(Ch 45) Anticancer and Immunomodulating Drugs Flashcards
DNA Synthesis Inhibitors
Name 3:
- Methotrexane
- Mercaptopurine
- Fluorouracil
DNA Cross-linking and Intercalating Drugs
Name 6:
- Cyclophosphamide*
- Carmustine*
- Cisplatin*
- Busulfan*
- Bleomycin*
- Doxorubicin*
DNA Topoisomerase Inhibitors
Name 2:
- Etoposide*
- Irinotecan*
Mitotic Inhibitors
Name 2:
- Paclitaxel
- Vincristine
Enzyme and Proteasome Inhibitors
Name 3:
- Bortezomib
- Imatinib
- Vemurafenib
Cancer Immunotherapy Agents
Name 3:
- Rituximab
- Trastuzumab
- Interferon alfa
Immunosuppressant Drugs
Name 7:
- Azathioprine*
- Mycophenolate*
- Basiliximab*
- Daclizumab*
- Cyclosporine*
- 6 Sirolimus*
- Tacrolimus*
Calcineurin and mTOR inhibitors
name 3:
- Cyclosporine*
- Sirolimus*
- Tacrolimus*
Immunomodulatory Monoclonal Antibodies :
Name 2
Basiliximab
Daclizumab
Antiproliferative Agents:
Name 2
Azathrioprine
Mycophenolate
- Cytokines and Interferons*
- Name 2*
Aldesleukin
Interferon alfa-2b
Antineoplastic mTOR inhibitors
Name 2
Temsirolimus
Everolimus
- Antineoplastic Monoclonal Antibodies*
- name 3*
Rituximab
Ipilimumab
Trastuzumab
DNA cross-linking Drugs
Name 4
- Cyclophosphamide*
- Carmustine*
- Cisplatin*
- Busulfan*
Ribonucleotide Reductase Inhibitor
1
Hydroxyurea
- Pyrymidine Analogues*
- 2*
- Cytarabine*
- Fluorouracil*
Purine Analogues
Mercaptopurine
Thioguanine
- Folate Antagonist*
- 2*
- Methothrexate*
- Pemetrexed*
2 main types of cancer:
(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
- What are the most common*
- solid tumor malignanices?*
lungs
colon
breast
prostate
- Most common*
- hematologic malignancies*
- hematologic malignancies include:*
- leukemias consisting of malignant white blood cells (leukocytes)
- lymphomas comprised of malignant lymphocytes,
- multiple myeloma
Cancer results from what ?
- transformation of normal cells into malignant neoplastic cells that exhibit loss of normal function (de-differentiation),
- uncontrolled cell division
- invasiveness
- metastasis.
Define
process of angiogenesis
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.
What is
Malignant transformation
caused by ?
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 .
Some oncogenes are able to encode
WHAT?
Example ?
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
receptor tyrosine kinases (GF)
Provide example:
epidermal growth factor receptor (EGFR) that is overexpressed (excessively produced) in lung and breast cancer.
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 inhibiting apoptosis (programmed cell death) that normally serves to destroy nascent cancer cells.
Radiation
is also called
- (Adjuvant Therapy)*
- to eradicate micrometastases and locally advanced cancer,*
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
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.
What is the definition of a neoplasm?
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.
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
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
Cell cycle–specific drugs include:
5
- Antimetabolites*
- Mitotic inhibitors*
Bleomycin
Etoposide
Steroid hormones
What are
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 slow- growing tumors.
Cell** **(CCNS) cycle–nonspecific agents
include ?
alkylating agents
cisplatin
- nitrosoureas*
- antibiotics.*
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
State 6 classes of antineoplastic agents
1. Alkylating agents
2. Antibiotics
3. Antimetabolites
4. Hormones and related agents
5. Mitoticinhibitors
6. Monoclonal antibodies
1. Alkylating agents—
name 9
busulfan
cyclophosphamide - cisplatin
dacarbazine
lomustine
melphalan
procarbazine
streptozocin
2. Antibiotics—
4
bleomycin
dactinomycin
doxorubicin
daunorubicin
3. Antimetabolites—
5
cytarabine
5- fluorouracil
hydroxyurea
methotrexate
6- mercaptopurine
4. Hormones and related agents—
4
flutamide
glucocorticoids
leuprolide
tamoxifen
5. Mitotic inhibitors—
etoposide
paclitaxel
vinblastine
vincristine
- Monoclonal antibodies—*
- 3*
rituximab
trastuzumab
gemtuzuma
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
Can antineoplastic drugs
be used in combination?
Yes.
Many cancer treatment protocols involve more than one drug simultaneously.
What are
DNA alkylating agents?
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.
What are
2 major classes of alkylating agents?
1. Nitrogen mustards
(Mechlorethamine, Cyclophosphamide, Infosfamide, Melphalan, Chlorambucil)
2. Nitrosoureas (carmustine, lomustine, streptozocin)
Cancer arises as a result of ?
- -genetic changes in the cell,*
- -main genetic changes being;*
- inactivation of tumor suppressor genes and activation of oncogenes.*
Most anticancer drugs are ?
antiproliferative
and hence affect rapidly growing dividing normal cells.
Define
Antiproliferative
substance used to prevent or retard the spread of cells, especially malignant cells, into surrounding tissues.
Anticancer** (antineoplastic) **drugs
are broadly
classified into 2 categories
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).*
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
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.
2. Antimetabolites
- name:*
- MOA:*
2. Antimetabolites
(e. g. methotrexate, fluorouracil, mercaptopurine):
- These drugs blocks or destabilize pathways
in DNA synthesis.
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.
4. Plant derivatives
- Name:*
- MOA:*
4. Plant derivatives
(e. g. vincristine):
* -Inhibits mitosis*
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.
Can Protein Tyrosine kinases mutate ?
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.
In the treatment of some types of cancer,
specific drug regimens are used
- induction*
- consolidation*
- maintenance*
Induction therapy
Define
Induction therapy
-used in acute lymphocytic leukemia,
-produces a rapid reduction in the tumor cell burden and symptomatic improvement
Consolidation therapy
Define
completes and extends the remission, while maintenance therapy sustains the remission as long as possible.
Chemotherapy
defiene
Chemotherapy regimens
often employ multiple drugs administered as intermittent courses of therapy rather than as continuous therapy.
- Intermittent therapy*
- define*
Intermittent therapy
allows the bone marrow and other normal host cells to recover between treatment courses and reduces the level of toxicity.
According to the
log-kill concept….
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.
First-line drugs
are employed for ?
First-line drugs
are employed for the
initial treatment of tumors
second-line drugs
indicated for Patients WHEN ?
second-line drugs
are indicated for patients who have r_elapsed_ after first-line therapy.
cytotoxic drugs
can be classified as
- cell cycle–specific*
- cell cycle–nonspecific agents.*
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
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
- Growth fraction*
- Define*
The proportion of cells in a tumor population that are actively dividing
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”*
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
Cyclins
are growth factors that regulate the progression of cells through the cell cycle and are targets of new drug development
Tumor growth factors
Stimulate?
Tumor growth factors
often stimulate cyclins and cyclin-dependent kinases.
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.
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.
Most antineoplastic drugs have
3 major limitations:
- susceptibility to tumor cell resistance
- production of host toxicity
- an inability to suppress metastasis
Innate drug resistance
may result from?
oncogenes that inactivate tumor suppressor genes Ex: p53 in cancer cells.
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.
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
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.
-MDR pumps in the cell membrane extrudes many foreign substances out of the cells and some pumps can have a broad specificity.
Acquired drug resistance
can result from ongoing WHAT
genomic mutations and abnormal gene expression as cancer cells evolve.
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 transport many naturally occurring drugs out of tumor cells,
including: anthracyclines, taxanes, and vinca alkaloids
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 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.
myelosuppression
Define :
(bone marrow suppression)
produced by many antineoplastic drugs often results in leukopenia and thrombocytopenia, although anemia can also occur
Leukopenia
(leukocyte deficiency)
predisposes patients to serious infections,
thrombocytopenia
(platelet deficiency)
can lead to bleeding.
- Nitrosourea drugs*
- Ex:*
- MOA:*
(e.g., carmustine)
produce a more delayed and long-lasting suppression of leukocyte production.
Emetic
Define:
causing vomiting.
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*
C. Resistance to Anticancer Drugs
name
Mechanisms of resistance:
6
- Increased DNA repair
- Formation of trapping agents
- Changes in target enzymes
- Decreased activation of prodrugs
- Inactivation of anticancer drugs
- Decreased drug accumulation
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.
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.
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.
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.
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.
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.*
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)
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.
What drugs can cause
Cardiotoxicity?
then name drug that prevents
Anthracycline-induced Caritoxidity?
- Cause:* doxorubicin (anthracyclines)
- Prevents: Dexrazoxane*
What drugs can cause
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.
What drug can cause
renal toxicity ?
cisplatin
Drug that can cause
pulmonary toxicity ?
bleomycin or busulfan
Druga that can cause
neurotoxicity.
- vincristine*
- paclitaxel*
- other vinca alkaloids*
- taxanes*
What drugs prevents
hemorrhagic cystitis ?
Another cytoprotective drug,
“Mesna”
was developed to prevent
cyclophosphamide-induced hemorrhagic cystitis.
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.
Drug resistance can occur through failure of the drug to reach its target
because of
WHAT?
Drug Efflux form tumor cells
Name 2 important Efflux pumps :
- P-glycoprotein (Pgp)*
- Multidrug-resistance protein (MRP)*
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.
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.
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.
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.*
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.
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
Methotrexate
- Chemistry*
- Mechanisms*
MTX
inhibits dihydrofolate reductase, the enzyme that converts dietary folate to the active tetrahydrofolate form required for thymidine and purine synthesis
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).*
MTX and pemetrexed are structural analogs of WHAT?
of folic acid
(Vitamin B 9)
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.
Dihydrofolate reductase (DHFR)
is an enzyme that reduces
WHAT?
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
thymidylate synthase.
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
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.
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
- 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.
- 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.*
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
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.
What can be administerd to prevent adverse effects of
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
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.
(stomatitis)
define:
oral ulceration
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.
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.
Purine Analogs
Mercaptopurine and thioguanine are
the analogs of WHAT?
the thio analogs of the
urine bases hypoxanthine and guanine
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 thymine.
These four bases form complementary pairs in the DNA polymer,…
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
phosphori- bosyltransferase
The active metabolites 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.*
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
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
Mercaptopurine is metabolized by _______
whereas
thioguanine is _______ by other enzymes.
- Mercaptopurine* is metabolized by xanthine oxidase, whereas
- thioguanine* is degraded by other enzymes.
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.
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.
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.
allantoin
define:
a crystalline oxidation product (C 4H 6N 4O 3 )
of uric acid** used to promote healing of **local wounds** and **infections.
What is an alternative to Allopurinol ?
a new recombinant formulation of the enzyme uricase,
which converts uric acid to allantoin
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.
Fludarabine is a highly active agent
in the treatment of ?
chronic lymphocytic leukemia (CLL)
and
low-grade non-Hodgkin lymphoma
Cladribine
(Purine Analog)
is primarily used for?
hairy cell leukemia
——————————-
is treated with what Drug/class
Clofarabine
and
nelarabine
are new purine nucleoside analogs for treating
refractory
or
relapsed acute lymphocytic leukemia.
