • Prodrug activated by liver P450s
  • Poor penetration into CNS
  • Blader toxicity (sterile hemorrhagic cystits) that can be partially prevented with mesna

**Very broad spectrum; most widely used alkylating agent (for lymphoma, leukemia, breast/endometrium, lung cancer, etc)

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9
Q

What are characteristics of carmustine?

A
  • Also called BCNU
  • Cycle nonspecific
  • Crosses the BBB very well (unlike cyclophosphamide)
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10
Q

What are common properties of antimetabolites?

A
  • Structural analogs of compounds required for intermediary metabolism
  • Greatest effectiveness in tumors where cell proliferation is rapid
  • S phase specific
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11
Q

What is the MOA of methotrexate?

A

Binds to dihydrofolate reductase (DHFR) and prevents formation of tetrahydrofolate (needed for purine/pyrmidine synthesis)

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12
Q

What is leucovorin?

A

A fully reduced folate that does not require DHFR… Dose given after high doses of methotrexate (normal cells take up leucovorin better than tumors; save them but still kill cancer)

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13
Q

What are the side effects of methotrexate?

A
  • Intestinal epithelium damage
  • BM suppression
  • Renal tubular necrosis
  • Displaces other drugs from serum albumin
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14
Q

What are the uses for methotrexate?

A
  • Acute lymphocytic leukemia
  • Choriocarcinoma (rare tumor in pregnant women)
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15
Q

What is the MOA for fluorouracil?

A
  • 5-FU; a pyrimidine analog
  • Activated in cells to…
    • FUTP which inhibits RNA synthesis
    • FdUMP which interferes with thymidylate synthase -> ultimately inhibiting DNA synthesis
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16
Q

What are the side effects of 5-FU?

A
  • Nausea, anorexia, diarrhea
  • Myelosuppression
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17
Q

What are the uses for 5-FU?

A

**Broad spectrum of uses

  • Stomach, colon, pancreas, bladder
  • Ovary, breast
  • Head and neck
  • Basal cell carcinoma

(note: not for leukemia)

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18
Q

What is cytarabine (Ara-C)

A
  • pyrimidine (cytidine) analog that competes for phosphorylation of cytidine
  • competes for incorporation into DNA and causes chain termination
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19
Q

What are the side effects of cytarabine? What is it used for?

A
  • Myelosuppression (dose limiting)
  • Neurotoxicity

**used for acute leukemias (e.g. acute myelocytic leukemia)

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20
Q

What is gemcitabine?

A

Similar to cytarabine (also a pyrimidine analog) but also inhibits ribonucleotide reductase

**used in pancreatic cancer

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21
Q

What is the MOA of mercaptopurine?

A
  • Purine analog
  • Converted in cells to ribonucleotide that inhibits RNA and DNA synthesis
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22
Q

What are the side effects and uses of mercaptopurine?

A
  • BM depression
  • Vomiting, nausea, anorexia
  • Jaundice
  • ~10% patients have 1 nonfunctional copy of TPMT (thiopurine methyltransferase) gene and require reduced doses… <1% cannot get drug b/c they have 2 bad copies

**used for acute leukemias

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23
Q

What is the MOA of hydroxyurea?

A
  • Inhibits ribonucleotide reductase
  • Blocks conversion of ribonucleotides to dNTPs, therby preventing DNA synthesis
  • Arrests cells at G1-S interface (useful with radiation; prevents cellular repair)
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24
Q

What are the side effects and uses for hydroxyurea?

A
  • Hematopoietic depression
  • GI disturbances

**used mainly in granulocytic leukemia

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25
Q

What is the MOA of vinca alkaloids? Examples?

A

Bind to tubulin, inhibiting proper formation of microtubules and mitotic spindles

**e.g. Vincristine and Vinblastine (structurally related but different toxicities and antitumor spectrums)

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26
Q

What are the side effects and uses of vinblastine?

A
  • Strongly myelosuppressive (dose limiting)
  • Epithelial ulcerations

**used to treat lymphomas and breast cancer

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27
Q

What are the side effects and uses of vincristine?

A
  • Significantly less BM toxicity than vinblastine
  • Alopecia
  • Neuromuscular abnormalities (e.g. peripheral neuropathy)

**used for lymphomas, acute lymphocytic leukemia, Wilm’s tumor, neuroblastomas, and many others

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28
Q

What is the general MOA for taxanes?

A
  • Enhance assembly and stability of microtubules by binding to beta subunit of tubulin (different binding site than vinca alkaloids)
  • Blocks late in G2 phase (increased radiation sensitivity in G2)
29
Q

What are the side effects and uses for paclitaxel?

A
  • Dose limiting leukopenia
  • Peripheral neuropathy
  • Myalgia/arthralgia

**useful for refractory ovarian cancer and breast cancer

30
Q

What is the MOA of doxorubicin?

A
  • Intercalates in DNA, distorting DNA helix
  • Causes lipid peroxidation and free radical generation
  • Binds to DNA + topoisomerase II -> prevents resealing of DNA strand breaks

**cell cycle specific/phase nonspecific

31
Q

What are the side effects and uses for doxorubicin?

A
  • Cardiomyopathy
  • BM depression
  • Alopecia
  • GI problems

**The most widely prescribed natural product chemotherapy (lymphomas, breast, ovary, small cell lung, and many others)

32
Q

What is the MOA of bleomycin?

A
  • Mixture of iron containing glycopeptides that bind to DNA (not active wihtout chelated Fe)
  • Causes oxidative-like damage to DNA which leads to strand breaks

**phase specific for G2

33
Q

What are the side effects and uses of bleomycin?

A
  • Minimal myelosuppression
  • Pulmonary toxicity (e.g. pneumonitis, fibrosis)
    • Dose related
    • Cumulative and potentially fatal
  • Skin vesiculations, hyperpigmentation

(lung and skin have lowest levels of bleomycin hydrolase)

**used for germ cell tumors of testes/ovaries, head/neck, lung, and lymphomas

34
Q

What is the MOA of etoposide (VP16)?

A
  • Stabilizes DNA topoisomerase II complexes (making them irreversibly bound to the ends of broken DNA)
  • Results in dsDNA breaks that cannot be repaired
  • Blocks in late G2 phase
35
Q

What are the side effects and uses of etoposide?

A
  • Leukopenia (dose limiting)
  • Nausea, vomiting, diarrhea
  • Alopecia

**used for lymphomas, actue leukemia, small cell lung, testis, Kaposi’s sarcoma, and others

36
Q

What are biological response modifiers?

A

Naturally occuring proteins or therapeutic molecules designed to mimic or impact natural proteins (e.g. G-CSF, IFN, interleukins, TNF, TKIs, etc)

**Intended to alter a patient’s own biological response to a tumor or treatment regimen

37
Q

What is filgrastim (G-CSF)?

A

**Granulocyte colony stimulating factor

  • Goal is to limit chemo induced neutropenia
  • Promotes progenitors of neutrophils
  • Expands the absolute population of neutrophils -> quicker recovery from BM suppression
  • SE= bone pain
38
Q

What is imatinib?

A

(Gleevec)

  • CKIT tyrosine kinase inhibitor
  • An example of targeted drug therapy of KIT mutation in GI stromal tumors
39
Q

What is the MOA of trastuzumab?

A

Humanized monoclonal Ab that binds the HER2 receptor (blocking proliferation of cells)

40
Q

What are the side effects and uses of trastuzumab?

A
  • Cardiomyopathy
  • Hypersensitivity
  • Infusion reactions (fever, chills)

**Used for breast cancers that overexpress HER2 (tend to be less responsive to anti-extrogen strategies and to many drugs except for doxorubicin and paclitaxel)

41
Q

What is the MOA of cisplatin?

A
  • Platinum coordination complex
  • Hydrolysis yields activated species which causes DNA crosslinks
  • Cycle specific and phase non-specific
42
Q

What are the side effects and uses of cisplatin?

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

**Wide antitumor spectrum; used for testicular, ovarian, head/neck, bladder, small lung, colon and esophagus cancers + more

43
Q

What is the MOA of procarbazine?

A

Activated in vivo by liver enzymes to a methylating agent which causes chromosomal damage (an atypical alkylating agent, no cross-resistance with other alkylating agents)

44
Q

What are the side effects and uses of procarbazine?

A
  • Myelosuppression
  • Nausea/vomiting

**Used for hodgkin’s lymphoma and several others

45
Q

What tumors are hormone/anti-hormone chemotherapies most effective against?

A

Tumors that are steroid hormone dependent;

  • 33% of all breast cancers respond to hormonal therapy
  • 66% of breast cancers with good estrogen receptor

**presence of both estrogen (ER) and progesterone (PR) receptors in breast tumors increases the probability of response

46
Q

What are the two possible strategies for hormone therapy?

A
  • “Opposite” steroidal compounds
    • e.g. estrogens for prostate cancer
  • Anti-hormonal compounds
    • e.g. antiandrogens for prostate cancer
    • Decrease in growth fraction of responding tumor (hormone dependent)
    • More cells in Go phase

**responses to hormonal therapy can be dramatic and prolonged… some benefitial SEs such as appetite stimulation

47
Q

What is the MOA of prednisone?

A
  • Binds to steroid receptors
  • May arrest cells at G1
  • Depresses expression of many growth related genes
  • Induces nucleases which may modulate cell lysis
48
Q

What are the side effects and uses of prednisone?

A
  • Immunosuppression (at doses and duration generally used, there’s limited myelosuppression)
  • Weight gain, fluid retention
  • Psychologic effects

*Used for lymphomas, leukemia, and breast cancer… good in combination therapy

**Anti-emetic/stimulates appetite and anti-inflammatory

49
Q

What are the antiestrogenic (ER+) classes and examples?

A
  • Estrogen receptor antagonists
    • Tamoxifen (TAM) and Raloxifene
  • Non-steroidal
    • Ietrozole
    • Advantages; oral/rapid onset, estrogen below detectable levels, no androgenic SEs
50
Q

What is the MOA of tamoxifen?

A
  • Activated by CYP2D6 (ultrafast metabolizers have more side effects)
  • Nonsteroidal antiestrogen that competitvely blocks estrogen receptor activity in breast tissue
  • Generally cytostatic (holds cells in Go/G1)
    • Stopping cell growth without necessarily killing the cells
    • Tumor regrows when tamoxifen removed
51
Q

What are the side effects and uses of tamoxifen?

A
  • Nausea
  • Hot flashes (menopause-like symptoms)
  • Fatigue
  • Bone and other musculoskeletal pain
  • May increase rates of uterine/endometrial cancer (Raloxifene reduces risk)

**Used in advanced post-menopausal breast cancer, pre-menopausal metastatic breast cancer (estrogen competes), and breast cancer prophylaxis for women at high risk

52
Q

What is aromatase?

A

P450 that converts androgens to estrogens (the major way of generating estrogen in post-menopausal women)

53
Q

What is the MOA of letrozole?

A

Blocks conversion of androgens to estrogens by inhibiting aromatase (CYP19)

54
Q

What are the side effects and uses of letrozole?

A

(Same as tamoxifen):

  • Hot flashes
  • Nausea
  • Fatigue
  • Bone and other musculoskeletal pain

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

55
Q

What are the two antiandrogenic approaches to prostate cancer?

A
  • GnRH analogs
    • Leuprolide
  • Non-steroidal androgen receptor blockers
    • Flutamide
56
Q

What is the MOA of leuprolide?

A
  • Analog of GnRH
  • After 2-4 weeks, it desenitizes GnRH signaling, decreasing LH/FSH and testosterone to castration levels
57
Q

What are the side effects and uses of leuprolide?

A
  • Hot flashes
  • Impotence

**Used for advanced hormonally responsive prostate cancer

58
Q

What is the MOA of flutamide?

A

Nonsteroidal antiandrogen that blocks androgen receptors

59
Q

What are the side effects and uses of flutamide?

A
  • Gynecomastia
  • Diarrhea
  • Hepatotoxicity (uncommon)

**Used in treatment of metastatic prostate cancer (in combination with GnRH agonist or other 2nd line therapy)

60
Q

Describe how resistance develops to anti-neoplastics. What are the main mechanisms of drug resistance?

A
  • Tumors will contain a small fraction (1 in 1,000,000 cells) that are resistant to a drug and its relatives
  • Selection and overgrowth of these is a major cause of chemotherapeutic failure
  • Resistance from…
    • increased efflux/decreased influx
    • activation of DNA repair/detoxifying systems (P450s)
    • blocked apoptosis
61
Q

Describe MDR

A

Multi-drug resistance can cause simultaneous resistance to many drugs (even those in different classes)

**Mediated by ATP-dependent drug efflux pumps

62
Q

What are the main principles of combination chemotherapy?

A
  • different cell cycle specifications
  • active as single agents
  • non-overlapping toxicities (note: vincristine, prednisone, and bleomycin lack significant BM toxicity)
  • different MOAs
63
Q

What other methods can be used in addition to just different mechanisms of combo therapy?

A
  • sequential blockade
  • concurrent inhibition
  • complementary inhibition
  • rescue
  • synchronization
  • recruitment
64
Q

What is sequential blockade?

A

Simultaneous action of two inhibitors acting on different steps of a linear metabolic pathway (e.g. hydroxyurea and cytarabine)

65
Q

What is concurrent inhibition?

A

Inhibitors block two separate pathways that lead to the same end product (no clear cut examples)

66
Q

What is complementary inhibtion?

A

One drug affects the function of an end prodcut, the other drug affects the synthesis of that end product (or its precursors)

**e.g. cytarabine inhibits DNA synthesis and doxorubicin causes DNA damage

67
Q

What is “rescue”?

A

“Rescue” the patient’s normal cells from the treatment

**e.g. leucovorin to rescue cells after high dose methotrexate, or autologous BM or stem cell transplant

68
Q

What is synchronization?

A

Synchronize cells so they are in one phase and then use a drug that’s specific for that phase

*e.g. low dose fluorouracil to block in S phase, high dose cytarabine to kill in S phase

**attempts to synchronize in vivo have not proven very successful

69
Q

What is recruitment?

A

Bring cells out of Go and back into cell cycle (mobilizing slowly proliferating or non-proliferating cells)

*combine with cell cycle non-specific drugs (mechlorethamine or carmustine/BCNU)

**aka bring non-dividing cells into cycle and then hit them with cycle specific drugs

FPP: pre-midterm (19 decks)

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