FARMACOLOGÍA ANTITUMORAL

CANCER

karkinoma (griego)
cancer (latín)
 Glossary of Terminology
Neoplasm
• “New plasma”…abnormal tissue growth with
rapid growth
Benign
• No metastasis. No invasion of surrounding tissues.
Malignant
• Local invasion and destructive growth.
Metastasis
• Spread form primary via lymphatic and/or
circulatory system
 CARACTERÍSTICAS DE LA CÉLULA TUMORAL
(FENOTIPO MALIGNO)

 Proliferación descontrolada (aumentada) e indefinida

Ciclo celular
Oncogenes
Genes supresores tumorales
Envejecimiento celular

 Supervivencia prolongada (Evade el proceso de apoptosis)

 Invade territorios vecinos y forma colonias (metástasis)

 Induce y mantiene la angiogénesis

 Evade el sistema inmunitario

 Invade territorios vecinos y forma colonias (metástasis)

Evade el proceso de apoptosis

Induce y mantiene la angiogénesis

Proliferación descontrolada Evade el sistema inmunitario

 CARCINOGENESIS

 QUÍMICA

 FÍSICA

 VIRAL
Enfermedad genética
multifactorial
 CAMBIOS GENÉTICOS

Translocación Mutación puntual

Inserción Amplificación
Deleción
Duplicación o pérdida total
de un cromosoma (aneuploidía)
Daños del ADN

Reparación daños
 Proto- Genes supresores
oncogenes tumorales

Genes normales que participan en Genes normales que bloquean

algún aspecto de la proliferación el ciclo celular
celular. Al mutarse, se activan en
forma anormal  ONCOGEN
Proto-oncogenes are normal
cellular genes that are
involved in growth control.

Cancer results when these

genes become dysregulated
such that they are
inappropriately activated.
 Tumor Suppressor Genes
• A class of genes that normally suppress
cell proliferation. Examples are p53 and
Rb.
• Mutations that inactivate the tumor
suppressor gene products can release cells
from growth suppression and lead to
hyperproliferation.
• Both alleles of the tumor suppressor gene
must be inactivated by mutation for
hyperproliferation to occur.
Growth factors and cancer
iniciador promotor

CÁNCER

CÁNCER

NO CÁNCER
TUMOUR MICROENVIRONMENT

Decreasing
nutritients
and O2
Decreasing
pH
TREATMENT MODALITIES
SURGERY
Curative

Prophylactic

Diagnostic

Staging

Palliative

Adjuvant or Supportive

Reconstructive/Rehabilitative
 RADIATION
• Highest energy rays
that can kill any cell or
tissue
• May be external source
(brachytherapy)
• Curative
• Palliative
• 60% will receive XRT
• Divided into doses or
fractions
• (Preserve normal
cellular growth)
 Treatment of cancer – assessment of
response

• complete response (CR)

• partial response (PR)

• stable disease/no change (SD)

• progressive disease (PD)

Kinetics of cancer treatment
Chemotherapy
 Chemotherapy
Cytotoxic drugs that destroy cancer cells or prevent
cellular replication by interfering with DNA and
RNA and vital cellular proteins

Goal is to reduce the number of cells to a small

number that can be (theoretically) handled by the
immune system
 Chemotherapy
• Chemotherapy attacks tumors at the cellular level by
interrupting processes or inhibiting substances
necessary for cellular replication and life
• During the cell cycle, there is replication of the entire
genome and division of the cell into genetically identical
daughter cells
• Goals of Cancer Chemotherapy
– Cure
– Prolong survival
– Palliation
– Radiosensitive
The Main Goal of Antineoplastic Agents

IS to eliminate the cancer cells without affecting normal tissues (the concept of
differential sensitivity). In reality, all cytotoxic drugs affect normal tissues as
well as malignancies - aim for a favorable therapeutic index (therapeutic
ratio).
LD50
Therapeutic Index = -----
ED50

A therapeutic index is the lethal dose of a drug for 50% of the population (LD50)
divided by the minimum effective dose for 50% of the population (ED50).

30
 General rules of chemotherapy

Aggressive high-dose chemotherapy

•Dose- limiting is toxicity towards normal cells
•Cyclic regimens - repeated administrations with appropriate intervals
for regeneration of normal cells (e.g., bone marrow cells)
•Supportive therapy - to reduce toxicity
hematotoxicity – bone marrow transplantation, hematopoietic
growth factors
Specific antagonists: antifolate (methotrexate) – folate
(leucovorin)
MESNA - donor of –SH groups, decreased urotoxicity of
cyclophosphamide. Detoxifying agent.
dexrazoxane: chelates iron, reduced anthracycline cardiotoxicity
amifostine: reduces hematotoxicity, ototoxicity and neurotoxicity
of alkylating agents

31
The effects of tumor burden, scheduling, dosing, and
initiation/duration of treatment on patient survival.
Untreated patients

Infrequent scheduling of
treatment courses.
Prolongs survival but does not cure.

More intensive and

frequent treatment.
Kill rate > growth rate.

Early surgical removal of the

primary tumor decreases the tumor
burden. Chemotherapy will remove
persistant secondary tumors.
32
 General rules of chemotherapy

•Supportive therapy:
-Antiemetics (5-HT3 -antagonists)
-Antibiotic prophylaxis and therapy (febrile neutropenia)
-Prophylaxis of urate nephropathy (allopurinol)
-Enteral and parenteral nutrition
-Pain – analgesic drugs
-Psychological support

33
 The Cell Cycle
• G1 phase: cell prepares for DNA synthesis

• S phase: cell generates complete copy of

genetic material

• G2 phase: cell prepares for mitosis

• M phase: replicated DNA is condensed and

segregated into chromosomes

• G0 phase: resting state

 M Differentiation

G2 Treatment
1. Radiation

G12. Surgery
When neoplasms are disseminated and/or not
amenable to surgery, or as a supplement to
surgery and radiation:
1. Chemotherapy
2. Hormonal therapy
3. Immunotherapy
4. Combinations of above
Cell death (apoptosis) can
S occur at any phase in the cycle.

Phase Function % time

G1 RNA and Protein synthesis 40

S DNA synthesis 39

G2 Tetraploid; prepare for mitosis 19

M Mitosis; diploid daughter cells 2

G0 Quiescent; differentiation or re-enter cell cycle -

 Chemotherapy
• Cell cycle phase – specific
– agents with major activity in a particular
phase of cell cycle
– schedule dependent

• Cell cycle phase – nonspecific

– agents with significant activity in multiple
phases
– dose dependent
 Chemotherapy Toxicity
• Usually reflected by mechanism of
action of drug
• Toxicity depends on many factors
– Drug dosing and schedule
– Patient
– Disease
• Toxicity not always a class effect
• Chemotherapy regimens usually
combine drugs that have different
toxicity profiles
 Chemotherapy – toxicity
► myelosuppression

► immunosuppression

► nausea/vomiting

► alopecia

► mucositis

► diarrhea

► flu-like symptoms
Chemotherapy – toxicity (2)
► gonadal damage
 sterility
 hormonal changes
► organ damage
 cardiotoxicity
 pulmonary damage
 hepatotoxicity
 nephrotoxicity
► neuroxicity
► localcomplications (extravasation)
► second malignancies
Myelosupression
MYELOSUPRESSION
NEUTROPENIA

THROMBOCYTOPENIA

ANEMIA
 Pathophysiology
• Damage to stem cells in bone marrow with
decreased ability to make these important cells
• Hematologic malignancies cause the malignant
cells to crowd the bone marrow and therefore
difficult to make normal amount of normal cells
• Solid tumors metastasize to bone marrow with a
decreased normal cell production
• Radiation damages bone marrow’s ability to make
cells
 Neutropenia/Leukopenia
• Assess risk factors
– (Age, renal and liver function, nutrition, bone marrow, other
medications, prior chemotherapy and/or radiation)
• Manifestations include
– fever >38 C
– cough
– skin redness or tenderness, (mouth, perianal, rectal)
– urinary symptoms (dysuria frequency, hematuria, hesitancy)
– sepsis (hypotension, agitation, decreased urine)
 Thrombocytopenia

• Assess risk factors

– chemotherapy / radiation
– disease infiltration
– NSAID's
– petechiae
– bruising
– hemorrhage (skin, GI, GU)
– headaches, confusion, somnolence
<20,000 high risk
<10,000 critical risk
 Anemia
• Assess for
– chemotherapy
– kidney damage
– tumor infiltration of bone marrow, XRT
– bleeding, hemorrhage
– age
 Chemotherapy Toxicity
• Neurologic
– CNS: cytarabine, methotrexate, ifosfamide
– Peripheral: paclitaxel, oxaliplatin, vincristine
• Gastrointestinal
– Nausea and vomiting: cisplatin, doxorubicin,
cyclophosphamide
– Mucositis: methotrexate, melphalan, etoposide, 5-FU
• Pulmonary
– Methotrexate, bleomycin
• Cardiovascular
– Anthracyclines
 Chemotherapy Toxicity
• Hepatic
– busulfan
• Metabolic
– Ifosfamide, cisplatin
• Renal
– Hemorrhagic cystitis: cyclophosphamide, ifosfamide
– Renal failure: cisplatin
• Dermatologic
– Hand-foot syndrome: 5-FU, capecitabine, cytarabine
• Immune System
– Immunosuppression: fludarabine, cyclophosphamide,
steroids
– Hypersensitivity: paclitaxel, asparaginase, bleomycin
 Secondary Leukemias
• Leukemias secondary to chemotherapy agents have
poor prognosis.
• Secondary to alkylating agents
– Most often occur after 5 – 7 years
– Often have MDS preceding leukemia
– Alterations of chromosomes 5 and/or 7 in 60% – 90% cases
• Secondary to topo II inhibitors:
– Diagnosed 2 -3 years after treatment
– Frequent translocation of chromosome 11 (11q23)
t(11;19)(q23;p13)
Nausea and Vomiting
Strategies to maximize efficacy and
minimize side-effects
A. Optimization of dosing and route
B. Intermittent therapy to allow normal cell
recovery (e.g. bone marrow)
C. Combination therapy to reduce likelihood of
resistance
D. Rationally-designed therapy tailored to
patient’s molecular abnormalities – e.g. CML,
specific types of breast cancer
E. Prophylaxis – breast and cervical cancer
F. Supportive therapy
 Chemotherapy - strategy
• single drug – used rarely
• combination
– provides maximal cell kill within tolerable toxicity
– provides broader range of coverage of resistant
cells in a heterogeneous tumor
– prevents/slows the development of resistant cells
 Development
of combination chemotherapy
• drugs effective in particular tumor
• different mechanisms of action
• non-overlapping toxicity
• different patterns of resistance
• drugs used in their optimal dose and schedule
• drugs given at consistent (as short as possible)
intervals
 Drug Resistance

• De novo Resistance
• Acquired Resistance
• Multidrug Resistance (MDR)
 Cancer cell biology

 Goldie-Coldman hypothesis
spontaneous mutation (10-5) is 10x > normal cell
gene mutation/amplification, chromosome aberration
visible tumor contains ~109 cells (= 1 gm)
i.e., 104 resistant cells
If drug knows the target, it should kill.
In fact, few cancer cells escape from killing.

i.e., Drug >> select resistant cells

Genome is fluidy in cancer cells,

mutation rate: 10-5 (10x > normal cells)
mutation to one-drug resistance ~ 10-5
mutation to two-drug resistance: 10-5 x 10-5 = 10-10

>>> combination therapy should give cancer cells

much less chance to survive!
 Drug resistance

Temporary resistance:
reversible change in drug utility/metabolism,
cell kinetics/exposure, blood supply etc.
Permanent resistance:
irreversible change in genetic mutation
 Drug resistance

Intrinsic resistance:
cell mutation exists before drug exposure
Acquired resistance:
cell mutation exists after drug exposure
Mechanisms of drug resistance

 Drug resistance due to decreased drug accumulation.

 Impaired transport across cell membrane

 Multiple Drug Resistance (MDR) (pleiotropic resistance)

 Mutations in the target protein

Drug resistance due to decreased drug
accumulation

• Decreased influx (e.g. defective drug

carrier)
• Enhanced drug efflux (MDR)
 Impaired transport across cell
membrane
Some drugs require facilitated transport
(in contrast to passive diffusion). These
drugs bind to a carrier (= drug receptor
protein on the cell membrane).
examples:
• transport systems for methotrexate: RFC
(reduced folate carrier)
• transport systems for gemcitabine:
nucleoside transporter system
 Multiple Drug Resistance (MDR)
(pleiotropic resistance)
• P-glycoproteinn (p170) is a cell surface
glycoprotein of 170-KD size.
• P-glycoprotein is encoded by mdr-1 gene and
functions as a cellular pump for extruding toxic
molecules.
• Part of the P-gp is located in the interior aspect
of the cell membrane, and bind in this area to the
drug (by an ATP dependent process)
Multiple Drug Resistance (MDR)
(pleiotropic resistance)
• MDR is associated with overexpression of
P-glycoprotein.
• In-vitro MDR can be reversed by calcium
channel blockers (e.g. verapamil) and
cyclosporine
Multidrug-resistance protein (MRP)

• mrp gene encodes a 190-kD protein that

function in a similar action to that of p170
glycoprotein to mediate rapid efflux.
MDR-Cytotoxic drugs associated
with MDR
Drugs associated with MDR tend to be
large molecules that are derived from the
natural environment:
• Anthracyclines
• Vinca alkaloids
• Epipodophyllotoxins
• Actinomycin D (Dactinomycin)
• Taxanes
 Chemotherapy Classes
• Antimetabolites
– methotrexate
– purine antagonists
– pyrimidine antagonists
• Alkylating agents
– nitrogen mustards
– thiotepa, busulfan
– nitrosoureas, mitomycin
– procarbazine, dacarbazine
• Taxanes
– paclitaxel, docetaxel
– nab-paclitaxel
• Topoisomerase inhibitors
– Etoposide
– Irinotecan
• Platinum Complexes
– cisplatin, carboplatin
– oxaliplatin
• Anthracyclines
– doxorubicin, daunorubicin
– idarubicin, mitoxantrone
• Tubulin interactive agents
– vincristine, vinblastine
• Miscellaneous agents
– bleomycin
– asparaginase
– hydroxyurea
 Antimetabolites
• Interfere with nucleic acid synthesis rather than
preformed acids. Have little effect in G0 phase and
maximal effect in S phase
• Most effective for rapidly proliferating tumors like
leukemias.
• Not associated with delayed or prolonged
myelosupression
• Minimial risk of leukemogenesis or carcinogenesis
 Antimetabolites
• Structural analogues of naturally occurring
substances required for specific biochemical
reactions.

• Fraudulently substitute themselves for purines or

pyrimidines or they can inhibit critical enzymes that
are involved in nucleic acid synthesis.

• They affect DNA, RNA, protein synthesis and cellular

replication.
 Antimetabolites

4 drug categories:
– Folate Antagonists
– Pyrimidine Antagonists
– Purine Antagonists
– Adenosine Deaminase Inhibitors
 Overview of Antimetabolites

• Folate antagonists

• Purine analogs

• Pyrimidine analogs
Antagonistas del ácido fólico
Antimetabolites: sites of drug action

Purpose of folate pathway is to produce reduced folate cofactors to act as donors

of methyl groups necessary for synthesis of DNA base pairs and aminoacids
 Folate Antagonists

(DHFR)

Purpose of folate pathway is to produce reduced folate cofactors to act as donors

of methyl groups necessary for synthesis of DNA base pairs and aminoacids
 Folate Antagonists
• Methotrexate (MTX)
• Pemetrexed
• Trimetrexate
• Raltitrexed
 Methotrexate. Mechanism of Action
• Reversibly binds to dihydrofolate reductase (DHFR)
– Inhibits the formation of reduced folates
– Results in:
• Ineffective nucleic acid synthesis and DNA production
• Strand breakage and ineffective repair mechanism
• Ultimately cell death

• Specific for the S-phase of cell cycle

– Longer exposure to methotrexate allows for more cells to be replicating and be exposed
to cytotoxic effects of methotrexate

• Enters cell via folate transporter (facilitated process) and passive diffusion at
higher concentrations
– Intracellularly addition of glutamyl residues forms methotrexate polyglutamate
– Polyglutamates:
• More likely to be formed with longer periods of drug exposure
• Greater binding affinity for DHFR
• Increases intracellular half-life of methotrexate
• Occurs more readily in malignant cells leading to sustained levels and prolonged duration of
action
 Methotrexate
• Mechanism of action
– Folic acid analog
– Cell cycle specific (S-phase)
– Inhibits dihydrofolate
reductase, depleting
intracellular pools of
tetrahydrofolate which is
essential for purine and
thymidylate synthesis (DNA
synthesis)
• Pharmacology
– MTX becomes polyglutamated
once inside the cell
– Cytotoxicity is concentration
and time dependent
Mechanism of resistance to MTX

• Mutation in RFC (reduced folate carrier) or

FR (folate receptor -binding protein).
• Decreased polyglutamation (by folylpoly-
gamma-glutamate synthetase)
• Alteration in the target-DHFR:
-increased expression
-mutated DHFR with decreased affinity
to MTX
 Mechanism of Resistance

1. Decreased drug
transport
2. Altered DHFR
3. Decreased
polyglutamate
formation
4. Increased levels
of DHFR
 Methotrexate. Pharmacokinetics
• Absorption
– Saturable oral absorption
• Rapidly and well absorbed at low doses (<25 mg/m2)
– 60% bioavailability (BA)
• Incomplete at higher doses
– Time to peak concentration
• Oral route 1 – 2 hours
• IM route 10 – 30 minutes
 Methotrexate. Pharmacokinetics
• Distribution
– Very water soluble molecule
• Primarily distributes to total body water
– Low volume of distribution; 0.4 – 0.8 L/kg
– 50% protein bound
• Intracellular concentrations reach steady state in <30 minutes
– Penetrates slowly into 3rd space fluids (pleural effusions,
ascites)
• Subsequently exits slowly
• Cause for potential prolonged MTX exposure
– Poor distribution into CNS
• High CSF levels can be obtained by IT administration
• Enhanced levels after CNS irradiation
– Blood-brain barrier returns to normal after ~ 4 weeks
 Methotrexate. Pharmacokinetics
• Metabolism

– Primarily form polyglutamates intracellularly

– Extent of other routes of metabolism unknown

• 7-OH-MTX-undergoes polyglutamation by folylpolyglutamyl. Active
metabolite.
• <10% degradation by intestinal flora to the non-active DAMPA (2,4,
diamino-N10-methyl pteroic acid) by a carboxypeptidase
 Methotrexate. Pharmacokinetics
• Elimination
– Renal excretion accounts for 44 to 100%
• 50-80% of IV dose eliminated unchanged in urine during first 12 hours. It
is a weak acid and so is excreted better at high urine pH. Appropriate
hydration and alkalinizing the urine is important to prevent renal toxicity
with MTX.
• Not dialyzable
– Most dialysis methods decrease MTX levels followed by rebound increase of
10 – 221%
• Terminal Half life = 8 – 12 hours

– Biliary excretion accounts for about 10%

– Intrathecal administration: Half life = 12 hrs

 Methotrexate. Dosage & Administration

• Antineoplastic dosage range

– Conventional = 10 - 100 mg/m2
– Intermediate = 1 – 2 gm/m2
– High = 10 – 12 gm/m2
• Means of administration
– Slow IV push
– Short bolus infusion
– Continuous infusion over 24 hrs
– Intrathecal (IT)
 High-Dose MTX
• Patient must have adequate marrow, liver, and renal
function before therapy
• Maintain Urinary Output > 100 mL/hr
• Maintain urine pH > 7
– Add sodium bicarbonate or acetate to IVF
– Give oral sodium bicarbonate or oral acetazolamide
• Principle of high-dose MTX
– At high plasma levels, passive entry into tumor cells can
overcome resistance due to defective active transport
– Increased free intracellular MTX levels can overcome
resistance secondary to increased DHFR or altered enzyme
binding
– High, prolonged plasma levels increase polyglutamate
formation and prolongs drug action
 Methotrexate. Toxicity
• Bone Marrow Suppression
– Neutropenia – rarely Grade III or IV
• Nadir: ~ day 10
• Duration: 14 – 21 days
• More prevalent at higher doses
– Anemia
– Thrombocytopenia
• Emetogenic Potential
– Very low (< 10%) </=50mg/m2
– Low (10% to 30%) 50-250mg/m2
– Moderate (30 to 60%) 250-1000mg/m2
– High (60 to 90%) >1000 mg/m2
 Methotrexate. Toxicity
• Nephrotoxicity
– Potential to precipitate in kidneys when using intermediate
or high dose MTX
– Hydration and alkalinization may be used to prevent
precipitation of MTX in the renal tubules
• Hydration (3 L/m2/day)
– Begin 12 hrs before infusion and continue until level undetectable
– Urine output > 100 mL/hr (> 2 mL/kg/hr)
• Urine alkalinization
– Sodium bicarbonate in IV fluids (Add 50-150mEq per liter of
hydration)
– Maintain urine pH >7
 Methotrexate. Toxicity
• Mucositis and diarrhea
– Onset 3 – 5 days after administration
– Duration ~14 days
• Hepatotoxicity
– Acute elevations in transaminases and bilirubin
• Usually returns to normal within 10 days
– Hepatic fibrosis in patients receiving chronic daily administration of
methotrexate
• Intermittent, weekly therapy has less association
• Possibly related to lipid deposition in the liver, exact mechanism unknown
• Dermatologic Effects
– Rash, pruritis, photosensitivity, radiation recall
 Methotrexate.Toxicity
• CNS Toxicity
– Three distinct neurotoxic syndromes associated with IT MTX
• Chemical arachnoiditis
– Arises immediately after administration
– Severe headaches, nuchal rigidity, vomiting, fever
• Subacute form
– Occurs after third or fourth course of intrathecal therapy in ~10% of patients
– Most common in adults with active meningeal leukemia
» consists of motor paralysis, cranial nerve palsy, and seizures or coma
– Change in therapy is absolutely indicated
» Continued treatment with intrathecal MTX may result in death
• Chronic, demyelinating encephalopathy
– Occurs primarily in children months to years after intrathecal MTX therapy
– Dementia, limb spasticity, and, in advanced cases, coma
 Methotrexate. Toxicity
• Pneumonitis
– Self-limiting lung process
• Characterized by fever, cough, and interstitial pulmonary infiltrates
• No current recommended therapy
• High dose MTX therapy
– Occasionally associated with acute, transient cerebral
dysfunction
• Paresis, aphasia, and behavioral abnormalities, and seizures
– Symptoms occur within 6 days of MTX treatment
– Completely resolve within 48 to 72 hours
– Incidence: 4 - 15% of patients
 Methotrexate. Dosage adjustment
• Dosage in renal impairment
– Conventional-Dose MTX
• Clcr 61 – 80 mL/min Reduce dose by 25%
51 – 60 mL/min Reduce dose by 30%
10 – 50 mL/min Reduce dose by 50 – 70%
< 10 mL/min Avoid use
– High-dose MTX
• Clcr < 60 mL/min Avoid use
• Dosage in hepatic impairment
– Total billirubinema
• < 3 mg/dL. No adjustment necessary
• 3.1 – 5 mg/dL or AST > 180 Reduce dose by 25%
• > 5 mg/dL Avoid use
 MTX Drug Interactions
• Avoid concomitant nephrotoxins
– Cisplatin, probenecid, NSAIDS compete for excretion and
decrease elimination of MTX
• Salicylates and sulfonamides (Bactrim, PCN) may
displace MTX from binding sites
• Oral antibiotics may interfere with oral absorption of
MTX and with enterohepatic recycling
 Methotrexate. Special Precautions
• Doses between 100 - 500mg/m2 may require
leucovorin rescue
• Dose > 500 mg/m2 require leucovorin rescue
• Factors associated with toxicity and delayed
clearance
– Renal dysfunction
– “Third space” fluid (pleural effusions, ascites,
gastrointestinal obstruction)
• Creates a reservoir for methotrexate
– Hepatic dysfunction
 Standard methods to neutralize
MTX toxicity
• 5-formyltetrahydrofolate (leucovorin):
This compound is a reduced folate...
undergoes intracellular polyglutamation,
competes with MTX and MTX polyglutamates
on inhibition of TS and de novo purine
synthesis and on cellular transport.
(the commercially available form is a mixture
of d and l -forms. Only the l-isomer is active).
• Vigorous hydration & urine alkalization….
 Leucovorin Rescue

Mechanism of action of
methotrexate and the effect of
administration of leucovorin.
• FH2 = dihydrofolate
• FH4 = tetrahydrofolate
• dTMP = deoxythymidine
monophosphate
• dUMP = deoxyuridine mono
phosphate.
 Leucovorin. Mechanism of Action
• Antidote for folic acid antagonists
– Supplies the cell with reduced folate whose
production is blocked by methotrexate
– Preferentially rescues normal tissue versus
malignant cells
• Prevents extensive toxicity to bone marrow and
gastrointestinal epithelium
• Potentiates the effects of fluorouracil by
stabilizing the binding of 5-dUMP and
thymidylate synthetase
 Leucovorin. Pharmacokinetics
• Absorption
– Saturable depending on dosage
• Doses < 25 mg 98% absorption
• Doses > 25 mg less absorption
– > 100 mg less than 40% absorbed
– Onset of action 30 minutes
• Metabolism
– Intestinal mucosa and hepatically converted to 5-methyl-
tetrahydrofolate (5MTHF) active compound
• Elimination
– 80 – 90% renal excretion of leucovorin and metabolites
• Leucovorin half life = 15 minutes
• 5MTHF half life = 33 – 35 minutes
– 5 – 8% fecal
 Leucovorin. Toxicity
• Dermatologic
– Rash, pruritis, erythema, urticaria
• Hematologic
– Thrombocytosis
• Respiratory/Anaphylactoid reactions
– Wheezing
• Gastrointestinal
– Nausea, diarrhea
• Do not administer intrathecally/ intraventricularly
 Leucovorin. Clinical Applications
• Methotrexate rescue
• In combination regimens with 5-fluorouracil
for GI tumors
• Treatment of megaloblastic anemia
 Leucovorin. Administration
• Methotrexate Rescue
– Administered every 6 hours (either IV or PO)
– Should be administered IV in patients with:
• GI toxicity
• Nausea, vomiting
• Individual doses >25 mg
– IV infusion should not exceed 160 mg/minute
 Folate Antagonists
• Methotrexate (MTX)
• Pemetrexed
• Trimetrexate
• Raltitrexed
Pemetrexed
 Pemetrexed. Mechanism of Action
• Converted to polyglutamates
– Active inhibitors of multiple enzymes involved in folate pathway
– Increases intracellular half-life
– Occurs more readily in malignant cells leading to sustained levels and
prolonged duration of action
• Inhibits all major enzymes in folate metabolism
– Thymidylate synthase (TS)
– Dihydrofolate reductase (DHFR)
– Glycinamide ribonucleotide formyltransferase (GARFT)
– Aminomidazole carboxamide ridonucleotide formyltransferase
(AICARFT)
• Inhibition leads to blocking of purine and thymidine
nucleotide and protein synthesis
 Pemetrexed. Pharmacokinetics
• Absorption
– Not given orally
• Distribution
– Volume of distribution = 16.1 L
– Protein binding ~81%
• Metabolism
– Minimal
• Primarily converted intracellularly to polyglutamates
• Elimination
– Renal
• 70 to 90% as unchanged drug
– Half-life = 3.5 hours with normal renal function (> 90 mL/min)
 Pemetrexed. Toxicity
• Cardiovascular
– Lower extremity edema in 21% of patients (mostly Grade I
or II)
• CNS
– Fatigue/lethargy (80% incidence)
• Gastrointestinal
– Emetogenic potential
• Moderate as monotherapy
– 30 to 60% overall incidence
– Grade III or IV: 10 to 12%
• Primarily caused by cisplatin when given in combination
 Pemetrexed. Toxicity
• Hematologic
– Neutropenia
• Any grade 58%
• Grade III or IV = 24% in combination with cisplatin
• Nadir 8 – 10 days
• Recovery 12 – 17 days
– No cumulative toxicity with repeat administration
• Musculoskeletal
– Arthralgia = 24% incidence
• Renal
– Similar elevations in serum creatinin when given in
combination with cisplatin
 Pemetrexed. Toxicity
• Skin
– Cutaneous rash in ~20% of patients
• Pretreat with dexamethasone reduces the incidence and severity
of cutaneous reactions
• Dexamethasone 4 mg po bid the day before, day of, and day after
pemetrexed
– Use of leucovorin rescue
• In clinical trials for Grade IV leucopenia lasting > 3 days OR
• Grade IV neutropenia > 3 days OR
• Immediately if Grade IV thrombocytopenia, bleeding in
conjunction with Grade III thrombocytopenia, or Grade III or IV
mucositis develop
– Recommended doses of leucovorin 100 mg/m2 IV once followed by
50 mg/m2 IV q6hrs x 8 days
 Pemetrexed
Special Precautions to decrease toxicity
• Vitamin Supplementation
– Folic acid 400 mcg PO daily
• Start 5 – 7 days before treatment, and continue during treatment and for
21 days following last dose
– Vitamin B12 1000 mcg IM
• Started one week before initiation of pemetrexed therapy, then every 3
cycles during therapy
– Reduce incidence and severity of hematologic (38% vs. 24%)
– Reduce gastrointestinal toxicity and N/V (34% vs. 12%)
• Retreatment criteria
– ANC > 1500 cells/mm3
– Platelets > 100,000 cells/mm3
– Clcr > 45 mL/min
 Folate Antagonists
• Methotrexate (MTX)
• Pemetrexed
• Trimetrexate
• Raltitrexed
 Trimetrexate
Similarity to MTX:
• inhibits DHFR
Differences from MTX:
• more lipid soluble
• does not undergo polyglutamation
• does not require RFC for cellular transport
• does serve as a substrate for P-glycoprotein (I.e., affected
by expression of the classic MDR phenotype).
• clearance-mainly hepatic
 Folate Antagonists
• Methotrexate (MTX)
• Pemetrexed
• Trimetrexate
• Raltitrexed
 Raltitrexed-a selective
inhibitor of TS
Similarity to MTX:
• undergoes polyglutamation
• clearance-mainly renal
Difference from MTX:
• main target is Thymidilate synthase (and not
DHFR)