4. ◎ Methotrexate
○ 4-amino-10-methyl analog of folic acid
◎ Pemetrexed
○ a pyrrolopyrimidine, multitargeted antifolate analog that targets
multiple enzymes (TS, DHFR, GAR formyltransferase, AICAR
formyltransferase)
◎ Pralatrexate
○ bind with higher affinity to the reduced folate carrier (RFC)-1
transport protein when compared with MTX, leading to enhanced
membrane transport into tumor cells
○ a more potent inhibitor of the folate-associated enzymes, including
TS, DHFR 4
Anti-Folates
7. ◎ tight-binding inhibitors of DHFR
○ maintains the intracellular folate pools in their fully reduced form as
tetrahydrofolates
7
Anti-Folates- Mechanism of Action
8. ◎ alterations in antifolate transport
◎ decreased polyglutamation of the antifolate parent
compound
◎ alterations in the target enzymes DHFR and/or TS
◎ mediated by induction of the unfolded protein
response (UPR), which leads to phosphorylation of
eukaryotic translation initiation factor 2 alpha
(EIF2S1)
8
Anti-Folates- Mechanisms of Resistance
9. ◎ Oral bioavailability of MTX is saturable and erratic at doses
>25 mg/m2
◎ completely absorbed from parenteral and peak serum levels
are achieved w/in 30 to 60 mins.
◎ fluid collections (PE and ascites) should be drained prior to
initiation of treatment
○ slow release of accumulated drug from these third-space collections over time
prolongs the terminal half-life of the drug, leading to potentially increased clinical
toxicity.
○ plasma drug concentrations should be closely monitored
◎ Excretion: RENAL
9
Anti-Folates- Clinical Pharmacology
10. ◎ Main S/E (reversible w/in 14 days)
○ Myelosuppression
○ GI
◎ MTX-induced nephrotoxicity
○ results from the intratubular precipitation of parent drug and its metabolites in acidic
urine
○ exert a direct toxic effect on the renal tubules
○ Tx: Vigorous hydration and urinary alkalinization
◎ Increased LFTs and hyperbilirubinemia (high-dose therapy)
○ Return to Normal in 10 days
◎ Risk of soft tissue necrosis and osteonecrosis
○ If given concomitantly with radiotherapy
◎ Leucovorin- folic acid analog 10
Anti-Folates- Toxicity
11. ◎ Pemetrexed and Pralatrexate
○ GI toxicity and myelosuppression
◉ Reduced by supplementation with folic acid (350 μg orally daily)
and vitamin B12 (1,000 μg SC given at least 1 week before
starting therapy and then repeated every 3 cycles).
○ mucositis
○ skin rash, usually in the form of the hand-foot syndrome
○ LFT Alterations,
○ anorexia and fatigue syndrome
11
Anti-Folates- Toxicity
12. ◎ 5-fluorouracil (5-FU) – 1950’s
◎ serve as the main backbone for regimens used
to treat metastatic CRC and as adjuvant therapy
of early-stage colon CA.
12
5-Fluoropyrimidines
13. (1) inhibition of TS
(2) incorporation into RNA
(3) incorporation into DNA
13
5-Fluoropyrimidines
Mechanism of Action
15. ○ alteration in the target enzyme TS with
increased expression
○ cell lines and tumors with higher levels of TS
are relatively more resistant to 5-FU.
○ Mutations in the TS protein have been
identified with reduced binding affinity
of cytotoxic (FdUMP) to the TS protein.
15
Mechanism of Resistance
16. ○ 5-FU is not administered via the oral route.
◉ catabolic enzyme DPD present in the
gut mucosa
○ IV Bolus-rapid elimination Half-life (8-
15mins)
○ Up to 80% to 85% of 5-FU is inactivated by
○ 3% to 5% -partial DPD deficiency
○ 0.1%- complete DPD deficiency
◉ mucositis, diarrhea,
myelosuppression, neurologic toxicity,
death 16
5-Fluoropyrimidines
Clinical Pharmacology
17. ○ the reduced folate leucovorin (LV) has been the main
biochemical modulator of 5-FU
○ prolonged exposure of tumor cells to 5-FU would increase
the fraction of cells being exposed to the drug.
○ overall safety profile is improved with infusional regimens.
○ DeGramont et al.
◉ hybrid schedule of bolus and infusional 5-FU.
○ 46-hour infusion
◉ Maintained clinical activity of 5-FU
17
5-Fluoropyrimidines
Biomodulation of 5-FU
19. ◎ oral fluoropyrimidine analog
◎ first-line treatment of metastatic colorectal
cancer (mCRC) and as adjuvant therapy for
stage III colon cancer when fluoropyrimidine
therapy alone is preferred.
◎ XELOX- mCRC, adjuvant therapy of stage III
colon cancer.
19
Capecitabine
20. ○ rapid and extensively
absorbed by the gut
○ 3 steps
◉ 1st two steps= liver
◉ 3rd step = tumor tissue
○ Excretion=RENAL
◉ >50CrCl= no DR
◉ 30-50= 25% DR
◉ <30= Contraindicated
20
Clinical Pharmacology
Capecitabine
21. ○ diarrhea and hand-foot syndrome
○ ↓ myelosuppression, neutropenic fever, mucositis,
alopecia, and N/V
21
Toxicity
Capecitabine
24. ○ Rapid absorption through the GI tract
○ Reduced absorption with taken with food.
24
Clinical Pharmacology
25. ○ Myelosuppression
◉ main dose-limiting toxicity
○ Nausea/vomiting, diarrhea, and abdominal pain
○ Fatigue, asthenia, and anorexia
○ NOT associated with mucositis or dermatologic
toxicity.
25
Toxicity
26. • deoxycytidine nucleoside
analog isolated from the
Cryptotethya crypta sponge.
• combined with an
anthracycline given as a 5- or
7-day continuous infusion is
considered the standard
induction treatment for AML.
26
Cytarabine
28. ○ increased levels of
cytidine deaminase and
deoxycytidylate
deaminase
◉ Main mechanisms
with cytarabine
resistance
28
Mechanism of
Resistance
29. ○ Poor oral bioavailability
○ Within 24 hours, up to 80% of drug is recovered in
the urine as either the ara-U or ara-UMP
metabolite.
○ At high doses, cytarabine crosses the BBB
29
Clinical Pharmacology
30. ○ Myelosuppression (2 to 3 g/m2 per dose)
○ Leukopenia and thrombocytopenia
◉ After 7-14 days
○ GI toxicity
○ Neurologic Toxicity
○ Pulmonary complications
◉ noncardiogenic pulmonary edema, ARDS, and
Streptococcus viridans pneumonia
30
Toxicity
31. • difluorinated deoxycytidine analog.
• broad-spectrum clinical activity against several
human solid tumors, including pancreatic, bile
duct, gallbladder, small-cell and NSCLC,
bladder, ovary, and breast cancers as well
• as hematologic malignancies, including HL and
NHL.
31
Gemcitabine
33. ○ Reduced cellular transport arising from reduced
expression of the hENT1 transport protein.
○ Reduced expression and/or deficiency in deoxycytidine
kinase enzyme activity
○ tumor microenvironment and specifically tumor-
associated macrophages (TAM)
33
Mechanism of Resistance
34. ○ Administered via the IV route (30-minute infusion)
○ >90% of the metabolized drug being recovered in urine
○ Plasma clearance is about 30% lower in women and in
elderly patients
◉ result in an increased risk of toxicity
○ Infusion of 10 mg/m2 per minute
◉ yielded the highest accumulation of active
gemcitabine triphosphate
34
Clinical Pharmacology
35. ○ Myeolosuppression
◉ main dose-limiting toxicity
○ Toxicity is schedule dependent
○ Transient flu-like symptoms- 45%
○ Asthenia and transient ↑ of LFTs
○ Thrombotic microangiopathy syndromes (rare)
◉ TTP, HUS
35
Toxicity
36. ◎ 1950s
◎ 6-mercaptopurine (6-MP)
○ maintenance therapy for ALL
◎ 6-thioguanine (6-TG)
○ remission induction and in maintenance
therapy for AML
36
6- THIOPURINES
37. ○ Thiopurines inhibit specific enzymes involved in de novo
purine synthesis and purine interconversion reactions.
○ Their respective triphosphate nucleotide metabolites are
directly incorporated into either cellular RNA or
DNA, leading to the inhibition of RNA and DNA synthesis
and function.
37
Mechanism of Action
38. 6-mercaptopurine (6-MP)
○ Poor oral bioavailability
○ ↓ dose of 6-MP by at least
50-75% if given with
allopurinol.
39
Clinical Pharmacology
6-thioguanine (6-TG)
• Oral but erratic
39. ○ Myelosuppression
○ GI toxicity with N/V,
diarrhea, and mucositis
○ TPMT-deficient patients
• 5-25% DR
○ Thiopurine
Hepatotoxicity
• Cholestatic jaundice
40
Toxicity
40. • active agent in the treatment of chronic
lymphocytic leukemia (CLL) and mantle cell
lymphoma.
• no activity against solid tumors
41
Fludarabine
42. Decreased expression of the activating enzyme
deoxycytidine kinase
○ resulting in decreased intracellular formation of
fludarabine monophosphate
43
Mechanism of Resistance
44. ○ Myelosuppression and immunosuppression
○ Suppression of the immune system affects T-cell function
more
• Febrile neutropenia
• Opportunistic Infections (Varicella-zoster virus,
Candida, and Pneumocystis jirovecii)
45
Toxicity
45. ◎ purine deoxyadenosine analog with
activity in lowgrade lymphoproliferative
disorders
◎ DOC for Hairy Cell Leukemia
46
Cladribine
48. ○ orally bioavailable (50%)
○ SC- Near 100%
○ Able to cross BBB
○ Excretion
• 50% Kidneys
• 20-35% unchanged
49
Clinical Pharmacology
49. ○ Myelosuppression
○ Recovery
◉ Thrombocytopenia-2-4 wks
◉ Neutropenia-3-5 wks
○ CD4+ cells decrease within 1 to 4 weeks, and may remain
depressed for over 1 to 2 years
50
Toxicity
50. • purine deoxyadenosine nucleoside analog
• pediatric patients with relapsed or refractory
ALL
51
Clofarabine
52. ○ decreased activation of the drug through the reduced
expression of the anabolic enzyme deoxycytidine kinase
○ decreased transport of drug into cells via the respective
nucleoside transporters hENT1, hENT2, and hCNT3
○ increased expression of CTP synthetase activity, resulting
in increased concentrations of the competing physiologic
nucleotide substrate dCTP
53
Mechanism of Resistance
54. ○ Myelosuppression is dose limiting with
neutropenia, anemia, and thrombocytopenia.
○ Capillary leak syndrome (SIRS)
◉ tachypnea, tachycardia, pulmonary edema,
and hypotension
○ Tumor Lysis syndrome
55
Toxicity
55. • a purine deoxyguanosine nucleoside analog and
prodrug of arabinofuranosylguanine (ara-G).
• T-cell ALL (T-ALL) and T-cell lymphoblastic
leukemia (T-LBL)
56
Nelarabine
57. ○ Two main resistance mechanisms
◉ decreased activation of the drug through reduced
expression of deoxycytidine kinase
◉ decreased transport of drug into cells via the
nucleoside transporter protein
58
Mechanism of Resistance
58. ○ Nelarabine is rapidly eliminated from plasma with a mean
half-life of 18 minutes.
○ Only about 5% to 10% of the administered dose is cleared
by the kidneys
○ The effects of renal and hepatic impairment on the
pharmacokinetics of nelarabine have not been specifically
evaluated.
59
Clinical Pharmacology
59. ○ Myelosuppression
○ Neurotoxicity
◉ Dose-limiting
◉ headache, altered mental status, and peripheral
neuropathy with numbness, paresthesias, and motor
weakness.
60
Toxicity
63. Instructions for use
EDIT IN GOOGLE SLIDES
Click on the button under the
presentation preview that says "Use as
Google Slides Theme".
You will get a copy of this document on
your Google Drive and will be able to
edit, add or delete slides.
You have to be signed in to your Google
account.
EDIT IN POWERPOINT®
Click on the button under the
presentation preview that says
"Download as PowerPoint template". You
will get a .pptx file that you can edit in
PowerPoint.
Remember to download and install the
fonts used in this presentation (you’ll find
the links to the font files needed in the
Presentation design slide)
More info on how to use this template at www.slidescarnival.com/help-use-presentation-
template
This template is free to use under Creative Commons Attribution license. You can keep the
Credits slide or mention SlidesCarnival and other resources used in a slide footer.
64
64. Hello!
I am Jayden Smith
I am here because I love to
give presentations.
You can find me at:
@username
65
68. White
Is the color of milk and fresh
snow, the color produced by the
combination of all the colors of
the visible spectrum.
You can also split your content
Black
Is the color of ebony and of
outer space. It has been the
symbolic color of elegance,
solemnity and authority.
69
69. In two or three columns
Yellow
Is the color of gold,
butter and ripe
lemons. In the
spectrum of visible
light, yellow is found
between green and
orange.
Blue
Is the colour of the
clear sky and the deep
sea. It is located
between violet and
green on the optical
spectrum.
Red
Is the color of blood,
and because of this it
has historically been
associated with
sacrifice, danger and
courage.
70
70. A picture is worth a thousand words
A complex idea can be
conveyed with just a single
still image, namely making
it possible to absorb large
amounts of data quickly.
71
72. Use charts to explain your ideas
Gray
White Black
73
73. Or diagrams to explain complex ideas
Example text.
Lorem ipsum dolor sit amet,
consectetur adipiscing elit.
Nam venenatis nisi at nisl
tempor, et luctus diam
lobortis. Nulla sit amet metus
consequat velit iaculis
tempor.
Example text.
Lorem ipsum dolor sit amet,
consectetur adipiscing elit.
Nam venenatis nisi at nisl
tempor, et luctus diam
lobortis. Nulla sit amet metus
consequat velit iaculis
tempor.
74
74. And tables to compare data
A B C
Yellow 10 20 7
Blue 30 15 10
Orange 5 24 16
75
77. Presentation design
This presentations uses the following typographies and colors:
◎ Titles: Roboto Slab
◎ Body copy: Source Sans Pro
Download for free at:
https://www.fontsquirrel.com/fonts/roboto-slab
https://www.fontsquirrel.com/fonts/source-sans-pro
You don’t need to keep this slide in your presentation. It’s only here to serve you
as a design guide if you need to create new slides or download the fonts to edit
the presentation in PowerPoint®
78
80. Let’s review some concepts
Yellow
Is the color of gold, butter and ripe
lemons. In the spectrum of visible
light, yellow is found between
green and orange.
Blue
Is the colour of the clear sky and
the deep sea. It is located between
violet and green on the optical
spectrum.
Red
Is the color of blood, and because
of this it has historically been
associated with sacrifice, danger
and courage.
Yellow
Is the color of gold, butter and ripe
lemons. In the spectrum of visible
light, yellow is found between
green and orange.
Blue
Is the colour of the clear sky and
the deep sea. It is located between
violet and green on the optical
spectrum.
Red
Is the color of blood, and because
of this it has historically been
associated with sacrifice, danger
and courage.
81
81. You can insert graphs from Excel or Google Sheets
82
4000
3000
2000
1000
0
82. Mobile project
Show and explain your web,
app or software projects using
these gadget templates.
83
83. Tablet project
Show and explain your web,
app or software projects using
these gadget templates.
84
84. Desktop project
Show and explain your web, app or software projects using these gadget templates.
85
86. Credits
Special thanks to all the people who made and released
these awesome resources for free:
◎ Presentation template by SlidesCarnival
◎ Photographs by Unsplash
87
88. Timeline
89
DEC
NOV
OCT
SEP
AUG
JUL
JUN
MAY
APR
MAR
FEB
JAN
Blue is the colour of the
clear sky and the deep sea
Red is the colour of
danger and courage
Black is the color of ebony
and of outer space
Yellow is the color of gold,
butter and ripe lemons
White is the color of milk
and fresh snow
Blue is the colour of the
clear sky and the deep sea
Yellow is the color of gold,
butter and ripe lemons
White is the color of milk
and fresh snow
Blue is the colour of the
clear sky and the deep sea
Red is the colour of
danger and courage
Black is the color of ebony
and of outer space
Yellow is the color of
gold, butter and ripe
lemons
89. Roadmap
90
1 3 5
6
4
2
Blue is the colour of the
clear sky and the deep sea
Red is the colour of danger
and courage
Black is the color of ebony
and of outer space
Yellow is the color of gold,
butter and ripe lemons
White is the color of milk
and fresh snow
Blue is the colour of the
clear sky and the deep sea
91. SWOT Analysis
92
STRENGTHS
Blue is the colour of the clear
sky and the deep sea
WEAKNESSES
Yellow is the color of gold,
butter and ripe lemons
Black is the color of ebony
and of outer space
OPPORTUNITIES
White is the color of milk and
fresh snow
THREATS
92. Business Model Canvas
93
Key Activities
Insert your content
Key Resources
Insert your content
Value Propositions
Insert your content
Customer Relationships
Insert your content
Channels
Insert your content
Customer Segments
Insert your content
Key Partners
Insert your content
Cost Structure
Insert your content
Revenue Streams
Insert your content
94. Team Presentation
95
Imani Jackson
JOB TITLE
Blue is the colour of the clear
sky and the deep sea
Marcos Galán
JOB TITLE
Blue is the colour of the clear
sky and the deep sea
Ixchel Valdía
JOB TITLE
Blue is the colour of the clear
sky and the deep sea
Nils Årud
JOB TITLE
Blue is the colour of the clear
sky and the deep sea
97. 98
SlidesCarnival icons are editable shapes.
This means that you can:
● Resize them without losing quality.
● Change line color, width and style.
Isn’t that nice? :)
Examples:
99. You can also use any emoji as an icon!
And of course it resizes without losing quality.
How? Follow Google instructions https://twitter.com/googledocs/status/730087240156643328
✋👆👉👍👤👦👧👨👩👪💃🏃💑❤😂
😉😋😒😭👶😸🐟🍒🍔💣📌📖🔨🎃🎈
🎨🏈🏰🌏🔌🔑and many more...
100
100. Free templates for all your presentation needs
Ready to use,
professional and
customizable
100% free for personal
or commercial use
Blow your audience
away with attractive
visuals
For PowerPoint and
Google Slides
Editor's Notes
Pemetrexed is a pyrrolopyrimidine, multitargeted antifolate
analog that targets multiple enzymes involved in folate metabolism, including thymidylate synthase (TS), dihydrofolate reductase
(DHFR), glycinamide ribonucleotide (GAR) formyltransferase,
The third antifolate compound used in clinical practice in the United States is pralatrexate .
Pralatrexate
is currently approved for the treatment of relapsed or refractory
peripheral T-cell lymphoma
INtracellular folate is converted by the enzyme Dihydrofolate reductase to dihydrofolate. This compound then is reduced to tetrahydrofolate.
TDHF acts as a carbon carrier compound that donates methyl grps to end target molecules thru the enzymatic action of thymidine synthetase.
It binds to DHFR reversibly and inactivates it thus preventing methylation and decreases available supplies of purine and thymidine bases for DNA and RNA synthesis, thus inhibiting cellular reolication.
The cytotoxic effects of antifolates are mediated by their respective polyglutamate metabolites, with up to 5 to 7 glutamate residues added in a γ-peptide linkage to the terminal glutamate moiety present on the parent molecule. These polyglutamate metabolites
exhibit prolonged intracellular half-lives, thereby allowing for prolonged drug action in tumor cells. In addition, they are potent,
direct inhibitors of DHFR, TS, and specific enzymes involved in
de novo purine biosynthesis.1
Summary: MTX inhibits formation of tetrahydrofolate acid; require for thymidine synthesis which is incorporated into DNA.
The development of cellular resistance to antifolates remains a major obstacle to their clinical efficacy.
Resistance to antifolates arises from several mechanisms, including alterations in antifolate transport because of a defect in or reduced activity of either the reduced folate carrier transport protein or folate receptor systems, decreased polyglutamation of the antifolate parent compound through either decreased expression of FPGS or increased expression of the catabolic enzyme γ-glutamyl hydrolase, and alterations in the target enzymes DHFR and/or TS through increased expression of wild-type protein or overexpression of a mutant protein with reduced binding affinity for the antifolate.
Renal excretion is the main route of drug elimination for all antifolates
The main side effects of MTX are myelosuppression and gastrointestinal (GI) toxicity, and these toxicities are usually completely reversed within 14 days, unless drug-elimination mechanisms are impaired.
-In the setting of compromised renal function, even small doses of the drug may result in serious toxicity.
Leucovorin is a
As a derivative of folic acid, folinic acid is useful as an antidote to folic acid antagonists (i.e., methotrexate and pyrimethamine).[6] Frequently referred to as “leucovorin rescue,” folinic acid is used to counteract the toxic effects of high-dose methotrexate therapy.
--inhibits the dihydrofolate reductase enzyme thus causing folic acid deficiency
So why is leucovorin preferred??
If we give FA supplements….
fluoropyrimidine 5-fluorouracil (5-FU) was synthesized by Charles Heidelberger in the mid-1950s
Uracil is a normal component of RNA; as such, the rationale leading to the development
of the drug was that cancer cells might be more sensitive to molecules that mimic the natural compound than normal cells
This figure shows the 5-Fluorouracil (5-FU) metabolism.
5-FU enters cells via a facilitated uracil base transport mechanism.
Once inside the cell, it is metabolized via anabolism to various cytotoxic nucleotide forms by several biochemical pathways. In its parent
form, 5-FU is inactive, and once in the phosphorylated metabolite
form, it exerts its cytotoxic effects through various mechanisms,
including (1) inhibition of TS, (2) incorporation into RNA, and
(3) incorporation into DNA
----genotoxic stress resulting from TS inhibition may also activate programmed cell-death pathways in susceptible cells, leading to the induction of DNA fragmentation
-FU itself is devoid of antineoplastic activity.
It enters the cell through a carrier-mediated transport system and is converted to the corresponding deoxynucleotide (5-fluorodeoxyuridine monophosphate [5-FdUMP]; which competes with deoxyuridine monophosphate for thymidylate synthase, thus inhibiting its action.
DNA synthesis decreases due to lack of thymidine, leading to imbalanced cell growth and “thymidine-less death” of rapidly dividing cells
Despite being used in the clinic for now over
60 years, the relative contribution of each of these mechanisms in the
development of 5-FU resistance in the actual clinical setting remains
unclear and may well differ among individual patients.
dihydropyrimidine dehydrogenase (DPD)
After intravenous (IV) bolus doses, metabolic elimination is rapid, resulting in a short half-life of 8 to 15 minutes. Up to 80% to 85% of an administered dose of 5-FU is inactivated by DPD, the rate-limiting enzyme in the catabolism of 5-FU .
A pharmacogenetic syndrome has been identified in which partial or complete deficiency in the DPD enzyme is present in 3% to 5% and 0.1% of the general population, respectively.
Because this enzyme catalyzes the rate-limiting step in the catabolic pathway of 5-FU, a deficiency in this enzyme results in a significant increase in 5-FU cytotoxic metabolites.
Upon treatment with 5-FU, patients develop severe excessive toxicity in the form of mucositis, diarrhea, myelosuppression, neurologic toxicity, and in rare cases, death.
In patients being treated with 5-FU or any other fluoropyrimidine, it is important to consider DPD deficiency in patients who present with excessive, severe toxicity.2
Given the S-phase specificity of this agent, prolonged exposure of tumor cells to 5-FU would increase the fraction of cells being exposed to the drug.
Overall response rates are significantly higher in patients treated with infusional schedules of 5-FU than in those treated with bolus 5-FU.
Overall response rates are significantly higher in patients treated with infusional schedules of 5-FU than in those treated with bolus 5-FU, and this improvement in response rate has translated into an improved PFS progression-free survival.
A hybrid schedule of bolus and infusional 5-FU was originally developed by DeGramont and colleagues in France,16,17 and this regimen has superior clinical activity compared with bolus 5-FU schedules.
This hybrid schedule has been simplified by administering only the 46-hour infusion of 5-FU and completely eliminating the 5-FU bolus doses.
This modification has maintained the clinical activity of 5-FU while reducing some of the associated toxicities, specifically myelosuppression.
The spectrum of 5-FU toxicity is dose and schedule dependent.
the main side effects are diarrhea, mucositis, and myelosuppression
Acute neurologic symptoms have also been reported, and they include somnolence, cerebral dysfunction, cerebellar ataxia,
Diarrhea and the dermatologic hand-foot syndrome are more commonly observed with infusional 5-FU
rarely Cardiac toxicity (coronary vasospasm, cardiac enzyme elevations, and electrocardiographic changes)- common in INFUSIONs
LAST: Capecitabine can
also be substituted for infusional 5-FU with equal clinical efficacy
when combined with cisplatin in the treatment of metastatic gastric cancer.
Given its chemical structure, capecitabine, in sharp contrast to
5-FU, is rapidly and extensively absorbed by the gut mucosa, with
nearly 80% oral bioavailability.
Inactive in its parent form, capecitabine undergoes enzymatic conversion via three successive steps, with the first two reactions occurring primarily in the liver. The
third and final step occurs preferentially in tumor tissue and involves
conversion of 5-deoxy-5-fluorouridine to 5-FU by the enzyme thymidine phosphorylase, which is expressed at much higher levels in tumors when compared with corresponding normal tissue
This oral fluoropyrimidine is metabolized to a significant extent
by the liver CYP3A4 microsomal enzymes, and caution must be
used when this agent is combined with other drugs that are metabolized by CYP3A4 enzyme.
There is a black box warning on the drug–drug interaction between warfarin and capecitabine-based chemotherapy, and close monitoring of the coagulation parameters is recommended.
The main side effects of capecitabine are similar to what is
observed with infusional 5-FU, and they include diarrhea and
hand-foot syndrome
↓ myelosuppression, neutropenic fever, mucositis, alopecia, and N/V as compared with 5FU
Oral fluoropyrimidine that is
composed of two distinct molecules, trifluridine (FTD) and tipiracil hydrochloride (TPI), in a molar ratio of 1:0.5.
Trifluridine is a fluoropyrimidine nucleoside analog, and once transported inside
the cell, it is metabolized to the triphosphate metabolite, which
is then incorporated into DNA, resulting in inhibition of DNA
synthesis and function.
trifluridine monophosphate is an inhibitor
of TS, albeit a much weaker inhibitor of TS than the 5-FU metabolite FdUMP.
Tipiracil is an inhibitor of thymidine phosphorylase
(TP), which typically degrades trifluridine, and the presence of
tipiracil decreases degradation of trifluridine, increasing its effects
Oral administration of TAS-102 results in rapid absorption through
the GI tract with peak plasma drug levels achieved in 2 hours.
Myelosuppression is the main dose-limiting toxicity associated with
TAS-102 therapy, resulting in neutropenia, anemia, thrombocytopenia, and febrile neutropenia.
In contrast to the other fluoropyrimidines, TAS-102 therapy is usually not associated with mucositis or dermatologic toxicity.
Cytarabine is active against other hematologic malignancies, such as non-Hodgkin lymphoma, chronic myelogenous leukemia (blastic phase), and acute lymphocytic leukemia (ALL)
this agent does not exhibit
clinical activity against solid tumors.
Cytarabine enters cells via a specific nucleoside transport protein,
Once inside the cell, it requires activation for its cytotoxic effects.
The first metabolic step is conversion of the parent drug to the monophosphate form cytarabine monophosphate (ara-CMP) by the enzyme deoxycytidine kinase (dCK) with subsequent phosphorylation to the di- and triphosphate metabolites
Cytarabine triphosphate (ara-CTP) is a potent inhibitor of DNA polymerases α, β, and γ, which in turn leads to inhibition of DNA chain elongation, DNA synthesis, and DNA repair.
Ara-CTP is also incorporated directly into DNA, and in this manner, it functions as a DNA chain terminator, interfering with chain elongation
These catabolic enzymes convert the parent drug
cytarabine and ara-CMP into the inactive metabolites, ara-uridine
and ara-uridine monophosphate
poor oral bioavailability, Thus, cytarabine is only administered intravenously via continuous infusion
Within 24 hours, up to 80% of drug is recovered in the urine as either the arabinosyl uridine (ara-U) or arabinosyl uridine monophosphate (ara-UMP) metabolite.
GI toxicity commonly manifests as a mild-to-moderate degree of anorexia, nausea, and vomiting along with mucositis, diarrhea, and abdominal pain.
Neurologic toxicity Neurologic toxicity is more common with high-dose therapy
than with standard doses and presents with seizures, cerebral
and cerebellar dysfunction, and peripheral neuropathy.
Entry of gemcitabine into cells requires a specific nucleoside transporter system, human equilibrative nucleoside transporter 1 (hENT1)
Gemcitabine is still inactive…so it requires intracellular activation for its cytotoxic effects.
It is activated by the same enzymatic machinery to the active triphosphate metabolite.
The triphosphate metabolite is subsequently incorporated into DNA, resulting in chain termination and the inhibition of DNA synthesis and function.
The triphosphate form can also directly inhibit DNA polymerases α, β, and γ, with the processes of DNA chain elongation, DNA synthesis, and
DNA repair.
The gemcitabine diphosphate metabolite is a potent inhibitor of ribonucleotide reductase, which further mediates inhibition of DNA biosynthesis by reducing the levels of key deoxynucleotide pools.
Finally, the tumor microenvironment and specifically
tumor-associated macrophages (TAM) appear to play critical roles
as mediators of drug resistance
Plasma clearance is about 30% lower in women and in elderly patients, and this pharmacokinetic difference may result in an increased risk of toxicity in these respective patient Populations.
The initial findings from pilot pharmacokinetic studies suggested that gemcitabine, when given at a fixed dose rate IV
infusion of 10 mg/m2 per minute, yielded the highest accumulation of active gemcitabine triphosphate metabolites in peripheral blood mononuclear cells.
The main dose-limiting toxicity of gemcitabine is myelosuppression, with neutropenia more commonly observed than thrombocytopenia.
As with other antimetabolites, gemcitabine toxicity is schedule dependent, with prolonged infusions producing greater hematologic toxicity.
Transient flu-like symptoms, with fever, headache, arthralgias, and myalgias, occur in
45% of patients.
The development of purine analogs in cancer chemotherapy
began in the early 1950s with the synthesis of the thiopurines,
6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). 6-MP plays
an important role in maintenance therapy for ALL, while 6-TG
is active in remission induction and in maintenance therapy for
AML
6-MP and 6-TG are inactive in their parent forms, and their pharmacology and cellular biochemistry are similar.50 In their respective monophosphate nucleotide forms, the thiopurines inhibit
specific enzymes involved in de novo purine synthesis and purine
interconversion reactions. Their respective triphosphate nucleotide metabolites are directly incorporated into either cellular RNA
or DNA, leading to the inhibition of RNA and DNA synthesis and
function, respectively
the development of cellular resistance to 6-thiopurines results from a decreased level of key cytotoxic nucleotide metabolites, through either decreased formation or increased breakdown.
Resistant cells have been identified that express either complete or
partial deficiency of the activating enzyme hypoxanthine-guanine
phosphoribosyltransferase (HGPRT). I
In clinical samples derived from patients with AML, drug resistance has been associated with increased concentrations of a membrane-bound alkaline phosphatase or a conjugating enzyme, 6-thiopurine methyltransferase (TPMT), which leads to reduced formation of cytotoxic thiopurine nucleotides.
Finally, decreased expression of mismatch repair enzymes, including hMLH1 and hMSH2, has been associated with cellular drug resistance.
Oral absorption of 6-MP is highly erratic, and the relatively poor
oral bioavailability results from the rapid first-pass metabolism in
the liver.
6-MP is oxidized to the inactive metabolite 6-thiouric acid by xanthine oxidase. Enhanced 6-MP
toxicity may result from the concomitant administration of 6-MP and the xanthine oxidase inhibitor allopurinol. In patients receiving both 6-MP and allopurinol, the 6-MP dose must be reduced xby at least 50% to 75%.
The major dose-related toxicities of the thiopurines are myelosuppression and GI toxicity with nausea/vomiting, anorexia, diarrhea,
and mucositis
In TPMT-deficient patients, dose reduction to 5% to 25% of the standard dosage is recommended to prevent severe excessive toxicity.
Caucasian population expresses either a homozygous deletion or a mutation of both alleles of the TPMT gene. In these patients, the loss of TPMT activity results in significantly elevated thiopurine nucleotides concentrations, and profound myelosuppression with pancytopenia and extensive GI symptoms are observed in response to thiopurine treatment.
Thiopurine hepatotoxicity is observed in up to 30% of adult patients and presents mainly as
cholestatic jaundice, although elevations of hepatic transaminases may also be seen.
The active cytotoxic metabolite is fludarabine triphosphate, which
competes with deoxyadenosine triphosphate (dATP) for incorporation into DNA, where it serves as a highly effective chain terminator. The triphosphate metabolite also directly inhibits enzymes involved in DNA replication, including DNA polymerases, DNA primase, DNA ligase I, and ribonucleotide reductase.56 Fludarabine triphosphate is incorporated into RNA, leading to inhibition of RNA function, processing, and mRNA translation.
In contrast
to other antimetabolites, fludarabine is active against nondividing
cells.
Decreased expression of the activating enzyme deoxycytidine
kinase resulting in diminished intracellular formation of fludarabine monophosphate is a main resistance mechanism
Peak concentrations of fludarabine are reached 3 to 4 hours after
IV administration. Of note, fludarabine is orally bioavailable
The main route of elimination is via the kidneys, with
about 25% of a given dose of drug being excreted unchanged in
the urine.
Myelosuppression and immunosuppression are the major side
effects of fludarabine, as highlighted by dose limiting and
possibly cumulative lymphopenia and thrombocytopenia
Upon entry into the cell, cladribine undergoes initial conversion
to the monophosphate form via the reaction catalyzed by deoxycytidine kinase(dCK), which is then subsequently metabolized to the active
triphosphate metabolite. Cladribine triphosphate competitively
inhibits incorporation of the normal dATP nucleotide into DNA,
a process that results in the termination of chain elongation.61 Progressive accumulation of the triphosphate metabolite leads to an
imbalance in deoxyribonucleotide pools, thereby inhibiting further DNA synthesis and repair.
Resistance to cladribine has been attributed to altered intracellular drug metabolism.
A reduction in the activity of deoxycytidine
kinase, the enzyme responsible for generating cytotoxic nucleotide
metabolites, is a major determinant of acquired resistance.
Cladribine is orally bioavailable, with 50% of an administered dose
absorbed orally. In there is nearly 100% bioavailability when the
drug is administered via the subcutaneous route.
This nucleoside is able to cross the blood–brain barrier with penetration
into the cerebrospinal fluid.
Approximately 50% of an administered dose of drug is cleared by the kidneys, and
20% to 35% of the drug is excreted unchanged in the urine.
At conventional doses, myelosuppression is dose limiting.
Inactive in its parent form, clofarabine requires intracellular activation
by deoxycytidine kinase to first form the monophosphate nucleotide,
which undergoes further metabolism to the cytotoxic triphosphate
metabolite. The triphosphate metabolite is subsequently incorporated into DNA, resulting in chain termination and inhibition of
DNA synthesis and function, and the triphosphate metabolite can
directly inhibit DNA polymerases α, β, and γ, which in turn, interfere
with DNA chain elongation, DNA synthesis, and DNA repair
To date, the precise resistance mechanism(s) that is relevant in the clinical setting remains to be determined.
Approximately 50% to 60% of an administered dose of drug is
excreted unchanged in the urine. For this reason, dose reduction
is recommended in the setting of renal impairment.
tumor lysis syndrome and results from rapid breakdown of peripheral leukemic cells following treatment.4
In its parent form, nelarabine is inactive,
Nelarabine is metabolized by adenosine deaminase to form araG,
and it requires intracellular activation by deoxycytidine kinase to initially form the monophosphate metabolite and eventually to the triphosphate metabolite.
Ara-GTP is subsequently incorporated into DNA, resulting in chain termination
and inhibition of DNA synthesis and function, and the triphosphate metabolite can directly inhibit DNA polymerases α, β, and
γ, which, in turn, interfere with DNA chain elongation, DNA synthesis, and DNA repair. As with other antimetabolites, nelarabine
is a cell cycle–specific agent with activity in the S-phase
Myelosuppression is a common side effect presenting with neutropenia, anemia, and thrombocytopenia (see Table 8.1). However, neurotoxicity is dose limiting and presents with headache,
altered mental status, and peripheral neuropathy with numbness, paresthesias, and motor weakness
