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Block 3 - Fundamentals and Heme > Anticancer Drugs > Flashcards

Anticancer Drugs Flashcards

0
Q

What are three confounding factors making chemotherapy more difficult?

A

Tumor doesn’t idle between doses - it seeks to repopulate, But patient needs time to recover
Tumor not homogenous - cells on surface grow faster, must penetrate
Tumors develop resistance over time - multiple drug resistant pump exports variety of drugs

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1
Q

What does it mean that cell kill with chemotherapy is first order?

A

Fixed percentage of cells can be killed with cancer drug per dose
Also called logarithmic kill

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2
Q

What are anti metabolites? What is their major use?

A

Analogs of purines or pyrimidines or corresponding nucleosides
Many are pro drugs
Inhibit DNA polymerase or cause chain termination
Some inhibit synthesis of bases or nucleosides directly
Major use is leukemia and lymphomas

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3
Q

Fluorouracil (5FU) - mechanism of action

A

Activated to 5-FdUMP which mimics dUMP, the substrate for thymidylate synthase, which synthesizes thymidine nucleotides
Thymidine levels drop and cells in s phase killed
Nucleotides derived can also incorporate into DNA or RNA

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4
Q

Fluorouracil - adverse effects

A

Bone marrow depression

Oral and GI ulcers

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5
Q

Fluorouracil - therapeutic uses

A

Pancreatic cancer and other adenomas

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6
Q

Cytarabine - mechanism of action

A

Cytosine analog
Converted to triphosphate, incorporates into DNA, and inhibits chain elongation
Cells exposed in s phase die - block between g1 and s

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7
Q

Cytarabine - therapeutic uses

A

Single most important agent for AML

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8
Q

Methotrexate - mechanism of action

A

Analog of folic acid
Binds to mammalian DHFR and inhibits it - depletes building blocks for DNA and RNA synthesis and buildup of toxic product
Cells in s phase most sensitive

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9
Q

Methotrexate with leucovorin

A

Normal cells exposed to high dose methotrexate can be rescued by leucovorin if given within 36 hrs - a folate coenzyme

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10
Q

Methotrexate - adverse effects

A

Myelosuppression and GI ulceration

*Pneumonitis

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11
Q

Methotrexate - therapeutic uses

A

Leukemias
Choriocarcinoma and other neoplasms
Anti inflammatory

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12
Q

Methotrexate - resistance

A

Caused by amplification of DHFR gene

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13
Q

DNA alkylating agents - mechanism of action

A

Contain chemical groups that can cyclize to generate positively charged reactive intermediates that can be attacked by lone pair of electrons on nitrogen or oxygen
Result is alkylation of DNA and cross linking of strands
Toxic - don’t discriminate between cancer and normal cells
Phase nonspecific but cells don’t die until they enter s phase

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14
Q

Cyclophosphamide

A

Alkylating agent - nitrogen mustard
Oral and inactive until pass through liver and activated by p450 oxidase - easier to administer and less toxic
*Can irritate bladder causing hemorrhagic cystitis - avoid dehydration

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15
Q

Alkylating agents - adverse effects

A

Bone marrow suppression

GI ulcers

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16
Q

Alkylating agents - therapeutic uses

A

Leukemias and solid tumors

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17
Q

Cisplatin - mechanism of action

A

Platinum complex alkylating agents
Bifunctional - react with guanines on same or different DNA strands
Water replaces chlorides creating carbonium ions that are attacked by N7 of guanine bases

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18
Q

Cisplatin - adverse effects

A

Ototoxicity and peripheral neuropathy
*Renal toxicity if dehydrated
Nausea and vomiting
Myelosuppressive

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19
Q

Cisplatin - therapeutic uses

A

Solid tumors - particularly testicular and ovarian

20
Q

Mechlorethamine

A

Nitrogen mustard alkylating agent

21
Q

Anthracyclines - mechanism of action

A

Antibiotics produces by a fungus
Tetracycline ring that can intercalate into DNA
Can be reduced within cells generating semiquinones that autoxidize and generate reactive oxygen radicals
Cause DNA strand breaks by radical damage or interfering with topoisomerase type II

22
Q

Anthracyclines (doxorubicin) - adverse effects

A

*Unique cardiomyopathy - usually irreversible, happens with cumulative overdose
Dose dependent

23
Q

Doxorubicin

A

Anthracycline

Major use in carcinomas of breast, ovary, uterus, testicle, and lung, and for many sarcomas

24
Q

Bleomycin - mechanism of action

A

Chelates iron and copper and binds to DNA
Leads to toxic radicals that cause strand breaks and chromosomal aberrations
Concentrates in late s and g2 - g2 specific agent

25
Q

Bleomycin - adverse effects

A

Not toxic to bone marrow
*Pulmonary fibrosis
Various skin conditions inc hyper pigmentation and ulcers

26
Q

Bleomycin - therapeutic uses

A

Effective against germ cell tumors of testes and ovary and for squamous cell carcinomas

27
Q

Irinotecan - mechanism of action

A

A camptothecin
Bind and inhibit topoisomerase I
Results in first single stranded DNA breaks then double strand during s phase when DNA polymerase collides with drug enzyme complex
S phase specific
Metabolized to SN-38 - elim by glucoronidation by UGT1A1

28
Q

Irinotecan - side effects

A

Nausea
Leukopenia
Patients with less active UGT1A1 more susceptible

29
Q

Irinotecan - uses

A

Several solid tumors, particularly ovarian, lung, breast, and colorectal cancer

30
Q

Etoposide

A

Epipodophyllotoxin
Bind and inhibits topoisomerase II leading to DNA breaks
Useful against leukemias and lymphomas

31
Q

Vinca alkaloids (vincristine, vinblastine)

A

Bind tubulin alpha beta dimers and prevent formation of MTs
M phase specific
Myelosuppressive and neurotoxic
*peripheral neuropathy

32
Q

Where is vincristine used vs. vinblastine?

A

Vincristine - childhood leukemias and lymphomas

Vinblastine - testicular cancer and other solid tumors

33
Q

Paclitaxel

A

A taxane
Bind to existing MTs and inhibits disassembly which inhibits mitosis
Effective for breast and ovarian cancers

34
Q

Prednisone

A

Glucocorticoid
Great for leukemias
Better response in children
Resistance quickly unless other drugs used together

35
Q

Tamoxifen

A

Selective estrogen receptor modulator - binds competitively
Treatment of breast cancer - only tumors with this receptor respond
Prophylactic treatment in women at high risk
Better response in post menopausal women w/ lower estrogen
Hot flashes often accompany first use

36
Q

Anastrozole

A

Nonsteroidal reversible inhibitor of aromatase
Aromatase catalyzes conversion to estrogen in peripheral tissues in post menopausal women
Useful for estrogen sensitive breast tumors

37
Q

Flutamide

A

Anti androgen
Treatment for prostate cancer
Combo with GnRH agonist to cause chemical castration

38
Q

Leuprolide

A

GnRH agonist
Cause transient release of FSH and LH followed by feedback inhibition to cease testosterone production
Treatment of prostate cancer
Combo with flutamide to block effect of initial FSH/LH surge

39
Q

Bevacizumab

A

Monoclonal antibody that binds to and inhibits VEGF
Colorectal, breast, and lung cancer (but not breast anymore)
Side effects are increased bleeding and slow wound healing

40
Q

What type of cancer has interleukin-2 been approved for?

A

Malignant metastatic melanoma

Appears active for other tumors and leukemias

41
Q

Bortezomib

A

Inhibits proteosome

I-kappaB degradation allows NF-kappaB to migrate to nucleus and activate genes but this degradation doesn’t happen now

42
Q

Tretinoin (ATRA)

A

Binds to RAR and displaces transcription inhibitor to promote differentiation
Treats APL
ATRA syndrome - pulmonary infiltration causing inflammation and *respiratory distress, can be prevented by adding glucocorticoids

43
Q

Thalidomide

A

Role in inhibiting angiogenesis and stimulating immune system
Imp in treatment of multiple myeloma
Blocking of TNF and VEGF pathways and prevents production of il-6 which normally promotes adhesion of tumor cells to bone marrow stroma

44
Q

How are colony stimulating factors used in the treatment of cancer?

A

Increase number of normal blood cells

Epo, granulocytes colony stimulating factor and granulocytes-macrophage colony stimulating factor all available

45
Q

What is one combination of drugs given commonly but limited in dose due to overlapping toxicities?

A

Cyclophosphamide and doxorubicin

46
Q

What is the primary treatment for brain metastases and why?

A

Radiation

Most chemotherapy doesn’t cross BBB

47
Q

What is dose dense treatment?

A

Admin of same doses and number of cycles of chemotherapy but over shorter time
Combine with growth factor support to maintain blood counts at acceptable range

48
Q

What is one drug that is synergistic with irinotecan?

A

5-fluorouracil

Block 3 - Fundamentals and Heme (8 decks)

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