(Ch 45) Anticancer and Immunomodulating Drugs Flashcards
1
Q
DNA Synthesis Inhibitors
Name 3:
A
- Methotrexane
- Mercaptopurine
- Fluorouracil
2
Q
DNA Cross-linking and Intercalating Drugs
Name 6:
A
- Cyclophosphamide*
- Carmustine*
- Cisplatin*
- Busulfan*
- Bleomycin*
- Doxorubicin*
3
Q
DNA Topoisomerase Inhibitors
Name 2:
A
- Etoposide*
- Irinotecan*
4
Q
Mitotic Inhibitors
Name 2:
A
- Paclitaxel
- Vincristine
5
Q
Enzyme and Proteasome Inhibitors
Name 3:
A
- Bortezomib
- Imatinib
- Vemurafenib
6
Q
Cancer Immunotherapy Agents
Name 3:
A
- Rituximab
- Trastuzumab
- Interferon alfa
7
Q
Immunosuppressant Drugs
Name 7:
A
- Azathioprine*
- Mycophenolate*
- Basiliximab*
- Daclizumab*
- Cyclosporine*
- 6 Sirolimus*
- Tacrolimus*
8
Q
Calcineurin and mTOR inhibitors
name 3:
A
- Cyclosporine*
- Sirolimus*
- Tacrolimus*
9
Q
Immunomodulatory Monoclonal Antibodies :
Name 2
A
Basiliximab
Daclizumab
10
Q
Antiproliferative Agents:
Name 2
A
Azathrioprine
Mycophenolate
11
Q
- Cytokines and Interferons*
- Name 2*
A
Aldesleukin
Interferon alfa-2b
12
Q
Antineoplastic mTOR inhibitors
Name 2
A
Temsirolimus
Everolimus
13
Q
- Antineoplastic Monoclonal Antibodies*
- name 3*
A
Rituximab
Ipilimumab
Trastuzumab
14
Q
DNA cross-linking Drugs
Name 4
A
- Cyclophosphamide*
- Carmustine*
- Cisplatin*
- Busulfan*
15
Q
Ribonucleotide Reductase Inhibitor
1
A
Hydroxyurea
16
Q
- Pyrymidine Analogues*
- 2*
A
- Cytarabine*
- Fluorouracil*
17
Q
Purine Analogues
A
Mercaptopurine
Thioguanine
18
Q
- Folate Antagonist*
- 2*
A
- Methothrexate*
- Pemetrexed*
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
20
Q
- What are the most common*
- solid tumor malignanices?*
A
lungs
colon
breast
prostate
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
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.
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.
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 .
25
Some ***oncogenes*** are able to encode
WHAT?
Example ?
***growth factors*** and ***their receptors***
## Footnote
***Ex:** such as the **receptor tyrosine kinases (**GF) coupled with **signaling pathways** leading to continuous activation of **cyclins** and **cell replication***
26
***receptor tyrosine kinases (GF)***
*Provide example:*
***epidermal growth factor receptor (EGFR)*** that is *overexpressed (excessively produced) in lung and breast cancer.*
27
Provide an example of
important mechanism of cancer development
***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 i**nhibiting apoptosis** (programmed cell death) that normally serves to destroy nascent cancer cells.*
28
***Radiation***
is also called
* (Adjuvant Therapy)*
* to eradicate **micrometastases** and locally advanced cancer,*
29
***Antineoplastic drugs***
*are also used to treat ?*
***hematologic cancers***
that cannot be surgically excised
EX: ***leukemia and lymphoma***
***-*** and to treat ***inoperable*** and ***advanced metastatic tumors***
30
therapy for ***metastatic disease*** is often ?
***palliative*** rather than ***curative***.
***Palliative therapy*** *can prolong life and reduce incapacitating symptoms but does not eradicate the malignancy.*
31
*What is the definition of a **neoplasm**?*
The word “***neoplasm***” simply refers to a ***collection of abnormally proliferating cells****.*
## Footnote
***-Benign neoplasms** _do not **i**_**nvade surrounding tissue**.*
*-**Malignant neoplasms** _can invade_ and **metastasize** to all parts of the body and are usually fatal.*
32
*Name the **5 stages** of the cell cycle.*
***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*
33
*What is the significance of a*
***cell cycle–specific (CCS) antineoplastic agent**?*
***“Cell cycle–specific”** means that the **drug will primarily affect the cells that are actively replicating** or **cycling through G1 to M***
34
***Cell cycle–specific drugs include:***
*5*
* Antimetabolites*
* Mitotic inhibitors*
***Bleomycin***
***Etoposide***
*Steroid hormones*
35
What are
## Footnote
**cell cycle–nonspecific (CCNS) drugs?**
***CCNS** _drugs_ k**ill cells** whether they are **cycling or resting (G0).***
*They are more toxic but are **more effective** for s**low- growing tumors.***
36
***Cell** **(CCNS) cycle–nonspecific agents***
*include ?*
## Footnote
*alkylating agents*
***cisplatin***
* nitrosoureas*
* antibiotics.*
37
*What are the options for treating*
- Surgery
- immunotherapy
- radiotherapy
are often used initially to reduce the
**neoplastic cell burden (debulking)**;
*this is often followed by chemotherapy*
38
State **6 classes of antineoplastic agents**
***1. Alkylating agents***
***2. Antibiotics***
***3. Antimetabolites***
***4. Hormones and related agents***
***5. Mitoticinhibitors***
***6. Monoclonal antibodies***
39
***1. Alkylating agents—***
***name 9***
busulfan
cyclophosphamide - cisplatin
dacarbazine
lomustine
melphalan
procarbazine
streptozocin
40
**2. Antibiotics—**
**4**
bleomycin
dactinomycin
doxorubicin
daunorubicin
41
***3. Antimetabolites—***
5
cytarabine
5- fluorouracil
hydroxyurea
methotrexate
6- mercaptopurine
42
***4. Hormones and related agents—***
*4*
flutamide
glucocorticoids
leuprolide
tamoxifen
43
*5. Mitotic inhibitors—*
etoposide
paclitaxel
vinblastine
vincristine
44
* 6. Monoclonal antibodies—*
* 3*
rituximab
trastuzumab
gemtuzuma
45
*How does resistance to chemotherapeutic drugs develop?*
*Neoplastic cells can defend themselves in several ways including:*
- Increased DNA repair
- Changes in target enzymes
- Drug inactivation
- Decreased drug accumulation
-Alternative metabolic pathways
46
Can ***antineoplastic drugs***
be *used in combination*?
Yes.
## Footnote
*Many cancer treatment protocols involve more than one drug simultaneously.*
47
What are
***DNA alkylating*** agents?
A group of ***cell cycle–nonspecific compound***s *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.***
48
What are
***2 major classes*** of ***alkylating agents***?
**1.** ***Nitrogen mustards***
*(Mechlorethamine, Cyclophosphamide, Infosfamide, Melphalan, Chlorambucil)*
***2. Nitrosoureas*** (carmustine, lomustine, streptozocin)
49
***Cancer** arises as a result of ?*
* -genetic changes in the cell,*
* -**main genetic changes being**;*
* inactivation of tumor suppressor genes and **activation of oncogenes.***
50
*Most **anticancer** drugs are ?*
***antiproliferative***
*and hence affect rapidly growing dividing normal cells.*
51
# Define
***Antiproliferative***
*substance used to prevent or retard the spread of cells, especially malignant cells, into surrounding tissues.*
52
***Anticancer** (antineoplastic) **drugs***
*are broadly*
***classified into 2 categories***
***1. cytotoxic drugs/agents*** *(that nonspecifically inhibiti DNA replication or mitosis)*
## Footnote
***2. hormones***
* (and their antagonists are used in hormone sensitive tumors*
* (eg. _glucocorticoids_ for lymphomas)*
* (_oestrogens_ for prostatic cancer)*
* (_tamoxifen_ for breast tumors).*
53
***1. cytotoxic drugs***
*further classified into :*
***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
54
***1. Alkylating agents***
* name:*
* MOA:*
***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.
55
***2. Antimetabolites***
* name:*
* MOA:*
***2. Antimetabolites***
(e. g. methotrexate, fluorouracil, mercaptopurine):
- These drugs blocks or destabilize pathways
in DNA synthesis.
56
***3. Cytotoxic antibiotics***
* Name:*
* MOA:*
***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.
57
***4. Plant derivatives***
* Name:*
* MOA:*
***4. Plant derivatives***
(e. g. vincristine):
* -Inhibits mitosis*
58
***Tyrosine Kinases***
* Define*
* Function*
***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.
59
*Can Protein **Tyrosine*** ***kinases*** mutate ?
## Footnote
*What is are the results?*
* 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.*
60
*In the treatment of some types of cancer,*
***specific drug regimens are used***
* induction*
* consolidation*
* maintenance*
61
***Induction therapy***
*Define*
***Induction therapy***
***-**used in acute lymphocytic leukemia,*
*-produces a rapid reduction in the tumor cell burden and symptomatic improvement*
62
***Consolidation therapy***
*Define*
completes and extends the remission, while maintenance therapy sustains the remission as long as possible.
63
***Chemotherapy***
*defiene*
***Chemotherapy regimens***
*often employ multiple drugs administered as intermittent courses of therapy rather than as continuous therapy.*
64
* Intermittent therapy*
* define*
***Intermittent therapy***
## Footnote
*allows the bone marrow and other normal host cells to recover between treatment courses and reduces the level of toxicity.*
65
According to the
***log-kill concept....***
***each course of therapy*** *eliminates a constant fraction of the remaining tumor cells (e.g., 99.9%),*
## Footnote
*and*
***repeated courses of treatment** would ideally **reduce the number of tumor cells** to the **level** that the **immune system can eradicate.***
66
***First-line drugs***
*are employed for ?*
***First-line drugs***
*are employed for the*
***initial treatment of tumors***
67
***second-line drugs***
*indicated for Patients WHEN ?*
***second-line drugs***
*are indicated for patients who have r**_elapsed_** after **first-line therapy.***
68
***cytotoxic drugs***
## Footnote
*can be classified as*
* 1. cell cycle–specific*
* 2. cell cycle–nonspecific agents.*
69
*Cell cycle-nonspecific (CCNS) drug*
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
*Cell cycle-specific (CCS) drug*
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
* Growth fraction*
* Define*
*The proportion of cells in a tumor population that are actively dividing*
72
Myelosuppressant
define
* 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
***Oncogene***
***define***
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
***Cyclins***
are *growth factors* that *regulate* the *progression of cells* through the *cell cycle* and are *targets of new drug development*
75
***Tumor growth factors***
Stimulate?
***Tumor growth factors***
*often stimulate **cyclins** and **cyclin-dependent kinases**.*
76
***Drugs** that **act during a specific phase***
***of the** cell cycle are called ?*
***(cell cycle–specific drugs)***
*Cell cycle–specific drugs include:*
***all DNA synthesis inhibitors***
***mitotic inhibitors**.*
77
***drugs** that are **active throughout the cell cycle***
*are called ?*
*(cell cycle–nonspecific drugs)*
***Cell cycle–nonspecific drugs include all:***
***-DNA alkylating agents***
***-most DNA intercalating agents.***
78
*Most **antineoplastic drugs** have*
***3 major limitations:***
1. susceptibility to tumor cell resistance
2. production of host toxicity
3. an inability to suppress metastasis
79
***Innate drug resistance***
*may result from?*
***oncogenes*** *that **inactivate tumor suppressor genes Ex:** **p53** in **cancer cells.***
80
Expression of *WHAT antiapoptotic Protein*
can
produce resistance to drugs
and
by intefering with *WHAT type of SIGNAL* normally induced by antineoplastic agent ?
*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
*Damage to* **Bcl-2 gene** *has been indentified as a couse for ?*
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
***efflux pump***
* define:*
* also known as ?*
*Multidrug resistance pumps (MDR pumps)* also known *Multidrug efflux pumps* are a type of ***efflux pump*** and ***P-glycoprotein.***
## Footnote
*-MDR pumps in the cell membrane extrudes many foreign substances out of the cells and some pumps can have a broad specificity.*
83
Acquired drug resistance
can result from ongoing WHAT
***genomic mutations*** and ***abnormal gene expression*** as cancer cells evolve.
84
*Drug resistance can occur through **failure of the drug to reach its target** because of **drug efflux** from tumor cells.*
**Provide an EX:**
***For example,***
***P-glycoprotein (Pgp) efflux pump*** _expressed_ by the ***MDR1 gene*** acts to t***ransport many naturally occurring drugs out of tumor cells***,
including: *anthracyclines, taxanes, and vinca alkaloids*
85
Other examples of acquired drug resistance
include:
***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 o***verexpression 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
***myelosuppression***
*Define :*
***(bone marrow suppression)***
*produced by many antineoplastic drugs often results in **leukopenia** and **thrombocytopenia**, although **anemia** can also occur*
87
*Leukopenia*
**(leukocyte deficiency)**
predisposes patients to serious infections,
88
***thrombocytopenia***
***(platelet deficiency)***
can lead to bleeding.
89
* Nitrosourea drugs*
* Ex:*
* MOA:*
***(e.g., carmustine)***
*produce a more delayed and long-lasting suppression of leukocyte production.*
90
***Emetic***
Define:
***causing vomiting.***
91
Among the ***antineoplastic drugs***,
the ***most emetic***
are:
***cisplatin***
***carmustine***
*(antineoplastic drugs)*
***stimulate the chemoreceptor trigger zone in the medulla***
* and*
* elicit nausea and vomiting*
92
***C. Resistance to Anticancer Drugs***
***name***
***Mechanisms of resistance:***
***6***
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
*1. Increased DNA repair*
—An increased rate of DNA repair in tumor cells
can be responsible for resistance and is particularly important for
*alkylating agents* and *cisplatin.*
94
*2. Formation of trapping agents*
—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
*3. Changes in target enzymes*
—*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
*4. Decreased activation of prodrugs*
—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
***5. Inactivation of anticancer drugs***
*—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
*6. Decreased drug accumulation*
* —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
***Nausea and vomiting***
can be substantially reduced by
*pretreatment* with a
***combination of antiemetic drugs***
***name:***
***serotonin***
***antagonists*** *(e.g., ondansetron)*
***corticosteroids*** *(e.g., dexamethasone)*
100
***alopecia***
***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
What drugs can cause
***Cardiotoxicity***?
then name drug that prevents
***Anthracycline-induced Caritoxidity?***
* Cause:* ***doxorubicin (anthracyclines)***
* Prevents: **Dexrazoxane***
102
What drugs can cause
## Footnote
***hemorrhagic cystitis ?***
***Define :***
***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
What drug can cause
## Footnote
***renal toxicity ?***
***cisplatin***
104
Drug that can cause
## Footnote
***pulmonary toxicity ?***
***bleomycin or busulfan***
105
Druga that can cause
## Footnote
***neurotoxicity.***
* vincristine*
* paclitaxel*
* other vinca alkaloids*
* taxanes*
106
What drugs prevents
## Footnote
***hemorrhagic cystitis ?***
Another ***cytoprotective drug***,
***"Mesna"***
was developed to prevent
***cyclophosphamide-induced hemorrhagic cystitis.***
107
***Cisplatin- induced renal toxicity***
can be partly prevented by
WHAT?
***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
Drug resistance can occur through failure of the drug to reach its target
because of
WHAT?
***Drug Efflux form tumor cells***
109
*Name 2 important **Efflux pumps** :*
* 1. P-glycoprotein (Pgp)*
* 2. Multidrug-resistance protein (MRP)*
110
***P-glycoprotein (Pgp)***
*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
***topoisomerase***
*define:*
***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
***Anticancer drugs** can be divided into*
*2 broad categories:*
(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
***Antifolates***
***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
***Cytotoxic Agents***
* DNA Synthesis Inhibitors*
* are analogs of WHAT?*
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
***Methotrexate***
* \_\_\_\_\_\_ Antagonist:*
* Clinical Use:*
***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
***Methotrexate***
* Chemistry*
* Mechanisms*
***MTX***
*inhibits **dihydrofolate reductase**, the _enzyme_ that **converts dietary folate** to **the active tetrahydrofolate form** _required_ for **thymidine** and **purine synthesis***
117
Methotrexate
***Pharmacokinetics:***
* 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
**MTX** and **pemetrexed** are structural analogs of WHAT?
***of folic acid***
***(Vitamin B 9)***
119
***pemetrexed***
Administration:
*MOA:*
***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
***Dihydrofolate reductase (DHFR)***
is an enzyme that reduces
WHAT?
***Dihydrofolate reductase, or DHFR***,
is an *enzyme that reduces dihydrofolic acid* to t*etrahydrofolic acid,*
***using NADPH as electron donor***,
which can be converted to the kinds of ***tetrahydrofolate cofactors used in 1-carbon transfer chemistry***
121
***thymidylate synthase.***
***Thymidylate synthase (TS***) *is an enzyme that **catalyzes the conversion of deoxyuridine monophosphate (dUMP)** to **deoxythymidine monophosphate (dTMP).***
## Footnote
***Thymidine** is one of the **nucleotides in DNA.***
*With i**nhibition of TS,** an **imbalance of deoxynucleotides** and **increased levels of dUMP arise**. Both cause DNA damage*
122
*Inhibition of DNA synthesis by methotrexate (MTX) and fluorouracil.*
***Understand:***
*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
***Methotrexate Indications:***
***Used in TX of***
***choriocarcinoma (a trophoblastic tumor)***
***breast cancer***
***osteosarcoma***
*routinely given by intrathecal administration to prevent meningeal metastases during chemotherapy of acute lymphocytic leukemia*
124
* Intrathecal administration*
* Define:*
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
* Pemetrexed*
* is indicated for the treatment of:*
***Pemetrexed***
*is indicated for the treatment*
***of non-squamous***
***non–small cell lung cancer***
* and*
* the treatment of **mesothelioma**, _both in combination_ with **cisplatin**.*
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***Mesothelioma***
***Define***
* 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
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***myelosuppression***
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.
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What can be administerd to prevent adverse effects of
## Footnote
**MTX**
**and**
**Permetrexed:**
*without imparing drug efficacy.*
Administration of fully
*activated form of*
***folic acid (leucovorin)***
***Note:** it cannot reverse AE once after they have occurred*
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***Adverse Effects***
***MTX*** *and* ***pemetrexed***
* -Myelosuppression (bone marrow suppression)*
* -gatrointestinal mucosa*
* -oral ulceration (stomatitis)*
***-hepatotoxicity** with **long-term/low-dose therapy** for **psoriasis** and **rheumatoid conditions.***
130
(stomatitis)
define:
oral ulceration
131
Pemetrexed
is a novel ______ drug.
it rapidly metabolizes to WHAT?
***Active Polyglutamate forms** that _inhibit_ several **tetrahydrofolat-dependent enzymes***
*_involved_ in the _synsthesis_ of*
***Purine** and **Pyrimidine bases,** including*
***Thymidylate synthase.***
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***Thiol***
***define:***
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
***Purine Analogs***
***Mercaptopurine*** and ***thioguanine*** are
the analogs of WHAT?
the ***thio analogs*** of the
***urine bases hypoxanthine*** *and* ***guanine***
134
4 types of nucleotides found in DNA:
name:
***guanine -******cytosine-******adenine -******thymine***
These are nitrogenous bases and are subdivided into purines and pyrimidines.
***purines*** are *adenine and guanine*
**pyrimidines** are *cytosine and thymin*e.
These four bases form complementary pairs in the DNA polymer,...
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***Mercaptopurine*** *and* ***thioguanine***
* Both drugs can be converted to* ***What***
* by addition of* ***What?***
Both drugs are converted to ***nucleotides by the addition of ribose phosphate***, a r_eaction catalyzed_ by ***hypoxanthine guanine***
## Footnote
***phosphori- bosyltransferase***
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The ***active metabolite*s** of ***mercaptopurine*** and ***thioguanine***
inhibit several steps in the biosynthesis of WHAT?
MOA:
*_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.*
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***Mercaptopurine*** is given with \_\_\_\_\_
to maintain remission in patients with ______ \_\_\_\_\_\_
Mercaptopurine is given with ***MTX*** to ***maintain remis- sion*** *in patients with* ***acute lymphocytic leukemia***
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***Thioguanine*** is used to maintain
remission in patients with ____ \_\_\_\_ and ______ \_\_\_\_\_\_ \_\_\_\_\_\_\_.
Thioguanine is used to maintain
remission in patients with ***acute lymphocytic*** and ***acute myeloid leukemia***
139
***Mercaptopurine*** is metabolized by \_\_\_\_\_\_\_
whereas
***thioguanine*** is _______ by other enzymes.
* Mercaptopurine* is metabolized by ***xanthine oxidase,*** *whereas*
* thioguanine* is ***degraded*** by other enzymes.
140
Doses of ______ must be reduced by at least 50% in patients taking ***allopurinol***,
What is the MOA of ***Allopurinol***
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*.**
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***Allopurinol***
*Allopurinal is admisistered to a Patient undergoing what form of TX and why ?*
Allopurinol is often given to patients ***undergoing cancer chemotherapy*** because it ***inhibits the synthesis of uric acid and thereby prevents hyperuricemia and gout.***
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Cancer chemotherapy places patients at risk for *Hyperuricemia and Gout*..because the destruction of cancer cells
INCREASES WHAT?
destruction of cancer cells ***increases purine catabolism*** and ***uric acid formation***,
called
***tumor lysis syndrome.***
143
***allantoin***
define:
*a **crystalline oxidation** product (C 4H 6N 4O 3 )*
***of uric acid** _used to promote healing_ of **local wounds** and **infections.***
144
What is an _alternative_ to ***Allopurinol ?***
a new *recombinant formulation of the enzyme **uricase***,
## Footnote
*which **converts uric acid** to **allantoin***
145
***Name 2 Purine Analogs that***
are ***halogenated purine nucleoside*** _analogs_ whose ***triphosphate metabolites*** are
incorporated into nascent DNA,
causing DNA chain termination.
***Fludarabine*** *and* ***cladribine***
-------------------------------------------
are what type of Nucleotides and are incorporated into WHAT causing _____ termination.
146
***Fludarabine*** is a *highly active agent*
## Footnote
*in the treatment of ?*
***chronic lymphocytic leukemia (CLL)***
*and*
***low-grade non-Hodgkin lymphoma***
147
***Cladribine***
***(Purine Analog)***
is primarily used for?
***hairy cell leukemia***
***-------------------------------***
is treated with what Drug/class
148
***Clofarabine***
*and*
***nelarabine***
are new *purine nucleoside analogs* for _treating_
***refractory***
or
***relapsed acute lymphocytic leukemia.***
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