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Heme/Lymph Exam 1 (Erik Hammond) COPY > Cancer Pharm (Kruse) > Flashcards

Cancer Pharm (Kruse) Flashcards

1
Q

Compare and Contrast oncogenes and tumor supressors

A

Oncogenes are genes that positively influence tumor formation (ras)

Tumor supressors are genes that negatively impact tumor growth (p53)

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2
Q

Some cancers affect the cell cycle. Discuss

A

proteins or pathways involved in regulating the checkpoints between the phases of the cell cycle may be absent or mutated which can lead to uncontrolled and unregulated cell cycle proliferation

Certain drugs will target the cell cycle to help reduce this proliferation (cell-cycle specific)

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3
Q

Activation of oncogenes overrides what part of the cell cycle?

Inactivation of tumor suppressor genes overrides what part of the cell cycle?

A

overrides G1 arrest

Overrides G2 arrest

Now the cell isn’t arrested when it should be, and can cause cancer

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4
Q

What is primary chemotherapy?

A

chemotherapy that is given as the primary treatment

used for advanced cancers with no other alt. tx or advanced metastatic disease

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5
Q

What is the goal of primary chemotherapy?

A

relieve tumor related symptoms

improve quality of life

prolong time to tumor progession

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6
Q

In what cancers or patients can primary chemotherapy be curative?

A

HL and NHL, choriocarcinoma, germ cell cancer, and AML

Burkitt’s lymphoma, Wilm’s tumor, Embryonal rhabdomyosarcoma, ALL

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7
Q

What is neoadjuvant chemotherapy

A

chemo that is given for a localized cancer in which alternative therapies exist but are less than completely affective

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8
Q

What is the goal of neoadjuvant therapy?

A

reduce the size of the tumor to make surgery easier/spare normal organs

typically given after surgery as well (becomes adjuvant therapy at that point)

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9
Q

What is adjuvant chemotherapy?

A

chemo used as an adjuvant (or help) to local therapy and administered after surgery has been preformed

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10
Q

What is the goal of adjuvant therapy?

A

reduce the incidence of local and systemic recurrence

improve the overall survival

effective at prolonging dz-free state and survival

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11
Q

What is growth fraction?

A

ratio of cell proliferation to G0 cells

this is the major determinant of a cancer’s responsiveness to chemotherapy

antineoplastics will be more effective on cells with a high growth fraction and will impact noncancerous high growth cells

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12
Q

What are normal body cells with high growth fraction?

A

cells of the bone marrow, GI, hair, sperm forming cells

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13
Q

Solid tumors can be difficult to treat because of what rule?

A

the growth fraction

the initial rate of growth is fast, but decreases overtime, such that by the time it is detected, it is no longer proliferating as rapidly, thus certain drugs won’t be as effective

Ex: burkitt’s lymphoma with high growth fraction, easier to cure with chemo, vs. colorectal carcinoma with a low growth fraction, chemo has a minor effect

Note, surgery/rad increase growth fraction which can increase chemo efficacy!

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14
Q

What is the log cell kill hypothesis?

A

antineoplastic therapy follows first-order kinetics: a given dose of drug destroys a constant fraction of cells

log cell kill hypothesis states that antineoplastic agents kill a fraction of cells rather than an absolute number per dose

therefore, only a limited log cell kill can be expected with each individual treatment

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15
Q

Why are antineoplastic agents delivered in a staggered/intermittent schedule?

A

high dose intermittent therapy allows recovery of normal, healthy tissues

agents given as constant infusions can include those that are rapidly metabolized or excreted as well as those that are cell cycle specific

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16
Q

What are some various routes of administration?

What are pharmacologic sanctuaries?

A

IV, PO

intracavity, intrathetcal, intraventricular, intraarterial, topical, isolated limb

implantable wafers

pharmacologic sanctuaries are regions where tumor cells are hard to reach (CNS)

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17
Q

What is combination chemotherapy?

A

it is the use of multiple agents, more successful than single agent regimens

  1. provides max cell killing within tolerated toxicity
  2. effective against broader range of cell lines with heterogenous population
  3. may delay or prevent drug resistant tumors
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18
Q

What are the 5 principles used in the design of combination chemotherapy regimens?

A
  1. each drug should have some individual therapeutic activity
  2. drugs that act by diff. mechanisms should net an increased log cell kill and decrease drug resistance
  3. drugs with different dose-limiting toxicities should be used in combination to avoid organ damage
  4. intensive intermittent treatment schedules should allow time for recovery in between
  5. several cycles of treatment should be given (6-8)
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19
Q

What are two primary(inherent) chemotherapy resistances?

A

drug resistance in the absence of prior exposure to available drugs

genomic instability of the cancer like p53 mutations

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20
Q

What are acquired chemotherapeutic drug resistances?

What are some examples?

A

develops after exposure to a cancer drug

gene amplification or supression

Examples:

decreased drug transport into the cell

reduced affinity of target

increased expression of enzyme that causes inactivation

increased expression of DNA repair enzymes

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21
Q

It is worth noting that exposure to chemo drugs can increase what?

A

increase the cancer heterogeneity, causing it to become less monoclonal and more difficult to treat and can become resistant to treatment

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22
Q

What is important about p-Glycoprotein?

To what kind of antineoplastics is there a high resistance to?

A

PGP expression is found in tissues with barrier functions (kidney, liver, GI) and BBB/PBB

a high baseline expression of PGP correlates with high primary resistance to natural products

if PGP is overexpressed, can lead to acquired drug resistance

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23
Q

What are common antineoplastic drug toxicities

A

death of rapidly proliferating normal cells

bone marrow

GI tract

hair follicles

oral mucosa

sperm forming cells

(many of these drugs can damage so much that they cause cancer later in life-alkylating agents)

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24
Q

Common adverse effects of antineoplastics?

A

N/V

fatigue

stomatitis

alopecia

myelosupression (dif. wound healing, increased infections)

low sperm count/azospermia

depressed development in children

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25
Q

How to minimize adverse effects of antineoplastics?

A

choose the route of administration with as little systemic toxicity

use of other pharm agents to decrease adverse effects (hemopoeitic agents, Zofran, bisphosphonates)

rest and recovery between doses

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26
Q

What are the five major types of alkylating agents?

A
  1. cyclophsphamide (N mustard)
  2. carmustine (Nitrosoureas)
  3. busulfan (alkyl sulfonates)
  4. procarbazine (methylhydrazine)
  5. dacarbazine (triazines)

also included is cisplatin, a platinum compound

27
Q

What is the most widely used alkylating agent?

A

Cyclophsphamide

(most vomiting, too)

28
Q

Alkylating agents are cell cycle (specific or nonspecific)?

A

Nonspecific!

29
Q

What is the MOA of alkylating agents?

A

alkylating agents form covalent links between DNA of between guanine which prevents unwinding of the DNA (and thus prevents replication)

30
Q

How is cyclophosphamide activated?

What are two cytotoxic products?

Which one causes hemorrhagic cystitis?

How is it treated?

A

Must past through CYP2B and hepatic cytochrome oxidase and hepatic aldehyde oxidase to become phosphoramide mustard (cytotoxic) and acrolein (cytotoxic)

Acrolein causes hem. cystitis

Mesna inactivates acrolein and is used prophylactically

31
Q

What are the pharmacological adverse effects of alkylating agents?

A

acute toxicity is seen within 30-60 minutes, including nasuea and vomiting and tissue damage at injection site (can do oral instead, pretreat with Zofran)

Delayed toxicites include bone marrow depression, alopecia, nephrotoxicity, mucosal uleration, GI changes

32
Q

What are some specific adverse effects of the following:

Cyclophosphamide

cisplatin

busulfan

A

hemorrhagic cystitis

renal tubular damage, ototoxicity

pulm. fibrosis

33
Q

What are antimetabolites and are they cell cycle (specific or nonspecific)?

A

they are structural analogs to compounds necessary for cell proliferation

they block pathways that are involved in cell replication

they are cell cycle specific

34
Q

What are the main categories of antimetabolites>

A
  1. folic acid analogs (methotrexate)
  2. pyrimidine analogs (5-fluorouracil)
  3. purine analogs (6-mercaptopurine)
35
Q

How does methotrexate work?

What is used in addition to avoid systemic cell toxicity?

A

inhibits dihydrofolate reductase and is useful for cancer, RA and psoriasis

Used in conjunction with reduced rolate leucovorin to rescue normal cells

36
Q

What drug is a pyrimidine structural analog?

How does the active compound work?

A

Fluorouracil

FdUMP covalently binds thymidylate synthase and blocks de novo synthesis of thymidylate

FdUTP and FUTP are incorporated into DNA and RNA to interfere with synthesis, function, processing and translation

37
Q

Which drug is a purine structural analog?

how is it metabolized?

Does it undergo first pass metabolism?

A

mercaptopurine

metabolized by HGPRT

Yes, if taken orally and then is inactivated by xanthine oxidase

38
Q

What is given along with 6MP (mercaptopurine) to prevent hyperuricemia due to tumor cell lysis?

If both allopurinol and PO 6MP are given together, what happens?

A

Allppurinol, a xanthine oxidase inhibitor

increased levels of 6MP and increased toxicity (fix by giving 50-75% less 6MP oral, or just give IV)

39
Q

What is the cell cycle specific target of antimetabolites?

After the initial dose, is there any acute toxicity? What about adverse side effects?

A

S phase

Relatively little acute toxicity; diarrhea, myelosupression, N/V, immunosupression, thrombocytopenia, leukopenia, hepatotoxicty

40
Q

What is the MOA for the Vinca alkaloids (vinblastine and vincristine)

Is it cell-cycle specific or nonspecific?

A

bind to B-tubulin and inhibit microtibile assembly (depolarization)

Cell cycle specific for the M phase (inhibits mitosis)

41
Q

What are some common adverse effects of vinblastine and vincristine?

A

alopecia and bone marrow depression

vinblastine can cause myelosuppresion to a greater extent than vincristine

vincristine can cause neuro toxicities

42
Q

What is the MOA for taxanes?

Are they cell cycle specific?

A

binds to B tubulin and stabilizes microtubule formation (so that they don’t work right)

Yes, for the M phase

43
Q

What are some adverse effects of Paclitaxel and docetaxel (both taxanes-for breast cancer)?

A

Paclitaxel can cause hypersensitivity reactions in hands, toes, and taste changes

Docetaxel is taken into cells and retained longer and better, leading to smaller dosing and fewer side effects, but can cause hypersensitivity, neutropenia, and alopecia

44
Q

What is the MOA for topoisomerase inhibitors?

What are the two classes?

Are they cell cycle specific?

A

Inhibiting topoisomerases leads to DNA damage and cell death

Camptothecins (topotecan, irinotecan) inhibit Topoisomerase I

Epipodophyllotocins (etoposide, teniposide) and anthracyclin antibiotics (doxorubicin and daunorubicin) inhibit toposiomerase II

Yes, at S mostly and G1/G2

45
Q

What are the five antitumor antibiotic classes?

What is their main effect?

A

anthracyclines

dactinomycin

bleomycin

mitomycin

they effect the DNA

46
Q

How do the anthracyclines work?

(Mainly Doxorubicin)

Is it cell cycle specific?

What kind of toxicity can occur?

A

Inhibits topoisomerase II, DNA intercalation

Not cell cycle specific

Can produce free radicals and cause cardiotoxicity, dysrhythmias and heart failure

47
Q

How does Bleomycin work?

What kind of adverse effects does it have?

A

Causes single and double stranded DNA breaks

can cause pulmonary toxicity and usually presents as pneumonitis with cough, dyspnea, crackles, but with minimal myelosuppression so good in combination

48
Q

How does Dactinomycin work?

A

Intercalation of DNA

49
Q

How does asparaginase work?

Is it cell specific?

What are the acute side effects?

What are delayed side effects/toxicities?

A

hydrolyzes circulating L-asparagine into aspartic acid and ammonia, effectively inhibiting protein synthesis

Yes, for G1

hypersensitivity reaction (fever, chills, n/v, urticaria)

increased risk of clotting, bleeding, pancreatitis, CNS toxicity

50
Q

What cancer is asparginase used for often?

A

ALL as a targeted therapy because they lack the enzyme aspariginase synthase

51
Q

How are differentiating agents used for cancer (Tretinoin)?

A

used for acute promyelocytic leukemia as it binds to the PML-RARa fusion protein and antagonizes the inhibitory effect on the transcription of target genes

the neoplastic cells differentate into neutrophils which rapidly die

very successful treatment

can cause vit. A toxicity and retinoic acid syndrome

52
Q

How can tyrosine kinases cause cancer?

A

When they are mutated, overexpressed or altered, tyrosine kinases can become oncoproteins

this can occur in the RTK or the cytoplasmic kinases

good news: good target for cancer therapy

53
Q

How can Imatinib treat Chronic myelogenous leukemia?

A

Imatinib is a small molecule inhibitor of the ABL tyrosine kinase and can target the BCR-ABL fusion protein that results from the t(9;22) translocation in pts with CML

can also inhibit RTKs PDGFR and KIT

54
Q

How do Erlotinib and gefitinib work?

what does it treat?

produces what side effects?

A

inhibit tyrosine kinase of the EFGR

refractory non-small cell lung cancer, pancreatic cancer

dermatologic toxicities

55
Q

What is the MOA for tyrosine kinase and growth factor receptor inhibitors?

A

inhibit growth factor receptor signaling

inhibit tyrosine kinase activity

56
Q

What is the mechanism of resistance of tyrosine kinase and growth factor receptor inhibitors?

What are common adverse effects?

A

point mutations in drug binding site can cause resistance

nausea, vomiting, acneform skin rash and hypersensitivity

57
Q

What are biologic response modifiers?

A

agents that act indirectly to mediate their antitumor effects by enhancing the immunologic response to neoplastic cells

Includes: interferons and interleukin-2

58
Q

How do interferons work?

What are the side effects?

A

inhibit cell growth, alter differentiation, interfere with oncogenes, alter surface antigens, increase phagocytic activity of macrophages, and augments cytotoxicity of lymphocytes for target cells

bone marrow depression, neutropenia, anemia, renal toxicity, edema, arrhythmias

59
Q

How does interleukin-2 work?

What is the major toxicity?

A

increases cytotoxicity killing by T cells and NK cells

capillary leak syndrome

60
Q

What is one of the cool things about using antibodies to treat cancer?

A

Antibodies can target spcific antigens on specific cancers

example: Rituximab-CD20 in non hodgkin’s lymphoma

61
Q

What are some treatments for malignant melanoma?

A

Dacarbazine and cisplatin (low response rate)

biologic agents like IFNa and IL2 (better response)

Nivolumab and pembrolizumab (if unresectable or metastatic as monotherapy)

62
Q

What is a common mutation in malignant melanoma?

What treatments are good treatment for this mutation?

A

BRAF V600E mutation present in a large majority of melanomas

constitutive activation of BRAF kinase

vemurafenib, dabrafenib, encorafenib target BRAF directly

63
Q

Common toxicities

A

Methotrexate, melphalan-mucositis

bleomucin, busulfan-pulmonary fibrosis

vincristine-peripheral neuropathy

cisplatin-ototoxicity

doxorubicin, daunorubicin-cardiotoxicity

cisplatin, cyclophosphamide-nephrotoxicty

cyclophphamide, ifosfamide-hemorrhagic cystits

Heme/Lymph Exam 1 (Erik Hammond) COPY (22 decks)

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