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BLOCK 2 FINAL > Cancer Chemotherapy > Flashcards

Cancer Chemotherapy Flashcards

1
Q

What are cell cycle non-specific (CCNS) drugs?

A

anticancer agent that acts on tumor cells when they are traversing the cell cycle and when they are in the resting G0 phase

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2
Q

What are cell cycle-specific (CCS) drugs?

A

anticancer agent that acts selectively on tumor stem cells when they are traversing the cell cycle and not when they are in the resting G0 phase

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3
Q

What is the growth fraction?

A

proportion of cells in a tumor population that are actively dividing

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4
Q

What is the log-kill hypothesis?

A

concept used in cancer chemotherapy to mean that anticancer drugs kill a fixed proportion of tumor cell population, not a fixed number of tumor cells (e.g. a 1-log-kill will decrease a tumor cell population by one order of magnitude)

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5
Q

What is a myelosuppresssant?

A

Drug that suppresses the formation of mature blood cells such as erythrocytes, leukocytes, and platelets. This effect is also known as “bone marrow suppression”

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6
Q

What is an oncogene?

A

Mutant form of a normal gene that is found in naturally occurring tumors and which, when expressed in noncancerous cells, causes them to behave like cancer cells

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7
Q

What is rescue therapy?

A

Administration of endogenous metabolites to counteract the effects of anticancer drugs on normal (nonneoplastic cells)

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8
Q

What does the term vesicant mean?

A

Drug that causes blisters on contact with tissues. Such drugs can be particularly damaging to veins if administered in high concentrations into small vessels (e.g. alyklating agent mechlorethamine)

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9
Q

When are CCS drugs most active and effective?

A

usually most active in a specific phase of the cell cycle and are particularly effective when a large proportion of the tumor cells are proliferating (i.e. high growth fraction)

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10
Q

Cytotoxic drugs obey what order of kinetics?

A

FIRST ORDER

given dose kills a constant proportion of a cell population rather than a constant number of cells

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11
Q

What are the possible mechanisms of resistance to anticancer drugs?

A

INCREASED DNA REPAIR (alkylating agents and cisplatin)
FORMATION OF TRAPPING AGENTS (bleomycin, cisplatin, anthracyclines)
CHANGES IN TARGET ENZYME (methotrexate)
DECREASED ACTIVATION OF PRODRUG (purine and pyrimidine antimetabolites)
INACTIVATION OF ANTICANCER DRUGS (purine and pyrimidine antimetabolites)
DECREASED DRUG ACCUMULATION (multidrug resistance; increased expression of normal gene -MDR1 gene-for cell surface P-glycoprotein)

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12
Q

Name the Alkylating Agents

A

NITROGEN MUSTARDS (chlorambucil, cyclophosphamide, mechlorethamine)

NITROSOUREAS (carmustine, lomustine)

ALKYLSULFONATES (busulfan)

Cisplatin, Dacarbazine, Procarbazine

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13
Q

Discuss the basic MOA and mechsim for resistance to Alkylating Agents

A

CCNS drugs!!!

Form reactive molecular species that alkylate nucleophilic groups on DNA bases, particularly the N-7 position of guanine. This leads to cross-linking of bases, abnormal base pairing, and DNA strand breakage

Tumor cell resistance to these drugs occurs through increased DNA repair, decreased drug permeability, and production of trapping agents such as thiols

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14
Q

Cyclophosphamide

A

M: covalently X-link (interstrand) DNA at guanine N-7. Require bioactivation by liver (CYP450 mediated transformation). one of the breakdown products is acrolein

U: solid tumors, leukemia, lymphomas, and some brain cancers

T: myelosuppresion, hemorrhagic cystitis resulting from formation of acrolein, partially prevented by mesna (thiol group of mesna binds toxic metabolite; prevents damage to bladder)

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15
Q

Mechlorethamine

A

U: Hodgkin’s lymphoma
T: GI distress, myelosuppresion, alopecia, and sterility are common. Marked vesicant actions!

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16
Q

Platinum Analogs (Cisplatin, Carboplatin, Oxalplatin)

A

M: Cross-link DNA
U: Testicular, bladder, ovary, and lung carcinomas. Oxaliplatin is used in advanced colon cancer.
T: nephrotoxicity and acoustic nerve damage. Renal toxicity can be reduced by use of mannitol with forced hydration.
PK: IV

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17
Q

Compare and contrast the 3 platinum analogs

A

Carboplatin is less nephrotoxic than cisplatin and is less likely to cause tinnitus and hearing loss, but it has greater myelosuppressant actions.

Oxiplatin causes DOSE LIMITING neurotoxicity

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18
Q

Procarbazine

A

M: forms hydrogen peroxide, which generates free radicals that cause DNA strand scission
U: component of regimens for Hodgkin’s lymphoma
T: myelosupprassant and causes GI irritation, CNS dysfunction, peripheral neuropathy, and skin reactions. Inhibits enzymes including MAO and those involved in hepatic drug metabolism. Disulfiram-like rxns have occured with EtOH. Leukemogenic.
PK: orally active, penetrates CSF. hepatic elimination

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19
Q

Busulfan

A

M: alkylates DNA
U: CML. Also able to ablate patient’s bone marrow before marrow transplantation.
T: pulmonary fibrosis, hyperpigmentation

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20
Q

Nitrosoureas (carmustine and lomustine)

A

M: require activation. cross BBB –> CNS
U: brain tumors (including glioblastoma multiforme)
T: CNS toxicity (dizziness, ataxia)

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21
Q

Name the antimetabolite drugs

A

Antagonists of folic acid (methotrexate)
Purines (mercaptopurine, thioguanine)
Pyrimidines (fluorouracil, cytarabine, gemcitabine)

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22
Q

What phase of the cell cycle do the antimetabolite drugs act on?

A

CCS drugs acting primarily in the S phase of the cell cycle

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23
Q

What is the MOA of Methotrexate

A

substrate for and inhibitor of DHFR –> decrease in synthesis of thymidylate, purine nucleotides, and AA and thus inerferes with nucleic acid and protein metabolism.

formation of polyglutamine derivatives of methotrexate appears to be important for cytotoxic actions.

24
Q

What is the clinical use and toxicity associated with Methotrexate?

A

U:
- Cancers: leukemias, lymphomas, choriocarcinoma, sarcomas
- Non-neoplastic: abortion, ectopic pregnancy, RA, psoriasis
T: myelosuppresion, macrovesicular fatty change in liver, toxic effects on GI mucosa (mucositis), teratogenic

25
Q

How is myelosuppresion reversible with Methotrexate?

A

toxic effects of methotrexate on normal cells may be reudced by administration of folinic acid (leucovorin); this strategy is called “leucovorin rescue”

26
Q

What is the PK of Methotrexate?

A

oral and IV administration; can’t reach CNS

not metabolized and its clearance is dependent on renal function

27
Q

What is the mechanism of resistance to Methotrexate?

A

decreased drug accumulation
changes in the drug sensitivity or activity of DHFR
decreased formation of polyglutamates

28
Q

Mercaptopurine (6-MP) and Thioguanine (6-TG)

A

M: purine (thiol) analogs that decrease purine synthesis. activated by HGPRT
U: leukemias
T: bone marrow suppression is DOSE LIMITING, but hepatic dysfunction also occurs (cholestasis, jaundice, necrosis).
PK: low oral bioavailability becuase of first-pass metabolism by hepatic enzymes. The metabolism of 6-MP by xanthine oxidase is inhibited by allopurinol.

29
Q

5-Fluorouracil (5-FU)

A

M: pyrimidine analog bioactivated to 5F-dUMP, which covalently complexes folic acid. This complex inhibits thymidylate synthase –> decrease dTMP –> decrease DNA and protein synthesis
U: colon cancer, TOPICAL use for keratosis and basal cell carcinoma
T: myelosuppression, GI distress and alopecia
PK: IV; enters CSF. Elimination via metabolism

30
Q

What is the mechanism of resistance to 5-FU

A

decreased activation of 5-FU
increased thymidylate synthase activity
reduced drug sensitivity of this enzyme

31
Q

Cytarabine (ARA-C)

A

M: pyrimidine antimetabolite; activated by kinases to AraCTP, an inhibitor of DNA polymerases
U: leukemias, lymphomas
T: leukopenia, thrombocytopenia, megaloblastic anemia
Resistance can occur as a result of decreased uptake or it’s decreased conversion to AraCTP

32
Q

Whats makes Cytarabine unique from the rest of the antimetabolites?

A

It is most specific for the S phase of the cell cycle

33
Q

Gemcitabine

A

M: Deoxycytidine analog that is converted into the active diphosphate and triphosphate nucleotide form.
Diphosphate form inhibits ribonucleotide reductase and thereby diminish the pool of deoxyribonunucleoside triphosphates required for DNA synthesis.
Triphosphate form causes chain termination

U: initially approved for pancreatic cancer, now widely used.

T: neutropenia

34
Q

Name the plant alkaloids

A 
CCS drugs
Vinca alkaloids = vinblastine, vincristine, vinorelbine
Podophyllotoxins = etoposide, teniposide
Camptothecins = topotecan, irinotecan
Taxanes = paclitaxil, docetaxel
35
Q

Vinblastine, Vincristine, Vinorelebine

A

M: block the formation of the mitotic spindle by preventing the assembly of tubulin dimers into microtubules: “Microtubules are the VINes of your cells”

U: solid tumors, leukemias, lymphomas

T:

  • Vincristine: neurotoxicity (areflexia, peripheral neuritis), paralytic ileus
  • VinBLAStine blasts bone marrow (suppression)

PK: must be given parenterally. no CSF penetration. cleared mainly by biliary excretion.

36
Q

Etoposide and Teniposide

A

M: inhibit topoisomerase II –> increased DNA degradation. also inhibits mitochondrial electron transport. most active in late S and early G2 phases of the cell cycle

U: used in combo w drugs for lung (small cell), prostate and testicular

T: myelosuppression, GI irritation, alopecia

PK: oral administration; elimination via kidneys

37
Q

Topotecan and Irinotecan

A

M: inhibit topoisomerase I. damage DNA by inhibiting an enzyme that cuts and releases single DNA strands during normal DNA repair process

U: Topotecan used as second-line therapy for advanced ovarian cancer and for small cel lung cancer. Irinotecan used for metastatic colorectal cancer

T: myelosuppression and diarrhea

38
Q

Discuss the PK of Topotecan and Irinotecan?

A

Irinotecan is a prodrug that is converted in the liver into an active metabolite.
Topotecan is eliminated renally, whereas Irinotecan and its metabolite are eliminated in the bile and feces

39
Q

Paclitaxel and Docetaxel

A

M: hyperstabilixze polymerized microtbules in M phase so that mitotic spindle cannot break down (anaphase cannot occur) - “It is TAXing to stay polymerized”

U: advanced breast and ovarian carcinoma

T: Paclitaxel causes neutropenia, thrombocytopenia, peripheral neuropathy, infusion reactions. Docetaxel causes neurotoxicity and BM depression

PK: IV

40
Q

How do the taxanes differ from the vinca alkaloids in MOA?

A

Both interefere with mitotic spindle

Taxanes prevent microtubule DISASSEMBLY into tubulin monomers whereas Vinca Alkaloids prevent ASSEMBLY of tubulin dimers into microtubules

41
Q

Name the ABXs

A 
doxorubicin
daunorubicin
bleomycin
dactinomycin
mitomycin
42
Q

Doxorubicin and Daunorubicin: MOA

A

Anthracyclines that intercalate between base pairs, inhibit topoisomerase II, and generate free radicals. they block the synthesis of RNA and DNA and cause DNA strand scission. Membrane disruption also occurs. These are CCNS drugs

43
Q

Doxorubicin and Daunorubicin: PK and Use

A

PK: must be given IV. metabolized in the liver and products are excreted in bile and urine

Doxorubicin used in lymphoma, myelomas, sarcomas, and breast, endometrial, lung, ovarian and thyroid cancers

Daunorubicin: acute leukemias

44
Q

What is the most distinctive adverse effect of Doxorubicin and Daunorubicin?

A

most distinctive adverse effect is cardiotoxicity, which includes initial electrocardiographic abnormalities (with the possibility of arrhytmias) and slowly developing cardiomyopathy and CHF

45
Q

What can you administer with Doxorubicin and Daunorubicin to protect against the distinctive adverse effect?

A

Dexrazoxane is an inhibitor of iron-mediated free radical generation, may protect against cardiotoxicity. Liposomal formulations of doxorubicin may be less cardiotoxic

46
Q

Bleomycin

A

M: generates free radicals, which bind to DNA, cause strand breaks, and inhibit DNA synthesis. CCS drug active in the G2 phase of tumor cell cycle
U: component of treatments for lymphoma, testicular cancer, and squamous cell carcinomas
T: pulmonary dysfunction (develops slowly and is DOSE LIMITING), hypersensitivity reactions, mucocutaneous reactions

47
Q

What is Bleomycin inactivated by?

A

Must be given parenterally

Inactivated by tissue aminopeptidases, but some renal clearance of intact drug also occurs

48
Q

Dactinomycin

A

M: CCNS drug that binds to dSDNA and inhibits DNA-dependent RNA synthesis.
U: melanoma and Wilm’s tumor
T: marrow suppression, skin reactions, GI irritation
PK: must be given parenterally and both intact drug and metabolites are excreted in bile

49
Q

Mitomycin

A

M: CCNS drug that is metabolized by liver enzymes to form an alkylating agent that cross-links DNA
U: hypoxic tumor cells
T: severe myelosuppresion and is toxic to heart, liver, lung, and kidney
PK: given IV and rapidly cleared via heptic metabolis

50
Q

Common Chemotoxicities: CHEMO-TOX MAN

A 
Cisplatin/Carboplatin: acoustic nerve damage (and nephrotoxicity)
Vincristine: peripheral neuropathy
Bleomycin, Busulfan: pulmonary fibrosis
Doxorubicin: cardiotoxicity 
Trastuzumab: cardiotoxicity 
Cisplatin/Cardioplatin: nephrotoxic (and acoustic nerve damage)
CYclophosphamide: hemorrhagic cystitis 
5-FU: myelosuppresion 
6-FU: myelosuppresion
Methotrexate: myelosuppresion
51
Q

What are the cardinal principles of combination chemotherapy?

A

Toxicity
Use drugs that work on different mechanisms
Resistance

52
Q

What concurrent agent do you administer with MTX and 5-FU?

What are the consequences?

A

Administer: Leucovorin
Consequence: metabolic rescue with MTX and enhanced action with 5-FU

53
Q

IV dosing to prevent hyperuricemia

A

Prevent high levels of uric acid in the renal tubules, because it precipitates out and cause renal failure.

54
Q

A patient with lung cancer recieves a course of chemotherapy before surgery. Drug use in this context is called…

A

Neo-adjunctive therapy - “neo” means before, giving the treatment to shrink the tumor

55
Q

What is sensitizing therapy

A

look up

56
Q

What is adjunctive therapy

A

comes after the surgery

57
Q

Analysis of a biopsy from a solid tumor indicates rate high levels of glutathione. The activity of which drug would most likely be diminished?

A

Cisplatin
Bleomycin
Doxorubicin and Daunorubicin

BLOCK 2 FINAL (10 decks)

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