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SBL > Cancer Pharmacology (Kruse) > Flashcards

Cancer Pharmacology (Kruse) Flashcards

1
Q

What are the curable cancers w/ primary chemotherapy in a small sub-set of patients?

A
  • Hodgkin’s and non-Hodgkin’s lymphoma, choriocarcinom, germ cell cancer, and AML
  • curable childhood cancers: Burkitt’s lymphoma, Wilms’ tumor, embryonal rhabdomyosarcoma, and ALL
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2
Q

How does tissue growth fraction determine a tumor’s responsiveness to chemo?

A
  • the higher the growth fraction of tissue, the more responsive it will be to chemo
  • this is also why noncancerous high growth cells are impacted during chemo (BM, GI tract, hair follicles, sperm-forming cells)
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3
Q

How does growth fraction of tumors relate to chemotherapy?

A
  • initial growth rate of most solid tumors is rapid but decreases over time
  • slower growing/dividing cancer cells are harder to treat w/ chemo, which are the type of cells that make up the inside of large tumors; this is why end stage cancers (larger tumors) are so difficult to tx w/ chemo
  • Burkitt lymphoma (high growth fraction, curable by chemo) vs. colorectal carcinoma (low growth fraction, chemo has minor activity)
  • some disseminated tumors can be cured by single-agent chemo
  • growth fraction of solid tumors can be increased by reducing tumor burden (surgery or radiation)
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4
Q
  • antineoplastic therapy follows first-order kinetics: a given dose of a drug destroys a constant fraction of cells
  • this means antineoplastic agents kill a fraction of cells rather than an absolute number per dose
  • if drug dose kills 99.9% of tumors cells: 10^12 to 10^9 cells, 10^6 to 10^3 cells
  • only a limited log cell kill can be expected w/ each individual tx
  • this is why chemo is given as a strict schedule b/c healthy cells are also being killed, so they need time to recover in between
A

log cell kill hypothesis

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5
Q

How is chemotherapy administered in terms of timing?

A
  • high-dose intermittent therapy allows recovery of nml, healthy tissues
  • agents given as constant infusions can include those that are rapidly metabolized or excreted (or both) as well as those that are cell cycle specific (practical limitations)
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6
Q

What are the common routes of administration for chemo?

A
  • IV and PO
  • alternative routes can reduce systemic toxicity and increase drug delivery (avoid pharmacologic sanctuaries - regions where tumor cells are less susceptible to antineoplastic agents (e.g. CNS))
  • alternative: intracavity, intrathecal, intraventricular, intraarterial, topical, isolated limb perfusion
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7
Q

Principles of combination chemo regimens:

A
  1. each drug should have some individual therapeutic activity
  2. drugs that act by diff mech may have additive/synergistic therapeutic effects, increasing log cell kill and diminishing probability of emergence of drug resistant tumor cells
  3. drugs w/ diff dose-limiting toxicities should be used in combo to avoid cumulative damage to single organ (if similar dose-limiting toxicities, doses should be reduced)
  4. intensive intermittent schedules of drug tx should allow time for recovery from acute toxic effects of antineoplastic agents
  5. several cycles of tx should be given (most curable tumors require at least 6-8 cycles of therapy)
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8
Q
  • chemo drug resistance in the absence of prior exposure of tumor cells to available standard agents
  • genomic instability of cancer (i.e. p53 mutations) contributes to this
A

primary/inherent chemotherapeutic resistance

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9
Q
  • develops in response to exposure of tumor cells to a given cancer chemo drug
  • genetic change > amplification or suppression of particular gene
  • examples: 1) decreased drug transport into cells, 2) reduced drug affinity d/t mutations/alterations of drug target, 3) increased expression of an enzyme that causes drug inactivation, 4) increased expression of DNA repair enzymes for drugs that damage DNA
A

acquired chemotherapeutic drug resistance

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10
Q

Relation of p-glycoprotein, PGP (MDR1) and drug resistance:

A
  • PGP expression: in tissues w/ barrier functions including the kidney, liver, and GI tract; in pharmacological barrier sites including blood-brain barrier and placental-blood barrier
  • high baseline expression of PGP correlates w/ primary/inherent resistance to nautral products
  • can be overexpressed leading to acquired drug resistance
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11
Q

What nml tissues are affected by chemo and what are the long term risks of taking chemo?

A
  • rapidly proliferating nml tissues are major sites of toxicity: BM (cytopenias, myelosuppression), GI tract, hair follicles, oral mucosa, sperm forming cells
  • can give rise to neoplasms years after tx (e.g. alkylating agents have caused AML and ALL)
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12
Q

Common adverse effects of chemo:

A
  • d/t classic antineoplastic agents: N/V, fatigue, stomatitis, alopecia
  • mylosuppression: can lead to impaired wound healing and predisposition to infection
  • low sperm counts and azoospermia
  • depressed development of children exposed to antineoplastic agents
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13
Q

Ways to minimize adverse effects of chemo:

A
  • choose route of admin that minimizes systemic toxicity
  • hematopoietic agents for: neutropenia, thrombocytopenia, anemia
  • serotonin receptor antagonist (ondansetron) for emetogenic effects
  • bisphosphonates to delay skeletal complications
  • rest and recovery
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14
Q
  • alkylating agents
  • nitrogen mustards
A
  • cyclophosphamide

- ifosfamide

  • mechlorethamine
  • melphalan
  • chlorambucil
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15
Q
  • alkylating agents
  • methylhydrazine derivative
A

procarbazine

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16
Q
  • alkylating agents
  • alkyl sulfonate
A

busulfan

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17
Q
  • alkylating agents
  • nitrosoureas
A
  • carmustine
  • streptozocin
  • bendamustine
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18
Q
  • alkylating agents
  • triazenes
A
  • dacarbazine
  • temozolomide
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19
Q
  • alkylating agents
  • platinum coordination complexes
A
  • cisplatin
  • carboplatin
  • oxaliplatin
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20
Q

5 major types of alkylating agents:

A
  1. nitrogen mustards (cyclophosphamide)
  2. nitrosoureas (carmustine)
  3. alkyl sulfonates (busulfan)
  4. methylhydrazine derivatives (procarbazine)
  5. triazines (dacarbazine)
    - honorable mention: platinum coordination complexes (cisplatin)
    - alkylating agents are cell cycle nonspecific
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21
Q

most widely used alkylating agent and one of the most emetogenic agents:

A

cyclophosphamide

(nitrogen mustard)

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22
Q

What is the MOA of alkylating agents?

A
  • AA’s form covalent linkages w/ DNA which prevents DNA helicase from splitting the DNA apart to be replicated (prevents cell growth)
  • this is cell cycle nonspecific b/c DNA access is needed all throughout the cell cycle
  • bifunctional AA’s can cause intrastrand linking and cross-linking
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23
Q

What is the MOA of cyclophosphamide (nitrogen mustard)?

A
  • since it’s an AA, it forms covalent linkages w/ DNA (2 Guanines) which prevents DNA helicase from splitting the DNA apart to be replicated (prevents cell growth)
  • this drug must be activated by a cytochrome P450, CYP2B, aka hepatic cytochrome oxidase
  • a byproduct of this drug’s rxn in the body is acrolein which causes hemorrhagic cystitis
  • mesna inactivates acrolein and is used for prophylaxis of chemo-induced cystitis
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24
Q

Pharmacological effects of alkylating agents:

A

(systemic toxicities are dose related)

  • direct vesicant (blistering) effects/tissue damage at site of injection (oral admin is great clinical benefit)
  • acute toxicity: N/V within 30-60 min (pretreat w/ serotonin antagonist)
  • delayed toxicities: BM depression, penias, nephrotoxicity, alopecia, mucosal ulceration, intestinal denudation
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25
Q

Special adverse effects of cyclophosphamide:

A

hemorrhagic cystitis

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26
Q

Special adverse effects of cisplatin:

A

renal tubular damage, ototoxicity

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27
Q

Special adverse effects of busulfan:

A

pulmonary fibrosis

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28
Q
  • antimetabolites
  • folic acid analogs
A
  • methotrexate (leucovorin rescue)
  • pemetrexed
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29
Q
  • antimetabolites
  • pyrimidine analogs
A
  • fluorouracil (5-fluorouracil; 5-FU)
  • capecitabine
  • cytarabine (cytosine arabinoside)
  • gemcitabine
  • 5-aza-cytidine
  • deoxy-5-aza-cytidine
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30
Q
  • antimetabolites
  • purine analogs
A
  • mercaptopurine (6-MP)
  • pentostatin
  • fludarabine
  • clofarabine
  • nelarabine
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31
Q

3 main categories of antimetabolites:

A
  1. folic acid analogs (methotrexate)
  2. pyrimidine analogs (5-fluorouracil)
  3. purine analogs (6-mercaptopurine)
32
Q

MOA for antimetabolites:

A
  • structural analogs to compounds necessary for cell proliferation
  • block or subvert pathways that are involved in, or lead to, cell replication (nucleotide and nucleic acid synthesis)
  • cell cycle specific (b/c DNA is only replicated during S phase)
33
Q

Methotrexate is an analog to:

A

folic acid

34
Q

MOA of methotrexate:

A
  • inhibits dihydrofolate reductase: converts dihydrofolic acid to tetrahydrofolic acid
  • also used as immune suppressant for tx of RA and psoriasis
  • reduced folate leucovorin is used w/ high-dose methotrexate to rescue nml cells (also antidote for accidental drug OD)
35
Q

MOA of fluorouracil:

A
  • pyrimidine structural analog
  • prodrug
  • active compound FdUMP covalently binds thymidylate synthetase and blocks de novo synthesis of thymidylate
  • active compounds (FdUTP and FUTP) are incorporated into both DNA and RNA respectively, interfering w/ DNA synthesis, DNA function, RNA processing, and mRNA translation
36
Q

MOA of mercaptopurine (6-MP):

A
  • purine structural analog
  • inactive in parent form
  • metabolized by hypo-xanthine-guanine phosphoribosyl transferase (HGPRT) to form monophosphate nucleotide 6-thioinosinic acid
  • biotransformation > metabolism to inactive metabolite, 6-thiouric acid by xanthine oxidase (1st pass effect)
  • allopurinol (xanthine oxidase inhibitor), often used as supportive care in tx of acute leukemias to prevent hyperuricemia d/t tumor cell lysis
  • simultaneous admin of allopurinol + PO 6-MP results in increased levels of 6-MP and increased toxicity

- thus, reduce oral 6-MP dose by 50-75%, IV dose unaffected

37
Q

Pharmacological effects of antimetabolites:

A
  • cell cycle specific (S phase)
  • relatively little acute toxicity after intial dose
  • oral, IV, intrathecal (methotrexate) are commons routes of admin
  • common toxicities: myelosuppression, N/V/D, immunosuppression, penias, hepatoxicity
38
Q
  • natural antineoplastic agents
  • vinca alkaloids
A
  • vinblastine
  • vinorelbine
  • vincristine
39
Q
  • natural antineoplastic agents
  • taxanes
A
  • paclitaxel
  • docetaxel
  • cabazitaxel
40
Q
  • natural antineoplastic agents
  • epipodophyllotoxins
A
  • etoposide
  • teniposide
41
Q
  • natural antineoplastic agents
  • camptothecins
A
  • topotecan
  • irinotecan
42
Q
  • natural antineoplastic agents
  • antibiotics
A
  • doxorubicin
  • dactinomycin (actinomycin D)
  • daunorubicin
43
Q
  • natural antineoplastic agents
  • echinocandins
A
  • yondelis
44
Q
  • natural antineoplastic agents
  • anthracenediones
A
  • bleomycin
  • mitoxantrone
  • mitomycin C
45
Q
  • natural antineoplastic agents
  • enzymes
A
  • L-asparaginase
  • pegaspargase
46
Q

MOA of vinca alkaloids (vinblastine and vincristine):

A
  • bind to β-tubulin and inhibit microtubule assembly (depolarization)
  • cell cycle specific mitosis inhibition (M phase)
47
Q

Adverse effects of vinca alkaloids (vinblastine and vincristine):

A
  • common: alopecia and BM depression
  • vinblastine: myelosuppression > vincristine
  • vincristine: cumulative neurological toxicities (numbness/tingling extremities, loss of DTR’s, motor weakness) compared to vinblastine
48
Q

MOA of taxanes:

A
  • bind to β-tubulin and stabilize microtubule formation, allowing nml function of cells to arrest in M phase
  • cell cycle specific mitosis inhibition
49
Q

Clinical relevance (use, toxicities, dosing) of taxanes:

A

(taxanes = paclitaxel, docetaxel, cabazitaxel)

  • paclitaxel: hypersensitivity rxns in hands/toes, change in taste
  • docetaxel: greater cell uptake/retained intracellularly longer than paclitaxel, leading to smaller dose/less side effects; side effects (hypersensitivity, neutropenia, hair loss)
  • traditional tx for breast cancer
  • P-glycoprotein expression often confers resistance to natural prod chemos; cabazitaxel avoids mechanism of resistance
50
Q

MOA of topoisomerase I inhibitors:

A
  • prevent the cutting of one strand of double-stranded DNA, the strand cannot relax and reanneal
  • causes DNA damage and leads to cell death
  • camptothecins (topotecan, irinotecan) inhibit Top I
  • cell cycle specific (primarily S; also G1 and G2)​
51
Q

MOA of topoisomerase II inhibitors:

A
  • prevent cutting of both strands of double-stranded DNA so that the strand cannot simultaneously coil and uncoil during replication
  • causes DNA damage and leads to cell death
  • epipodophyllotoxins (etoposide, teniposide) and anthracycline Ab’s (doxorubicin, daunorubicin) inhibit Top II
  • cell cycle specific (primarily S; also G1 and G2)
52
Q

All of the anticancer antibiotics currently in use are products of various strains of soil microbe:

A

Streptomyces

53
Q

general MOA of antitumor antibiotics:

A

effects are mainly on DNA

54
Q

Effective antitumor Ab agents include: (4)

A
  1. anthracyclines
  2. dactinomycin
  3. bleomycin
  4. mitomycin
55
Q
  • antitumor antibiotics
  • topoisomer II inhibitors (cell cycle specific, S phase), also cause DNA intercalation (cell cycle nonspecific)
  • produce free radicals: cardiotoxicity
  • cum cardiac damage can lead to dysrhythmias and heart failure
A

anthracyclines

(doxorubicin, daunorubicin, dactinomycin)

56
Q
  • antitumor antibiotics
  • causes single- and double-stranded DNA breaks
  • causes minimal myelosuppression: useful in combination w/ other drugs
  • can cause significant pulmonary toxicity (5-10%) and usually presents as pneumonities w/ cough, dyspnea, dry inspiratory crackles
A

bleomycin

57
Q
  • natural antineoplastic agents
  • targeted therapy for ALL (ALL tumor cells lack asparagine synthetase, require an exogenous source of L-asparagine)
  • MOA: hydrolyzes circulating L-asparagine into aspartic acid and ammonia, effectively inhibiting protein synthesis
  • cell cycle specific (G1)
  • can cause acute hypersensitivity rxn: fever, chills, N/V, skin rash, urticaria
  • delayed toxicities: increased risk of clotting/bleeding, pancreatitis, CNS toxicity (lethargy, confusion, hallucinations, coma)
A

enzymes: asparaginase, pegaspargase

58
Q
  • differentiating agent used as an antineoplastic
  • t(15;17) translocation creates fusion protein PML-RARα, inhibiting granulocytic maturation in APL
  • this drug binds to PML-RARα fusion protein and antagonizes the inhibitory effect on transcription of target genes
  • within 1-2 days, neoplastic promyelocytes begin to differentiate into neutrophils, which rapidly die
  • one of the most successful uses of targeted therapy in cancer
  • common adverse effects: vit A toxicity and retinoic acid syndrome
A

tretinoin (all-trans-retinoic acid, ATRA)

59
Q

How does tyrosine kinase dysfunction lead to cancer?

A
  • when mutated, overexpressed, or structurally altered, tyrosine kinases can become potent oncoproteins
  • abnml activation of TK has been found in many human neoplasms
  • aberrant TK activity can occur in receptor or cytoplasmic TK’s
  • attractive targets for cancer therapy
  • intracellular TK’s (nibs) vs. extracellular (mabs)
60
Q
  • BCR-ABL fusion protein that results from t(9;22) translocation is found in 95% of patients w/ CML
  • this drug is a small molecule inhibitor of the ABL tyrosine kinase and has been hailed as a conceptual breakthrough in targeted chemo
  • this drug can also inhibit receptor TK’s PDGFR and KIT
A

imatinib

61
Q
  • tyrosine kinase domain inhibitors of the EGFR
  • tx for refractory non-small cell lung cancer and pancreatic cancer
  • produces dermatologic toxicities
A

erlotinib and gefitinib

62
Q
  • recombinant fusion protein made up of portions of extracellular domains of human VEGF receptors (VEGFR) 1 and 2 which are fused to Fc portion of human IgG1 molecule
  • soluble receptor to VEGF-A, VEGF-B, and placental growth factor (PlGF)
  • binding of VEGF ligands prevents their interactions w/ VEGFR leading to an inhibition of VEGFR signaling
A

ziv-aflibercept

63
Q

mechanism of resistance for tyrosine kinase and growth factor receptor inhibitors:

A

point mutations in drug binding sites

64
Q

common adverse effects of tyrosine kinase and growth factor receptor inhibitors:

A
  • N/V
  • acneform skin rash and hypersensitivity (allergic rxn) (i.e. cetuximab)
65
Q
  • biological response modifiers: agents that act indirectly to mediate their antitumor effects by enhancing the immunologic response to neoplastic cells
  • inhibit cellular growth, alter state of cell differentiation, interfere w/ oncogene expression, alter cell surface antigen expression, increase phagocytic activity of macrophages, and augment cytotoxicity of lymphocytes for target cells
  • adverse effects: BM depression, neutropenia, anemia, renal toxicity, edema, arrhythmias
A

interferons (interferon-α2a and -α2b)

66
Q
  • biological response modifier: agent that acts indirectly to mediate antitumor effects by enhancing the immunologic response to neoplastic cells
  • increases cytotoxic killing by T cell and NK cells
  • major toxicity: capillary leak syndrome
A

interleukin-2

67
Q
  • antibody: rituximab
  • antigen:
  • cancer:
  • antigen function:
A
  • antibody: rituximab
  • antigen: CD20
  • cancer: non-hodgkin’s lymphoma
  • antigen function: proliferation, differentiation
68
Q
  • antibody: alemtuzumab
  • antigen:
  • cancer:
  • antigen function:
A
  • antibody: alemtuzumab
  • antigen: CD52
  • cancer: CLL
  • antigen function: unknown
69
Q
  • antibody: gemtuzumab
  • antigen:
  • cancer:
  • antigen function:
A
  • antibody: gemtuzumab
  • antigen: CD33
  • cancer: AML
  • antigen function: unknown
70
Q
  • antibody: trastuzumab
  • antigen:
  • cancer:
  • antigen function:
A
  • antibody: trastuzumab
  • antigen: HER2/neu
  • cancer: breast
  • antigen function: tyrosine kinase
71
Q
  • antibody: cetuximab
  • antigen:
  • cancer:
  • antigen function:
A
  • antibody: cetuximab
  • antigen: EGFR (ErbB-1)
  • cancer: colorectal, lung, pancreatic, breast
  • antigen function: tyrosine kinase
72
Q
  • antibody: bevacizumab
  • antigen:
  • cancer:
  • antigen function:
A
  • antibody: bevacizumab
  • antigen: VEGF
  • cancer: colorectal, lung
  • antigen function: angiogenesis
73
Q
  • antibody: ibritumomab and tositumomab
  • antigen:
  • cancer:
  • antigen function:
A
  • antibody: ibritumomab and tositumomab
  • antigen: CD20
  • cancer: non-hodgkin lymphoma
  • antigen function: proliferation, differentiation
74
Q

malignant melanoma

  • curable w/ surgical resection when it presents locally
  • once mets has occurred, one of most difficult cancers to tx
  • most active cytotoxic agents (drugs):
  • biologic agents:
  • other tx:
  • BRAF targets:
A

malignant melanoma

  • curable w/ surgical resection when it presents locally
  • once mets has occurred, one of most difficult cancers to tx
  • most active cytotoxic agents (drugs): dacarbazine, temozolomide, cisplatin (response rate to these agents is low)
  • biologic agents: IFN-α and interleukin 2 (IL-2), greater activity than traditional cytotoxic agents, tx w/ high dose IL-2 has led to cures in small subset of patients
  • nivolumab and pembrolizumab: approved for unresectable or metastatic melanoma as monotherapy
  • BRAF V600E mutation present in majority of melanomas: creates constitutive actication of BRAF kinase; vemurafenib, dabrafenib, and encorafenib target BRAF directly
75
Q

chemo-toxicities

  • mucositis:
  • pulm fibrosis:
  • peripheral neuropathy:
  • ototoxicity:
  • cardiotoxicity:
  • nephrotoxicity:
  • hemorrhagic cystitis:
A

chemo-toxicities

  • mucositis: Methotrexate, melphalan
  • pulm fibrosis: Bleomycin, busulfan
  • peripheral neuropathy: Vincristine
  • ototoxicity: Cisplatin
  • cardiotoxicity: Doxorubicin, daunorubicin
  • nephrotoxicity: Cisplatin, cyclophosphamide
  • hemorrhagic cystitis: Cyclophosphamide, ifosfamide

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