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(MUL) Pharmacology > (Ch 45) Anticancer and Immunomodulating Drugs > Flashcards

(Ch 45) Anticancer and Immunomodulating Drugs Flashcards

1
Q

DNA Synthesis Inhibitors

Name 3:

A
  1. Methotrexane
  2. Mercaptopurine
  3. Fluorouracil
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2
Q

DNA Cross-linking and Intercalating Drugs

Name 6:

A
    1. Cyclophosphamide*
    1. Carmustine*
    1. Cisplatin*
    1. Busulfan*
    1. Bleomycin*
    1. Doxorubicin*
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3
Q

DNA Topoisomerase Inhibitors

Name 2:

A
    1. Etoposide*
    1. Irinotecan*
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4
Q

Mitotic Inhibitors

Name 2:

A
  1. Paclitaxel
  2. Vincristine
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5
Q

Enzyme and Proteasome Inhibitors

Name 3:

A
  1. Bortezomib
  2. Imatinib
  3. Vemurafenib
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6
Q

Cancer Immunotherapy Agents

Name 3:

A
  1. Rituximab
  2. Trastuzumab
  3. Interferon alfa
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7
Q

Immunosuppressant Drugs

Name 7:

A
    1. Azathioprine*
    1. Mycophenolate*
    1. Basiliximab*
    1. Daclizumab*
    1. Cyclosporine*
  • 6 Sirolimus*
    1. Tacrolimus*
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8
Q

Calcineurin and mTOR inhibitors

name 3:

A
  • Cyclosporine*
  • Sirolimus*
  • Tacrolimus*
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9
Q

Immunomodulatory Monoclonal Antibodies :

Name 2

A

Basiliximab

Daclizumab

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10
Q

Antiproliferative Agents:

Name 2

A

Azathrioprine

Mycophenolate

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11
Q
  • Cytokines and Interferons*
  • Name 2*
A

Aldesleukin

Interferon alfa-2b

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12
Q

Antineoplastic mTOR inhibitors

Name 2

A

Temsirolimus

Everolimus

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13
Q
  • Antineoplastic Monoclonal Antibodies*
  • name 3*
A

Rituximab

Ipilimumab

Trastuzumab

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14
Q

DNA cross-linking Drugs

Name 4

A
  • Cyclophosphamide*
  • Carmustine*
  • Cisplatin*
  • Busulfan*
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15
Q

Ribonucleotide Reductase Inhibitor

1

A

Hydroxyurea

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16
Q
  • Pyrymidine Analogues*
  • 2*
A
  • Cytarabine*
  • Fluorouracil*
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17
Q

Purine Analogues

A

Mercaptopurine

Thioguanine

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18
Q
  • Folate Antagonist*
  • 2*
A
  • Methothrexate*
  • Pemetrexed*
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19
Q

2 main types of cancer:

A

(1) solid tumors that begin as abnormal tissue growths and often spread to other tissues
(2) hematologic malignancies that arise in the bone marrow or lymph nodes and produce large quantities of abnormal blood cells

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20
Q
  • What are the most common*
  • solid tumor malignanices?*
A

lungs

colon

breast

prostate

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21
Q
  • Most common*
  • hematologic malignancies*
A
  • hematologic malignancies include:*
  • leukemias consisting of malignant white blood cells (leukocytes)
  • lymphomas comprised of malignant lymphocytes,
  • multiple myeloma
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22
Q

Cancer results from what ?

A
  • transformation of normal cells into malignant neoplastic cells that exhibit loss of normal function (de-differentiation),
  • uncontrolled cell division
  • invasiveness
  • metastasis.
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23
Q

Define

process of angiogenesis

A

The invasiveness and metastasis of cancer cells depends on the expression of growth factors that promote the formation of new blood vessels to supply the growing tumor.

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24
Q

What is

Malignant transformation

caused by ?

A

Malignant transformation is caused by genetic mutations that convert proto-oncogenes to oncogenes (cancer forming genes)

These genes express proteins that promote uncon- trolled cell proliferation or that inactivate tumor suppressor genes .

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25
Q

Some oncogenes are able to encode

WHAT?

Example ?

A

growth factors and their receptors

Ex:** such as the **receptor tyrosine kinases (**GF) coupled with **signaling pathways** leading to continuous activation of **cyclins** and **cell replication

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26
Q

receptor tyrosine kinases (GF)

Provide example:

A

epidermal growth factor receptor (EGFR) that is overexpressed (excessively produced) in lung and breast cancer.

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27
Q

Provide an example of

important mechanism of cancer development

A

Inactivation of tumor suppressor genes

EX: solid tumors have a mutated p 53 gene (p53 gene that normally suppresses the malignant transformation of cells.)

Additinally: many tumors express one of the bcl-2 genes that promote cancer cell survival by inhibiting apoptosis (programmed cell death) that normally serves to destroy nascent cancer cells.

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28
Q

Radiation

is also called

A
  • (Adjuvant Therapy)*
  • to eradicate micrometastases and locally advanced cancer,*
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29
Q

Antineoplastic drugs

are also used to treat ?

A

hematologic cancers

that cannot be surgically excised

EX: leukemia and lymphoma

- and to treat inoperable and advanced metastatic tumors

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30
Q

therapy for metastatic disease is often ?

A

palliative rather than curative.

Palliative therapy can prolong life and reduce incapacitating symptoms but does not eradicate the malignancy.

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31
Q

What is the definition of a neoplasm?

A

The word “neoplasm” simply refers to a collection of abnormally proliferating cells.

-Benign neoplasms do not invade surrounding tissue.

-Malignant neoplasms can invade and metastasize to all parts of the body and are usually fatal.

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32
Q

Name the 5 stages of the cell cycle.

A

1. G1—synthesis of components needed

for DNA synthesis

2. S—DNA synthesis

3. G2—growth and replication of

cytoplasmic constituents

4. M—mitosis

5. G0-—resting phase

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33
Q

What is the significance of a

cell cycle–specific (CCS) antineoplastic agent?

A

“Cell cycle–specific”** means that the **drug will primarily affect the cells that are actively replicating** or **cycling through G1 to M

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34
Q

Cell cycle–specific drugs include:

5

A
  • Antimetabolites*
  • Mitotic inhibitors*

Bleomycin

Etoposide

Steroid hormones

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35
Q

What are

cell cycle–nonspecific (CCNS) drugs?

A

CCNS** drugs k**ill cells** whether they are **cycling or resting (G0).

They are more toxic but are more effective for slow- growing tumors.

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36
Q

Cell** **(CCNS) cycle–nonspecific agents

include ?

A

alkylating agents

cisplatin

  • nitrosoureas*
  • antibiotics.*
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37
Q

What are the options for treating

A
  • Surgery
  • immunotherapy
  • radiotherapy

are often used initially to reduce the

neoplastic cell burden (debulking);

this is often followed by chemotherapy

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38
Q

State 6 classes of antineoplastic agents

A

1. Alkylating agents

2. Antibiotics

3. Antimetabolites

4. Hormones and related agents

5. Mitoticinhibitors

6. Monoclonal antibodies

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39
Q

1. Alkylating agents—

name 9

A

busulfan

cyclophosphamide - cisplatin

dacarbazine

lomustine

melphalan

procarbazine

streptozocin

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40
Q

2. Antibiotics—

4

A

bleomycin

dactinomycin

doxorubicin

daunorubicin

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41
Q

3. Antimetabolites—

5

A

cytarabine

5- fluorouracil

hydroxyurea

methotrexate

6- mercaptopurine

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42
Q

4. Hormones and related agents—

4

A

flutamide

glucocorticoids

leuprolide

tamoxifen

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43
Q

5. Mitotic inhibitors—

A

etoposide

paclitaxel

vinblastine

vincristine

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44
Q
    1. Monoclonal antibodies—*
  • 3*
A

rituximab

trastuzumab

gemtuzuma

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45
Q

How does resistance to chemotherapeutic drugs develop?

A

Neoplastic cells can defend themselves in several ways including:

  • Increased DNA repair
  • Changes in target enzymes
  • Drug inactivation
  • Decreased drug accumulation

-Alternative metabolic pathways

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46
Q

Can antineoplastic drugs

be used in combination?

A

Yes.

Many cancer treatment protocols involve more than one drug simultaneously.

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47
Q

What are

DNA alkylating agents?

A

A group of cell cycle–nonspecific compounds that transfer an alkyl group, usually to the N7 nitrogen atom of guanine residues in one or both strands of DNA.

This prevents further replication of tumor cells.

All alkylating agents are carcinogenic and thus can lead to secondary cancer.

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48
Q

What are

2 major classes of alkylating agents?

A

1. Nitrogen mustards

(Mechlorethamine, Cyclophosphamide, Infosfamide, Melphalan, Chlorambucil)

2. Nitrosoureas (carmustine, lomustine, streptozocin)

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49
Q

Cancer arises as a result of ?

A
  • -genetic changes in the cell,*
  • -main genetic changes being;*
  • inactivation of tumor suppressor genes and activation of oncogenes.*
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50
Q

Most anticancer drugs are ?

A

antiproliferative

and hence affect rapidly growing dividing normal cells.

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51
Q

Define

Antiproliferative

A

substance used to prevent or retard the spread of cells, especially malignant cells, into surrounding tissues.

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52
Q

Anticancer** (antineoplastic) **drugs

are broadly

classified into 2 categories

A

1. cytotoxic drugs/agents (that nonspecifically inhibiti DNA replication or mitosis)

2. hormones

  • (and their antagonists are used in hormone sensitive tumors*
  • (eg. glucocorticoids for lymphomas)*
  • (oestrogens for prostatic cancer)*
  • (tamoxifen for breast tumors).*
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53
Q

1. cytotoxic drugs

further classified into :

A

1. Alkylating agents (e.g. cyclophosphamide, lomustine, thiotepa, cisplatin): These groups of drugs act by forming covalent bonds with DNA and thus impending DNA replication.

2. Antimetabolites (e.g. methotrexate, fluorouracil, mercaptopurine): These drugs blocks or destabilize pathways in DNA synthesis.

3. Cytotoxic antibiotics (e.g. Doxorubucin, bleomycin, dactinomycin): These drugs inhibit DNA or RNA synthesis or cause fragmentation to DNA chains or interfere with RNA polymerase and thus inhibit transcription.

4. Plant derivatives (e.g. vincristine): Inhibits mitosis

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54
Q

1. Alkylating agents

  • name:*
  • MOA:*
A

1. Alkylating agents

(e.g. cyclophosphamide, lomustine, thiotepa, cisplatin):

These groups of drugs act by forming covalent bonds with DNA and thus impending DNA replication.

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55
Q

2. Antimetabolites

  • name:*
  • MOA:*
A

2. Antimetabolites

(e. g. methotrexate, fluorouracil, mercaptopurine):
- These drugs blocks or destabilize pathways

in DNA synthesis.

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56
Q

3. Cytotoxic antibiotics

  • Name:*
  • MOA:*
A

3. Cytotoxic antibiotics

(e. g. Doxorubucin, bleomycin, dactinomycin):
- These drugs inhibit DNA or RNA synthesis or cause fragmentation to DNA chains or interfere with RNA polymerase and thus inhibit transcription.

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57
Q

4. Plant derivatives

  • Name:*
  • MOA:*
A

4. Plant derivatives

(e. g. vincristine):
* -Inhibits mitosis*

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58
Q

Tyrosine Kinases

  • Define*
  • Function*
A

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell.

It functions as an “on” or “off” switch in many cellular functions.

Tyrosine kinases belong to a larger class of enzymes known as protein kinases which also attach phosphates to other amino acids such as serine and threonine.

Phosphorylation of proteins by kinases is an important mechanism for communicating signals within a cell (signal transduction) and regulating cellular activity, such as cell division.

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59
Q

Can Protein Tyrosine kinases mutate ?

What is are the results?

A
  • YES*
  • Protein* Tyrosine kinases can become mutated,

stuck in the “on” position, and cause unregulated growth of the cell,

  • which is a necessary step for the development of cancer.*
  • Therefore,* kinase inhibitors (imatinib) are often effective cancer treatments.
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60
Q

In the treatment of some types of cancer,

specific drug regimens are used

A
  • induction*
  • consolidation*
  • maintenance*
61
Q

Induction therapy

Define

A

Induction therapy

-used in acute lymphocytic leukemia,

-produces a rapid reduction in the tumor cell burden and symptomatic improvement

62
Q

Consolidation therapy

Define

A

completes and extends the remission, while maintenance therapy sustains the remission as long as possible.

63
Q

Chemotherapy

defiene

A

Chemotherapy regimens

often employ multiple drugs administered as intermittent courses of therapy rather than as continuous therapy.

64
Q
  • Intermittent therapy*
  • define*
A

Intermittent therapy

allows the bone marrow and other normal host cells to recover between treatment courses and reduces the level of toxicity.

65
Q

According to the

log-kill concept….

A

each course of therapy eliminates a constant fraction of the remaining tumor cells (e.g., 99.9%),

and

repeated courses of treatment** would ideally **reduce the number of tumor cells** to the **level** that the **immune system can eradicate.

66
Q

First-line drugs

are employed for ?

A

First-line drugs

are employed for the

initial treatment of tumors

67
Q

second-line drugs

indicated for Patients WHEN ?

A

second-line drugs

are indicated for patients who have r_elapsed_ after first-line therapy.

68
Q

cytotoxic drugs

can be classified as

A
    1. cell cycle–specific*
    1. cell cycle–nonspecific agents.*
69
Q

Cell cycle-nonspecific (CCNS) drug

A

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

Traversing- travel across

70
Q

Cell cycle-specific (CCS) drug

A

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

71
Q
  • Growth fraction*
  • Define*
A

The proportion of cells in a tumor population that are actively dividing

72
Q

Myelosuppressant

define

A
  • 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”*
73
Q

Oncogene

define

A

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

74
Q

Cyclins

A

are growth factors that regulate the progression of cells through the cell cycle and are targets of new drug development

75
Q

Tumor growth factors

Stimulate?

A

Tumor growth factors

often stimulate cyclins and cyclin-dependent kinases.

76
Q

Drugs** that **act during a specific phase

of the cell cycle are called ?

A

(cell cycle–specific drugs)

Cell cycle–specific drugs include:

all DNA synthesis inhibitors

mitotic inhibitors.

77
Q

drugs** that are **active throughout the cell cycle

are called ?

A

(cell cycle–nonspecific drugs)

Cell cycle–nonspecific drugs include all:

-DNA alkylating agents

-most DNA intercalating agents.

78
Q

Most antineoplastic drugs have

3 major limitations:

A
  1. susceptibility to tumor cell resistance
  2. production of host toxicity
  3. an inability to suppress metastasis
79
Q

Innate drug resistance

may result from?

A

oncogenes that inactivate tumor suppressor genes Ex: p53 in cancer cells.

80
Q

Expression of WHAT antiapoptotic Protein

can

produce resistance to drugs

and

by intefering with WHAT type of SIGNAL normally induced by antineoplastic agent ?

A

Expression of antiapoptotic proteins such as Bcl-2 can produce resistance to drugs by interfering with the cell death signal (apoptosis) normally induced by an antineoplastic agent.

81
Q

Damage to Bcl-2 gene has been indentified as a couse for ?

A

Damage to the Bcl-2 gene has been identified as a cause of a number of cancers, including

melanoma, breast, prostate,

chronic lymphocytic leukemia,

lung cancer, and a possible cause of schizophrenia and autoimmunity.

It is also a cause of resistance to cancer treatments

82
Q

efflux pump

  • define:*
  • also known as ?*
A

Multidrug resistance pumps (MDR pumps) also known Multidrug efflux pumps are a type of efflux pump and P-glycoprotein.

-MDR pumps in the cell membrane extrudes many foreign substances out of the cells and some pumps can have a broad specificity.

83
Q

Acquired drug resistance

can result from ongoing WHAT

A

genomic mutations and abnormal gene expression as cancer cells evolve.

84
Q

Drug resistance can occur through failure of the drug to reach its target because of drug efflux from tumor cells.

Provide an EX:

A

For example,

P-glycoprotein (Pgp) efflux pump expressed by the MDR1 gene acts to transport many naturally occurring drugs out of tumor cells,

including: anthracyclines, taxanes, and vinca alkaloids

85
Q

Other examples of acquired drug resistance

include:

A

1. topoisomerase mutations that convey resistance to topoi- somerase inhibitors (e.g., etoposide). 2. Resistance to methotrexate (MTX) can occur through mutations in its target enzyme, dihydrofolate reductase, or through overexpression of the enzyme so as to overwhelm drug inhibition.

3. Mutations in genes for tubulin or microtubule-associated proteins can cause resistance to the vinca alkaloids and taxane drugs.

86
Q

myelosuppression

Define :

A

(bone marrow suppression)

produced by many antineoplastic drugs often results in leukopenia and thrombocytopenia, although anemia can also occur

87
Q

Leukopenia

A

(leukocyte deficiency)

predisposes patients to serious infections,

88
Q

thrombocytopenia

A

(platelet deficiency)

can lead to bleeding.

89
Q
  • Nitrosourea drugs*
  • Ex:*
  • MOA:*
A

(e.g., carmustine)

produce a more delayed and long-lasting suppression of leukocyte production.

90
Q

Emetic

Define:

A

causing vomiting.

91
Q

Among the antineoplastic drugs,

the most emetic

are:

A

cisplatin

carmustine

(antineoplastic drugs)

stimulate the chemoreceptor trigger zone in the medulla

  • and*
  • elicit nausea and vomiting*
92
Q

C. Resistance to Anticancer Drugs

name

Mechanisms of resistance:

6

A
  1. Increased DNA repair
  2. Formation of trapping agents
  3. Changes in target enzymes
  4. Decreased activation of prodrugs
  5. Inactivation of anticancer drugs
  6. Decreased drug accumulation
93
Q

1. Increased DNA repair

A

—An increased rate of DNA repair in tumor cells

can be responsible for resistance and is particularly important for

alkylating agents and cisplatin.

94
Q

2. Formation of trapping agents

A

—Some tumor cells increase their production of,

thiol trapping agents (eg, glutathione),

interact with anticancer drugs that form reactive electrophilic species.

This mechanism of resistance is seen with the alkylating agent :

bleomycin, cisplatin, anthracyclines.

95
Q

3. Changes in target enzymes

A

—Changes in the drug sensitivity of a target enzyme, dihydrofolate reductase, and increased synthesis of the enzyme are mechanisms of resistance of tumor cells to methotrexate.

96
Q

4. Decreased activation of prodrugs

A

—Resistance to the purine antimetabolites (mercaptopurine, thioguanine)

and

the pyrimidine antimetabolites (cytarabine, fluorouracil)

can result from a decrease in the activity of the tumor cell enzymes needed to convert these prodrugs to their cytotoxic metabolites.

97
Q

5. Inactivation of anticancer drugs

A

—Increased activity of enzymes capable of inactivating anticancer drugs is a mechanism of tumor cell resistance to most of the

purine and pyrimidine antimetabolites.

98
Q

6. Decreased drug accumulation

A
  • —This form of multidrug resistance involves the increased expression of a normal gene (MDR1) for a cell surface glycoprotein (P-glycoprotein).*
  • This transport molecule is involved in the accelerated efflux of many anticancer drugs in resistant cells.*
99
Q

Nausea and vomiting

can be substantially reduced by

pretreatment with a

combination of antiemetic drugs

name:

A

serotonin

antagonists (e.g., ondansetron)

corticosteroids (e.g., dexamethasone)

100
Q

alopecia

A

Hair loss (alopecia) can affect just your scalp or your entire body, and it can be temporary or permanent. It can be the result of heredity, hormonal changes, medical conditions or a normal part of aging.

101
Q

What drugs can cause

Cardiotoxicity?

then name drug that prevents

Anthracycline-induced Caritoxidity?

A
  • Cause:* doxorubicin (anthracyclines)
  • Prevents: Dexrazoxane*
102
Q

What drugs can cause

hemorrhagic cystitis ?

Define :

A

cyclophosphamide

ifosfamide

inflammation of the bladder defined by lower urinary tract symptoms that include dysuria, hematuria, and hemorrhage.

The disease can occur as a complication of cyclophosphamide, ifosfamide and radiation therapy. In addition to hemorrhagic cystitis, temporary hematuria can also be seen in bladder infection or in children as a result of viral infection.

103
Q

What drug can cause

renal toxicity ?

A

cisplatin

104
Q

Drug that can cause

pulmonary toxicity ?

A

bleomycin or busulfan

105
Q

Druga that can cause

neurotoxicity.

A
  • vincristine*
  • paclitaxel*
  • other vinca alkaloids*
  • taxanes*
106
Q

What drugs prevents

hemorrhagic cystitis ?

A

Another cytoprotective drug,

“Mesna”

was developed to prevent

cyclophosphamide-induced hemorrhagic cystitis.

107
Q

Cisplatin- induced renal toxicity

can be partly prevented by

WHAT?

A

Cisplatin- induced renal toxicity

can be partly prevented by

administering fluids, along with

mannitol and sodium thiosulfate.

-Mannitol maintains renal blood flow and tubular function

-Sodium thiosulfate inactivates the drug in the kidneys.

108
Q

Drug resistance can occur through failure of the drug to reach its target

because of

WHAT?

A

Drug Efflux form tumor cells

109
Q

Name 2 important Efflux pumps :

A
    1. P-glycoprotein (Pgp)*
    1. Multidrug-resistance protein (MRP)*
110
Q

P-glycoprotein (Pgp)

A

efflux pump (product of Multidrug Resistance 1) expressed by the MDR1 gene acts to transport many naturally occurring drugs out of tumor cells, including anthracyclines, taxanes, and vinca alkaloids Induction of Pgp by antineoplastic drugs can lead to multidrug resistance.

111
Q

topoisomerase

define:

A

enzymes** that participate in the **overwinding or underwinding of DNA.

In order to prevent and correct these types of topological problems caused by the double helix, topoisomerases bind to DNA and cut the phosphate backbone of either one or both the DNA strands. This intermediate break allows the DNA to be untangled or unwound, and, at the end of these processes, the DNA backbone is resealed again.

112
Q

Anticancer drugs can be divided into

2 broad categories:

A

(1) cytotoxic agents that nonspecifically inhibit cell replication

The term chemotherapy is often used to designate treatment with traditional cytotoxic drugs

(2) targeted and immunotherapy agents that inhibit specific proteins involved in tumor cell growth.

immunotherapy is used for treatment with monoclonal antibodies and other biologic agents that enhance tumor immunity.

113
Q

Antifolates

A

Antifolates

  • are a class of antimetabolite medications that antagonise (that is, block) the actions of folic acid (vitamin B9).*
  • Folic acid’s primary function in the body is as a cofactor to various methyltransferases involved in serine, methionine, thymidine and purine biosynthesis.*
114
Q

Cytotoxic Agents

  • DNA Synthesis Inhibitors*
  • are analogs of WHAT?*
A

Cytotoxic Agents

DNA Synthesis Inhibitors

The DNA synthesis inhibitors are analogs of folic acid or of the purine or pyrimidine bases found in DNA.

They act as antimetabolites that inhibit enzymes catalyzing various steps in DNA synthesis.

115
Q

Methotrexate

  • ______ Antagonist:*
  • Clinical Use:*
A

Folate Antagonist

  • -induce remission in children with childhood leukemia*
  • -used as an immunosuppressive drug in the treatment of autoimmune diseases*
  • Breast Cancer
  • osteosarcoma
  • lymphoma
  • choriocarcinoma
  • Bladder cancer
116
Q

Methotrexate

  • Chemistry*
  • Mechanisms*
A

MTX

inhibits dihydrofolate reductase, the enzyme that converts dietary folate to the active tetrahydrofolate form required for thymidine and purine synthesis

117
Q

Methotrexate

Pharmacokinetics:

A
  • administered orally or parenterally.*
  • The oral bioavailability of MTX is dose dependent, with lower doses absorbed more completely than higher doses.*
  • MTX is widely distributed but does not penetrate the central nervous system (CNS).*
118
Q

MTX and pemetrexed are structural analogs of WHAT?

A

of folic acid

(Vitamin B 9)

119
Q

pemetrexed

Administration:

MOA:

A

pemetrexed

is only given intravenously

  • and*
  • is mostly excreted unchanged in the urine.*

Pemetrexed** is converted to a_ctive forms_ that **inhibit several enzymes involved in DNA synthesis**, including **dihydrofolate reductase** and **thymidylate synthase.

120
Q

Dihydrofolate reductase (DHFR)

is an enzyme that reduces

WHAT?

A

Dihydrofolate reductase, or DHFR,

is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid,

using NADPH as electron donor,

which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry

121
Q

thymidylate synthase.

A

Thymidylate synthase (TS) is an enzyme that catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP).

Thymidine** is one of the **nucleotides in DNA.

With inhibition of TS, an imbalance of deoxynucleotides and increased levels of dUMP arise. Both cause DNA damage

122
Q

Inhibition of DNA synthesis by methotrexate (MTX) and fluorouracil.

Understand:

A

MTX inhibits dihydrofolate reductase and the conversion of dihydrofolate to tetrahydrofolate. This reduces the supply of 5,10-methylene- tetrahydrofolate, a substance required for the synthesis of deoxythymidine monophosphate (DTMP). The conversion of deoxyuridine monophosphate (DUMP) to DTMP, a critical step in DNA synthesis, is catalyzed by thymidylate synthetase. This enzyme is inhibited by 5-fluorodeoxyuridine monophosphate (5-FdUMP), which is the active form of fluorouracil. Pemetrexed inhibits both dihydrofolate reductase and thymidylate synthetase.

123
Q

Methotrexate Indications:

Used in TX of

A

choriocarcinoma (a trophoblastic tumor)

breast cancer

osteosarcoma

routinely given by intrathecal administration to prevent meningeal metastases during chemotherapy of acute lymphocytic leukemia

124
Q
  • Intrathecal administration*
  • Define:*
A

Intrathecal administration

is a route of administration for drugs via an injection into the spinal canal, or into the subarachnoid space so that it reaches the cerebrospinal fluid (CSF) and is useful in spinal anesthesia, chemotherapy, or pain management applications.

This route is also used to introduce drugs that fight certain infections, particularly post-neurosurgical.

125
Q
  • Pemetrexed*
  • is indicated for the treatment of:*
A

Pemetrexed

is indicated for the treatment

of non-squamous

non–small cell lung cancer

  • and*
  • the treatment of mesothelioma, both in combination with cisplatin.*
126
Q

Mesothelioma

Define

A
  • type of cancer that develops from the thin layer of tissue that covers many of the internal organs (known as the mesothelium).*
  • The most common area affected is the lining of the lungs and chest wall.*
  • Less commonly the lining of the abdomen and rarely the sac surrounding the heart, or the sac* surrounding the testis may be affected
127
Q

myelosuppression

A

or bone marrow suppression

-defined as a decrease in the ability of the bone marrow to produce blood cells.

This may result in a lack of red blood cells (anemia), white blood cells (leukopenia), and platelets (thrombocytopenia).

Myelosuppression may occur when the stem cells in the bone marrow are damaged (such as by chemotherapy drugs), when it is crowded (by tumor cells or fibrosis), or due to bone marrow failure.

128
Q

What can be administerd to prevent adverse effects of

MTX

and

Permetrexed:

without imparing drug efficacy.

A

Administration of fully

activated form of

folic acid (leucovorin)

Note: it cannot reverse AE once after they have occurred

129
Q

Adverse Effects

MTX and pemetrexed

A
  • -Myelosuppression (bone marrow suppression)*
  • -gatrointestinal mucosa*
  • -oral ulceration (stomatitis)*

-hepatotoxicity** with **long-term/low-dose therapy** for **psoriasis** and **rheumatoid conditions.

130
Q

(stomatitis)

define:

A

oral ulceration

131
Q

Pemetrexed

is a novel ______ drug.

it rapidly metabolizes to WHAT?

A

Active Polyglutamate forms** that inhibit several **tetrahydrofolat-dependent enzymes

involved in the synsthesis of

Purine and Pyrimidine bases, including

Thymidylate synthase.

132
Q

Thiol

define:

A

1: any of various compounds having the

general formula RSH

which are analogous to alcohols but in which sulfur replaces the oxygen of the hydroxyl group

and

which have disagreeable odors.

2 : the functional group−SH characteristic of thiols.

133
Q

Purine Analogs

Mercaptopurine and thioguanine are

the analogs of WHAT?

A

the thio analogs of the

urine bases hypoxanthine and guanine

134
Q

4 types of nucleotides found in DNA:

name:

A

guanine -cytosine-adenine -thymine

These are nitrogenous bases and are subdivided into purines and pyrimidines.

purines are adenine and guanine

pyrimidines are cytosine and thymine.

These four bases form complementary pairs in the DNA polymer,…

135
Q

Mercaptopurine and thioguanine

  • Both drugs can be converted to* What
  • by addition of* What?
A

Both drugs are converted to nucleotides by the addition of ribose phosphate, a r_eaction catalyzed_ by hypoxanthine guanine

phosphori- bosyltransferase

136
Q

The active metabolites of mercaptopurine and thioguanine

inhibit several steps in the biosynthesis of WHAT?

MOA:

A

inhibit several steps in the biosynthesis of purine bases (adenine and guanine)

  • and*
  • in p_urine recycling pathways_ that supply purine precursors, thereby impairing DNA synthesis.*
137
Q

Mercaptopurine is given with _____

to maintain remission in patients with ______ ______

A

Mercaptopurine is given with MTX to maintain remis- sion in patients with acute lymphocytic leukemia

138
Q

Thioguanine is used to maintain

remission in patients with ____ ____ and ______ ______ _______.

A

Thioguanine is used to maintain

remission in patients with acute lymphocytic and acute myeloid leukemia

139
Q

Mercaptopurine is metabolized by _______

whereas

thioguanine is _______ by other enzymes.

A
  • Mercaptopurine* is metabolized by xanthine oxidase, whereas
  • thioguanine* is degraded by other enzymes.
140
Q

Doses of ______ must be reduced by at least 50% in patients taking allopurinol,

What is the MOA of Allopurinol

A

Doses of mercaptopurine must be reduced by at least 50% in patients taking allopurinol,

Allopurinol - which inhibits xanthine oxidase and thereby elevates plasma levels of mercaptopurine.

141
Q

Allopurinol

Allopurinal is admisistered to a Patient undergoing what form of TX and why ?

A

Allopurinol is often given to patients undergoing cancer chemotherapy because it inhibits the synthesis of uric acid and thereby prevents hyperuricemia and gout.

142
Q

Cancer chemotherapy places patients at risk for Hyperuricemia and Gout..because the destruction of cancer cells

INCREASES WHAT?

A

destruction of cancer cells increases purine catabolism and uric acid formation,

called

tumor lysis syndrome.

143
Q

allantoin

define:

A

a crystalline oxidation product (C 4H 6N 4O 3 )

of uric acid** used to promote healing of **local wounds** and **infections.

144
Q

What is an alternative to Allopurinol ?

A

a new recombinant formulation of the enzyme uricase,

which converts uric acid to allantoin

145
Q

Name 2 Purine Analogs that

are halogenated purine nucleoside analogs whose triphosphate metabolites are

incorporated into nascent DNA,

causing DNA chain termination.

A

Fludarabine and cladribine

are what type of Nucleotides and are incorporated into WHAT causing _____ termination.

146
Q

Fludarabine is a highly active agent

in the treatment of ?

A

chronic lymphocytic leukemia (CLL)

and

low-grade non-Hodgkin lymphoma

147
Q

Cladribine

(Purine Analog)

is primarily used for?

A

hairy cell leukemia

——————————-

is treated with what Drug/class

148
Q

Clofarabine

and

nelarabine

A

are new purine nucleoside analogs for treating

refractory

or

relapsed acute lymphocytic leukemia.

149
Q
A

(MUL) Pharmacology (18 decks)

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