PHARMACOLOGY

Chemotherapy of Neoplasms
LEVEL 2 Dr. Cyril Jonas Planilla, MD, DPCP
October 3, 2019

OUTLINE CANCER DIAGNOSIS

GENERAL PRINCIPLES OF CANCER MEDICINE .......................1 - The diagnosis of cancer relies most heavily on invasive
CANCER DIAGNOSIS ..................................................................... 1 tissue biopsy and should never be obtained without
CANCER TREATMENTS ................................................................... 1 obtaining tissue; no non-invasive diagnostic test is sufficient
Systemic Treatments ............................................................. 1 to define a disease process as cancer.
CANCER TREATMENTS ................................................................... 2
CHEMOTHERAPEUTIC AGENTS .......................................................... 2
CELL CYCLE SPECIFICTY ................................................................. 2

CYTOTOXIC AGENTS .............................................................3

ALKYLATING AGENTS .................................................................... 3
Nitrogen Mustards ................................................................. 4
Triazenes ............................................................................. 4
Nitrosoureas ......................................................................... 4
PLATIINUM COORDINATION COMPLEXES ............................................... 5
Cisplastin ............................................................................. 5
Carboplatin .......................................................................... 6
Oxaliplatin ........................................................................... 6
ANTIMETABOLITES ....................................................................... 6
- The goal of cancer treatment is first to eradicate the cancer.
Folic Acid Analogs ................................................................. 6
- If the primary goal cannot be accomplished, the goal of
Pyrimidine Analogs ................................................................ 7
Cytidine Analogs ................................................................... 7 cancer treatment shifts to palliation, the amelioration of
Purine Analogs...................................................................... 8 symptoms, and preservation of quality of life while striving
NATURAL PRODUCTS .................................................................... 8 to extend life.
Microtubule-Damaging Agents: Vinca Alkaloids ......................... 8 - The dictum primum non nocere may not always be the
Microtubule-Damaging Agents: Taxanes .................................. 9 guiding principle of cancer therapy. When cure of cancer is
Antibiotics: Anthracyclines ..................................................... 9 possible, cancer treatments may be considered despite the
Epipodophyllotoxins .............................................................. 9
certainty of severe and perhaps life-threatening toxicities.
Drugs of Diverse Mechanism of Action ..................................... 9
- Every cancer treatment has the potential to cause harm, and
APPENDIX ...........................................................................11 treatment may be given that produces toxicity with no
benefit. The therapeutic index of any interventions may be
quite narrow, with treatments given to the point of toxicity.
GENERAL PRINCIPLES OF CANCER MEDICINE - Conversely, when the clinical goal is palliation, careful
- Cancer is the leading cause of mortality in developed attention to minimizing the toxicity of treatments becomes
countries and is the second leading cause of death in a significant goal.
developing countries
- Cancer is caused by uncontrolled and multifunctional cellular CANCER TREATMENTS
replication. Not only is there a failure of the cancer cell to - Divided into 2 main types:
maintain its specialized function but the cancer cell o Local treatments
competes to survive using natural mutability and natural  include surgery, radiation therapy (including
selection to seek advantage over normal cells in a photodynamic therapy), and ablative approaches,
recapitulation of evolution including radiofrequency and cryosurgical
approaches.
o Systemic treatments
 include chemotherapy (including hormonal therapy
and molecularly targeted therapy) and biologic
therapy (including immunotherapy).

Systemic Treatments
- Conventional “cytotoxic” chemotherapy agents
o These agents mainly target DNA structure or segregation
of DNA as chromosomes in mitosis.
- Targeted agents
o Refer to small molecules or “biologics” (generally
macromolecules such as antibodies or cytokines)
designed and developed to interact with a defined
molecular target important in maintaining the malignant
state or expressed by the tumor cells.
o Seeking to capitalize on the biology behind the aberrant
cellular behavior as a basis for therapeutic effects.
 E.g. Oncogene products, loss of cell cycle inhibitors,
or loss of cell death regulation
- Hormonal therapies
o Capitalize on the biochemical pathways underlying
estrogen and androgen function and action as a
therapeutic basis for approaching patients with tumors
of breast, prostate, and uterus.
- Biologic therapies
o Are often macromolecules that have a particular target
(e.g., antigrowth factor receptor or cytokine antibodies)

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or may have the capacity to induce a host immune CELL CYCLE SPECIFICTY
response to kill tumor cells.

CANCER TREATMENTS
- The usefulness of any drug is governed by the extent to
which a given dose causes a therapeutic effect (in the case
of anticancer agents, toxicity to tumor cells) as opposed to
a toxic effect to the host.
- The therapeutic index is the degree of separation between
toxic and therapeutic doses.
- Currently used chemotherapeutic agents have the
unfortunate property that their targets are present in both
normal and tumor tissues.
o Therefore, they have relatively narrow therapeutic
indices.
- Chemotherapy agents may be used for the treatment of
active, clinically apparent cancer.
o The goal of such treatment in some cases is cure of the
cancer, that is, elimination of all clinical and pathologic
evidence of cancer and return of the patient to an
expected survival no different than the general
population
- Chemotherapy can be administered as an adjuvant, i.e., in
addition to surgery or radiation, even after all clinically
apparent disease has been removed.
o This use of chemotherapy has curative potential in breast
and colorectal neoplasms, as it attempts to eliminate
clinically unapparent tumor that may have already
disseminated.
- Neoadjuvant chemotherapy refers to administration of - A phase that precedes DNA synthesis (G1)
chemotherapy before any surgery or radiation to a local - A DNA synthetic phase (S)
tumor in an effort to enhance the effect of the local - An interval following the termination of DNA synthesis (G2)
treatment. - The mitotic phase (M) in which the cell containing a double
- Chemotherapy is routinely used in “conventional” dose complement of DNA divides into two daughters
regimens.
o In general, these doses produce reversible acute side
effects, primarily consisting of transient
myelosuppression with or without gastrointestinal
toxicity (usually nausea), which are readily managed.

CHEMOTHERAPEUTIC AGENTS

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o Ethyleneimines
o Alkyl sulfonates
o Nitrosoureas
o Triazenes
o DNA-methylating drugs, including procarbazine,
temozolamide, and dacarbazine
- Because of similarities in their mechanisms of action and
resistance, platinum complexes are also discussed with
classical alkylating agents, even though they do not alkylate
DNA but instead form covalent metal adducts with DNA.

Mechanism of Action
- Chemotherapeutic alkylating agents have in common the
property of forming highly reactive carbonium ion
intermediates
- These reactive intermediates covalently link to sites of high
electron density such as phosphates, amines, sulfhydryl,
and hydroxyl groups.
- Their chemotherapeutic and cytotoxic effects are directly
related to the alkylation of reactive amines oxygens, or
phosphates on DNA
- Alkylating agents cause: Cytotoxic effects are due to:
o Mispair with thymine residues during DNA synthesis,
leading to the substitution of thymine for cytosine
(Mispairing)
o Creates lability in the imidazole ring, leading to opening
of the ring and excision of the damaged guanine residue.
Mispairing and imidazole ring opening can lead to
attempts to repair the damaged stretch of DNA, causing
strand breakage
o Cross-linking of two nucleic acid chains or the linking of
a nucleic acid to a protein, alterations that would cause
a major disruption in nucleic acid function
- The ultimate cause of cell death related to DNA damage is
not known.
- Specific cellular responses include cell-cycle arrest and
attempts to repair DNA.
- Recognition of extensively damaged DNA by p53 can trigger
apoptosis

Pharmacokinetics
- Alkylating agents may be activated or degraded in vivo in
the body via hepatic metabolism
- Cyclophosphamide, now the most widely used agent of this
class, undergoes metabolic activation (hydroxylation) by
CYP2B
- Ifosfamide is activated in the liver by CYP3A4
CYTOTOXIC AGENTS o Proceeds more slowly than activation of
ALKYLATING AGENTS cyclophosphamide, with greater production of
dechlorinated metabolites and chloroacetaldehyde.
o These differences in metabolism likely account for the
higher doses of ifosfamide required for equitoxic effects,
the greater neurotoxicity of ifosfamide, and possible
differences in the antitumor spectrum of
cyclophosphamide and ifosfamide.

- At present, six major types of alkylating agents are used in

chemotherapy of neoplastic diseases:
o Nitrogen mustards
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Nitrogen Mustards o Higher doses of 500 mg/m2 IV every 2-4 weeks are used
in combination with other drugs in the treatment of
Bendamustine breast cancer and lymphomas
- Newest approved drug o The neutrophil nadir of 500-1000 cells/mm3 generally
- The unique properties and activity of this drug may derive serves as a lower limit for dosage adjustments in
from this purine-like structure; the agent produces slowly prolonged therapy
repaired DNA cross-links, lacks cross-resistance with other o In regimens associated with bone marrow or peripheral
classical alkylators, and has significant activity in chronic stem cell rescue, cyclophosphamide may be given in
lymphocytic leukemia (CLL) and large-cell lymphomas total doses of 5-7 g/m2 over a 3-5 day period
refractory to standard alkylators. o GI ulceration, cystitis (counteracted by mesna and
diuresis) and less commonly, pulmonary, renal, hepatic,
Cyclophosamide and cardiac toxicities (a hemorrhagic myocardial
necrosis) may occur after high-dose therapy with high-
- Cyclophosphamide is well-absorbed orally and is activated
dose therapy with total doses >200 mg/kg
to the 4-hydroxy intermediate
- The rate of metabolic activation exhibits significant
interpatient variability and increases with successive doses Ifosfamide
in high-dose regimens - Ifosfamide is approved for treatment of patients with
o But appears to be saturable at concentrations of the relapsed germ cell testicular cancer and is frequently used
parent compound greater than 150 μM. for first-time treatment of pediatric or adult patients with
- 4-Hydroxycyclophosphamide and its tautomer, sarcomas.
aldophosphamide, travel in the circulation to tumor cells, - It is a common component of highdose chemotherapy
where aldophosphamide cleaves spontaneously, generating regimens with bone marrow or stem cell rescue. In these
stoichiometric amounts of phosphoramide mustard and regimens, in total doses of 12-14 g/m2, it may cause severe
acrolein. neurological toxicity, including hallucinations, coma, and
o 4-Hydroxycyclophosphamide may be oxidized further by death, with symptoms appearing 12 hours to 7 days after
aldehyde oxidase, either in liver or in tumor tissue, to beginning the ifosfamide infusion
inactive metabolites. - This toxicity is thought to result from a metabolite,
- Phosphoramide mustard is responsible for antitumor effects, chloroacetaldehyde.
while acrolein causes hemorrhagic cystitis often seen during - In addition, ifosfamide causes nausea, vomiting, anorexia,
therapy with cyclophosphamide. leukopenia, nephrotoxicity, and VOD of the liver
- Cystitis can be reduced in intensity or prevented by the - In nonmyeloablative regimens, ifosfamide is infused
parenteral coadministration of mesna. intravenously over at least 30 min at a dose of ≤ 1.2 g/m2/d
o Mesna does not negate the systemic antitumor activity for 5 days. Intravenous MESNA is given as bolus injections
of the drug. in a dose equal to 20% of the ifosfamide dose concomitantly
- Patients should receive vigorous intravenous hydration and an additional 20% again 4 and 8 hrs later, for a total
during high-dose treatment. MESNA dose of 60% of the ifosfamide dose.
- Brisk hematuria in a patient receiving daily oral therapy o Alternatively, MESNA may be given concomitantly in a
should lead to immediate drug discontinuation. Refractory single dose equal to the ifosfamide dose. Patients also
bladder hemorrhage can become life-threatening and may should receive at least 2 L of oral or intravenous fluid
require cystectomy for control of bleeding. daily.
- Inappropriate secretion of antidiuretic hormone has been o Treatment cycles are repeated every 3–4 weeks.
observed (usually at doses greater than 50 mg/kg) and can
lead to water intoxication because these patients usually are Pharmacokinetics
vigorously hydrated. o The parent compound, ifosfamide, has an elimination
- Cyclophosphamide can be used in full doses in patients with t1/2 in plasma of ~1.5 hours after doses of 3.8-5 g/m2
renal dysfunction because it is eliminated by hepatic and a somewhat shorter t1/2 at lower doses, although
metabolism. its pharmacokinetics are highly variable from patient to
- Patients with mild hepatic dysfunction (Bilirubin <3 mg/dL) patient due to variable rates of hepatic metabolism.
can receive full doses, but those with more significant o Hydroxylation by CYPs generates an active
hepatic dysfunction should receive reduced doses. phosphoramide mustard
- Can be administered IV or PO
- Maximal plasma concentrations are achieved about 1 h after Toxicity
oral administration; the t1/2 of parent drug in plasma is o Ifosfamide has virtually the same toxicity profile as
about 7 h. cyclophosphamide, although it causes greater platelet
- It is an essential component of many effective drug suppression, neurotoxicity, nephrotoxicity, and in the
combinations for non-Hodgkin lymphomas, other lymphoid absence of mesna, urothelial damage
malignancies, breast and ovarian cancers, and solid tumors
in children.
Triazenes
o Complete remissions and presumed cures have been
reported when cyclophosphamide was given as a single Dacarbazine
agent for Burkitt lymphoma. - Transfers methyl groups rather than ethyl groups
- It frequently is used in combination with doxorubicin and a - Requires initial activation by hepatic CYPs through an N-
taxane as adjuvant therapy after surgery for breast cancer. demethylation reaction. In the target cell, spontaneous
- Because of its potent immunosuppressive properties, cleavage of the metabolite, metyhyl-triazeno
cyclophosphamide has been used to treat autoimmune imidazolecarboxamide (MTIC), yields an alkylating moiety,
disorders, including Wegener’s granulomatosis, rheumatoid a methyl diazonium ion.
arthritis, and the nephrotic syndrome.
Nitrosoureas
Dosing
o As a single agent, a daily oral dose of 100 mg/m2 for 14 - Which include compounds such as 1,3-bis-(2-chloroethyl)-
days has been recommended for patients with 1-nitrosourea (carmustine [BCNU]), 1-(2-chloroethyl)-3-
lymphomas and CLL cyclohexyl-1-nitrosourea (lomustine [CCNU]), and its

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methyl derivative (semustine [methyl-CCNU]), as well as - Immunosuppression

the antibiotic streptozocin (streptozotocin) o Both cellular and humoral immunity are suppressed by
- Exert their cytotoxicity through the spontaneous breakdown alkylating agents, which have been used to treat various
to an alkylating intermediate, the 2-chloroethyl diazonium autoimmune diseases.
ion. o Reversible at usual doses, but opportunistic infections
may occur with extended treatment.
Pharmacologic Actions  Pneumocystis jiroveci pneumonia
- The capacity of alkylating agents to interfere with DNA  Fungal infections
integrity and function and to induce cell death in rapidly  Reactivation of hepatitis B
proliferating tissues provides the basis for their therapeutic - Mucosal Toxicity
and toxic properties o Alkylating agents are highly toxic to dividing mucosal
- Acute effects manifest primarily against rapidly proliferating cells and to hair follicles, leading to oral mucosal
tissues; however, certain alkylating agents may have ulceration, intestinal denudation, and alopecia.
damaging effects on tissues with normally low mitotic - Neurotoxicity
indices (e.g., liver, kidney, and mature lymphocytes); o Nausea and vomiting commonly follow administration of
effects in these tissues usually are delayed. nitrogen mustard or BCNU.
- Lethality of DNA alkylation depends on the recognition of the o Ifosfamide is the most neurotoxic of the alkylating
adduct, the creation of DNA strand breaks by repair agents and may produce altered mental status, coma,
enzymes, and an intact apoptotic response. generalized seizures, and cerebellar ataxia.
o Actual mechanism of cell death related to DNA alkylation  These side effects result from the release of
- are not yet well characterized chloroacetaldehyde from the phosphate-linked
- In nondividing cells, DNA damage activates a checkpoint chloroethyl side chain of ifosfamide.
that depends on the presence of a normal p53 gene. Cells o High-dose busulfan can cause seizures; in addition, it
thus blocked in the G1/S interface either repair DNA accelerates the clearance of phenytoin, an antiseizure
alkylation or undergo apoptosis. medication
- Malignant cells with mutant or absent p53 fail to suspend
cellcycle progression, do not undergo apoptosis, and can PLATIINUM COORDINATION COMPLEXES
exhibit resistance to these drugs.
- Platinum coordination complexes have broad antineoplastic
Mechanisms of Resistance activity and have become the foundation for treatment of
- Resistance to an alkylating agent develops rapidly when it is ovarian, head and neck, bladder, esophagus, lung, and colon
used as a single agent. cancers.
- Decreased permeation of actively transported drugs (e.g.,
mechlorethamine and melphalan) Mechanism of Action
- Increased intracellular concentrations of nucleophilic - Cisplatin, carboplatin, and oxaliplatin enter cells by the high
substances, principally thiols such as glutathione, which can affinity Cu2+ transporter CTR1 and in doing so contribute to
conjugate with and detoxify electrophilic intermediates the degradation of the transporter.
- Increased activity of DNA repair pathways, which may differ - Inside the cell, the chloride, cyclohexane, or oxalate ligands
for the various alkylating agents of the analogues are displaced by water molecules, yielding
- Increased rates of metabolic degradation of the activated a positively charged and highly reactive molecule
forms of cyclophosphamide and ifosfamide to their inactive - In the primary cytotoxic reaction, the aquated species of the
keto and carboxy metabolites by aldehyde dehydrogenase drug then reacts with nucleophilic sites on DNA and proteins
and detoxification of most alkylating intermediates by - DNA-platinum adducts inhibit replication and transcription,
glutathione transferases lead to single- and double-stranded breaks and miscoding,
- Loss of ability to recognize adducts formed by nitrosoureas and if recognized by p53 and other checkpoint proteins,
and methylating agents, as the result of defective MMR cause induction of apoptosis.
capability, confers resistance, as does defective checkpoint - The platinum analogues are mutagenic, teratogenic, and
function, for virtually all alkylating drugs carcinogenic. Cisplatin- or carboplatin-based chemotherapy
- Impaired apoptotic pathways, with overexpression of bcl-2 for ovarian cancer is associated with a 4-fold increased risk
as an example, confer resistance of developing secondary leukemia.

Toxicities Cisplastin
- Bone Marrow Suppression Pharmacokinebtics
o Most alkylating agents cause dose-limiting toxicity to - After intravenous administration, cisplatin has an initial
marrow elements and, to a lesser extent, intestinal plasma elimination t1/2 of 25–50 min; concentrations of
mucosa. total (bound and unbound) drug fall thereafter, with a t1/2
o Most alkylating agents (i.e., melphalan, chlorambucil, of 24 h or more.
cyclophosphamide, and ifosfamide) cause - More than 90% of the platinum in the blood is covalently
myelosuppression, with a nadir of the peripheral blood bound to plasma proteins.
granulocyte count at 6–10 days and recovery in 14–21 - High concentrations of cisplatin are found in the kidney,
days. liver, intestine, and testes; cisplatin penetrates poorly into
o Cyclophosphamide has lesser effects on peripheral blood the CNS.
platelet counts than do the other agents - Only a small portion of the drug is excreted by the kidney
o Busulfan suppresses all blood elements, particularly during the first 6 h; by 24 h, up to 25% is excreted, and by
stem cells, and may produce a prolonged and cumulative 5 days, up to 43% of the administered dose is recovered in
myelosuppression lasting months or even years. For this the urine, mostly covalently bound to protein and peptides.
reason, it is used as a preparative regimen in allogenic - Biliary or intestinal excretion of cisplatin is minimal.
bone marrow transplantation - Cisplatin is given only intravenously.
o Carmustine and other chloroethylnitrosoureas cause - The usual dosage is 20 mg/m2/day for 5 days, 20-30 mg
delayed and prolonged suppression of both platelets and weekly for 3-4 weeks, or 100 mg/m2 given once every 4
granulocytes, reaching a nadir 4–6 weeks after drug weeks.
administration and reversing slowly thereafer.

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o To prevent renal toxicity, it is important to establish a ANTIMETABOLITES

chloride diuresis by the infusion of 1–2 L of normal saline
prior to treatment. Folic Acid Analogs
- The appropriate amount of cisplatin then is diluted in a - Folic acid is an essential dietary factor that is converted by
solution containing dextrose, saline, and mannitol and enzymatic reduction to a series of tetrahydrofolate (FH4)
administered intravenously over 4–6 h. Because aluminum cofactors that provide methyl groups for the synthesis of
inactivates cisplatin, the drug should not come in contact precursors of DNA (thymidylate and purines) and RNA
with needles or other infusion equipment that contain (purines).
aluminum during its preparation or administration. - Interference with FH4 metabolism reduces the cellular
capacity for one-carbon transfer and the necessary
Toxicities methylation reactions in the synthesis of purine
- Cisplatin-induced nephrotoxicity ribonucleotides and thymidine monophosphate (TMP),
- Ototoxicity is manifested by tinnitus and high-frequency thereby inhibiting DNA replication.
hearing loss.
- Progressive peripheral motor and sensory neuropathy
(higher doses)
- Mild-to-moderate myelosuppression
- Electrolyte disturbances, including hypomagnesemia,
hypocalcemia, hypokalemia, and hypophosphatemia, are
common.
- Anaphylactic-like reactions

Carboplatin
- Similar profiles with Cisplatin
- Different pharmacokinetics
o Because carboplatin is much less reactive than cisplatin,
the majority of drug in plasma remains in its parent form,
unbound to proteins.
o Most drug is eliminated via renal excretion, with a t1/2
in plasma of ~2 hours.
o A small fraction of platinum binds irreversibly to plasma
proteins and disappears slowly, with a t1/2 of ≥ 5 days.
- Carboplatin is relatively well tolerated clinically, causing less
nausea, neurotoxicity, ototoxicity, and nephrotoxicity than
cisplatin.
- More Myelosuppression → Thrombocytopenia (Dose limiting
toxicity)
- More likely to cause a hypersensitivity reaction
- Carboplatin is an effective alternative for responsive tumors
in patients unable to tolerate cisplatin because of impaired
renal function, refractory nausea, significant hearing - The primary target of methorexate is the enzyme DHFR.
impairment, or neuropathy, but doses must be adjusted for - Inhibition of DHFR leads to partial depletion of the FH4
renal function. cofactors required for the respective synthesis of
thymidylate and purines.
- In addition, methotrexate, like its physiological counterparts
Oxaliplatin
(the folates), undergoes conversion to a series of
- Oxaliplatin, like cisplatin, has a very brief t1/2 in plasma polyglutamates (MTX-PGs) in both normal and tumor cells.
probably as a result of its rapid uptake by tissues and its These MTX-PGs constitute an intracellular storage form of
reactivity. folates and folate analogs and dramatically increase
- No dose adjustment is required for patients with a CrCl ≥20 inhibitory potency of the analog for additional sites.
ml/min; decreased renal function does not affect the rapid - Finally, dihydrofolic acid polyglutamates that accumulate in
chemical inactivation of the drug in the systemic circulation cells in behind the blocked DHFR reaction also acts as
and tissues (Takimoto et al., 2007). inhibitors of TS and other enzymes (Allegra et al., 1987b).
- Dose adjustment is not required for hepatic dysfunction - Inhibitors such as methotrexate, with a high affinity for
(Synold et al., 2007). DHFR, prevent the formation of FH4 and allow accumulation
- Oxaliplatin exhibits a range of antitumor activity (colorectal of the toxic inhibitory substrate, FH2 polyglutamate, behind
and gastric cancer) that differs from other platinum agents. the blocked reaction.
- Oxaliplatin’s effectiveness in colorectal cancer is perhaps - The absence of reduced folates shuts down the one-carbon
due to its MMR- and HMG-independent effects. transfer reactions crucial for the de novo synthesis of purine
- It also suppresses expression of thymidylate synthase (TS), nucleotides and thymiydylate and interrupts the synthesis of
the target enzyme of 5-fluorouracil (5-FU) action, which may DNA and RNA.
promote synergy of these two drugs (Fischel et al., 2002). - The toxic effects of methotrexate may be terminated by
- In combination with 5-FU, it is approved for treatment of administering leucovorin, a fully reduced folate coenzyme
patients with colorectal cancer. which repletes the intracellular pool of FH cofactors.
- The dose-limiting toxicity of oxaliplatin is a peripheral - Folate antagonists kill cells during the S phase of the cell
neuropathy. An acute form, often triggered by exposure to cycle and are most effective when cells are proliferating
cold liquids, manifests as paresthesias and/or dysesthesias rapidly.
in the upper and lower extremities, mouth, and throat.

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Methotrexate
- Methotrexate is readily absorbed from the GI tract at doses
of <25mg/m2, but larger doses are absorbed incompletely
and are routinely administered intravenously.
- Approximately 50% of methotrexate binds to plasma
proteins.
- Up to 90% of a given dose is excreted unchanged in the
urine within 48 hours, mostly within the first 8-12 hours. 5-Fluorouracil
Metabolism of methotrexate in humans usually is minimal. Mechanism of Action
- Therefore, the concurrent use of drugs that reduce renal - 5-FU requires enzymatic conversion to the nucleotide stat
blood flow (e.g. nonsteroidal anti-inflammatory agents), (ribosylation and phosphorylation) in order to exert I
that are nephrotoxic (e.g., cisplatin), or that are weak cytotoxic activity.
organic acids (e.g., aspirin, piperacillin) can delay drug - FdUMP inhibits TS and blocks the synthesis of TTP, a
excretion and lead to severe myelosuppression. necessary constituent of DNA.
- Methotrexate has been used in the treatment of severe,
disabling psoriasis in doses of 2.5 mg orally for 5 days,
followed by a rest period of at least 2 days, or 10-25 mg
intravenously weekly.
- It is also used at low dosage to induce remission in refractory
rheumatoid arthritis.
- Methotrexate is a critical drug in the management of acute
lymphoblastic anemia (ALL) in children.
- The primary toxicities of antifolates affect the bone marrow
and the intestinal epithelium and correct within 10-14 days

Pyrimidine Analogs - 5-FU is administered parenterally, because absorption after

- The antimetabolites as a class encompass a diverse group of oral ingestion of the drug is unpredictable and incomplete.
drugs that inhibit RNA and DNA function. Metabolic degradation occurs in many tissues, particularly in
- The fluoropyrimidines and certain purine analogs (6- the liver.
mercaptopurine and 6-thioguanine) inhibit the synthesis of - Given by continuous intravenous infusion for 24-120 hours.
essential precursors of DNA - 5-FU produces partial responses in 10-20% of patients with
- Others, such as cytidine and adenosine nucleoside analogs, metastatic colon carcinomas, upper GI tract carcinomas, an
become incorporated into DNA and block its further breast carcinomas but rarely is used as a single agent.
elongation and function. - 5-FU in combination with leucovorin and oxaliplatin or
- Other inhibitory effects of these analogs may contribute to irinotecan in the adjuvant setting is associated with a
their cytotoxicity and even their ability to induce survival advantage for patients with colorectal cancers.
differentiation.
Cytidine Analogs
Cytarabine
- Cytarabine (1-ß-D-arabinofuranosylcytosine; Ara-C) is the
most important antimetabolite used in the therapy of AML.
It is the single most effective agent for induction of
remission in this disease.
- Ara-C exposure activates a complex system of secondary
intracellular signals that determine whether a cell survives
or undergoes apoptosis
o It activates the transcription factor AP-1 and stimulates
the formation of ceramide, a potent inducer of apoptosis.
o It causes an increase in the cell damage response factor
- NF-kB in leukemic cells and activates checkpoint kinases.
- Due to the presence of high concentration of cytidine
deaminase in the GI mucosa and liver, only ~20% of the
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drug reaches the circulation after oral Ara-C administration; - The biological activities of the vincas can be explained by
thus, the drug must be given intravenously. their ability to bind specifically to B tubulin and to block its
- Peak concentration of 2-50 uM are measurable in plasma polymerization with a tubulin into microtubules
after intravenous injection of 30-300 mg/m2 but disappear - The very limited myelosuppressive action of vincristine
rapidly (t½ of 10 minutes) from plasma. makes it a valuable component of several combination
- Two dosage schedules are recommended for administration therapy regimens for leukemia and lymphoma, while the
of cytarabine: lack of severe neurotoxicity of vinblastine is a decided
1. Rapid intravenous infusion of 100 mg/m2 every 12 advantage in lymphomas and in combination with cisplatin
hours for 5-7 days, or against testicular cancer.
2. Continuous intravenous infusion of 100-200 - In large-cell non-Hodgkin's lymphomas, vincristine remains
mg/m2/day for 5-7 days. an important agent, particularly when used in the CHOP
- Cytarabine is a potent myelosuppressive agent capable of regimen with cyclophosphamide, doxorubicin and
producing acute, severe leukopenia, thrombocytopenia, and prednisone.
anemia with striking megaloblastic changes. - Vinblastine is employed in treating bladder cancer, testicular
- Other toxic manifestations include GI disturbances, carcinomas and Hodgkin’s disease.
stomatitis, conjunctivitis, reversible hepatic enzyme - The liver cytochromes extensively metabolized all 3 agents
elevations, noncardiogenic pulmonary edema, and and the metabolites are excreted in the bile (Robieux et al,
dermatitis. 1996).
- Only a small fraction of a dose (<15%) is found in the urine
unchanged.
Gemticabine
- In patients with hepatic dysfunction (bilirubin >3 mg/dL), a
- A difluoro analog of deoxycytidine, has become an important 50-75% reduction in dose of any the vinca alkaloids is
drug for patients with metastatic pancreatic; non-squamous, advisable, although firm guidelines for dose adjustment
non-small cell lung; ovarian; and bladder cancer. have not been established.
- The standard dosing schedule for gemcitabine (GEMZAR) is - The pharmacokinetics of each of the 3 drugs are similar, with
a 30-minute IV infusion of 1-1.25 g/m2 on days 1, 8, and an elimination t1/2 of 20 hours for vincristine, 23 hours for
15 of each 21- to 28-day cycle, depending on the indication. vinblastine, and 24 hours for vinorelbine.
- The principal toxicity of gemcitabine is myelosuppression.

Vinblastine
Purine Analogs
- Vinblastine sulfate (VELBAN, others) is given intravenously;
- 6-Mercaptopurine (6-MP) and 6-Thioguanine (6-TG) are
special precautions must be taken against subcutaneous
approved agents for human leukemias and function as
extravasation, because this may cause painful irritation and
analogs of the natural purines, hypoxanthine and guanine
ulceration.
- Both 6-TG and 6-MP are excellent substrates for
o The drug should not be injected into an extremity with
hypoxanthine guanine phosphoribosyl transferase (HGPRT)
impaired circulation.
and are converted in a single step to the ribonucleotides 6-
- After a single dose of 0.3mg/kg of body weight,
thioguanosine-5’–monophosphate (6-thioGMP) and 6-
myelosuppression reaches its maximum in 7-10 days.
thionosine-5’-monophosphate (T-IMP), respectively.
o If a moderate level of leukopenia (3000 cells/mm3) is
not attained, the weekly dose may be increased
Mechanism
gradually by increments of 0.05 mg/kg of body weight.
- 6-Thioguanine nucleotide is incorporated into DNA, where it
- In regimens designed to cure testicular cancer, vinblastine
induces strand breaks and base mispairing. Strand breaks
is used in doses of 0.3 mg/kg every 3 weeks.
depend on the presence of an intact MMR system, the
- Doses should not be reduced by 50% for patient with plasma
absence of which leads to resistance.
bilirubin >1.5mg/dL.
- Absorption of mercaptopurine is incomplete (10-50%) after
- The nadir of the leukopenia that follows the administration
oral ingestion; the drug is subject to first-pass metabolism
of vinblastine usually occurs within 7-10 days, after which
by xanthine oxidase in the liver. Food or Oral antibiotics
recovery ensues within 7 days.
decrease absorption.
- Other toxic effects include mild neurological manifestation.
- Oral bioavailability is increased when mercaptopurine is
GI disturbances including nausea, vomiting, anorexia, and
combined with high-dose methotrexate
diarrhea may be encountered.
- After and IV dose, the half-life of the drug in plasma is
- The syndrome of inappropriate secretion of antidiuretic
relatively short (~50 minutes in adults). Due to rapid
hormone has been reported. Loss of hair, stomatitis, and
metabolic degradation by xanthine oxidase and by
dermatitis occur infrequently. Extravasation during injection
thiopurine methyltransferase (TPMT)
may lead to cellulitis and phlebitis.
Toxicity
- The principal toxicity of 6-MP is bone marrow depression. Vincristine
- Vincristine sulfate used together with glucocorticoids is the
NATURAL PRODUCTS treatment of choice to induce remissions in childhood
leukemia and in combination with alkylating agents and
- Several anticancer agents act through the microtubules,
anthracycline for pediatric sarcomas; the common
either causing disorganized stabilization of microtubules in
intravenous dosage for vincristine is 2 mg/m2 of body
areas away from the centriole or causing destabilization of
surface area at weekly or longer intervals.
the mitotic spindle, interfering with mitosis.
- Tolerated better by children than by adults, who may
experience severe, progressive neurologic toxicity and
Microtubule-Damaging Agents: Vinca Alkaloids require a lower dose of 1.4 mg/m2
Mechanism - Administration of the drug more frequently than every 7
- The vinca alkaloids are cell-cycle-specific agents and, in days or at higher doses increases the toxic manifestations
common with other drugs such as colchicine, without proportional improvement in the response rate.
podophyllotoxin, the taxanes, and the epothilones, block - Precautions also should be used to avoid extravasation
cells mitosis during intravenous administration of vincristine. Doses
should be reduced by 50% or 75% for patients with plasma
bilirubin >1.5 mg/dL or >3mg/dL, respectively.
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- The clinically toxicity of vincristine is mostly neurological, - Erythematous streaking near the site of infusion
early sensory changes do not warrant dose reduction. (“ADRIAMYCIN flare”) is a benign local allergic reaction and
- Alopecia occurs in ~20% of patients given vincristine – should not be confused with extravasation. Facial flushing,
Reversible conjunctivitis, and lacrimation may occur rarely. The drug
may produce severe local toxicity in irradiated tissues (e.g.
Microtubule-Damaging Agents: Taxanes the skin, heart, lung, esophagus, and GI mucosa) even when
the two therapies are not administered concomitantly.
Paclitaxel - Cardiomyopathy is the most important long-term toxicity.
- Interest in paclitaxel was stimulated by the drug’s unique
ability to promote microtubule formation at cold Epipodophyllotoxins
temperature and in the absence of GTP
- It binds specifically to the B-tubulin subunit of microtubules Etoposide
and antagonizes the disassembly of this key cytoskeletal - Etoposide and teniposide are similar in their actions and in
protein, with the result that bundles of microtubules and the spectrum of human tumors affected. Like the
aberrant structures derived from microtubules appear in the anthracyclines, they form a ternary complex with
mitotic phases of the cell cycle. topoisomerase II and DNA and prevent resealing of the
- Arrest in mitosis follows. Cell killing is dependent on both break that normally follows topoisomerase binding to DNA
drug concentration and duration of cell exposure. Drugs that - The enzyme remains bound to the free end of the broken
bloc cell cycle progression prior to mitosis antagonizes the DNA strand, leading to an accumulation of DNA breaks and
toxic effects of taxanes. cell death
- Paclitaxel is administered as 3-hour infusion of 135-175 - Cells in the S and G2 phases of the cell cycle are most
mg/m2 every 3 weeks or as a weekly 1-hour infusion of 80- sensitive to etoposide and teniposide.
100 mg/m2. Prolonged infusions (96 hours) also have in - Oral administration of etoposide results in variable
different tumor histologies and are active. absorption that averages ~50%. After intravenous injection,
- The drug undergoes extensive metabolism by hepatic CYPs peak plasma concentrations of 30 μg/mL are achieved; there
(primarily CYP2C8 with a contribution of CYP3A4); <10% of is a biphasic pattern of clearance with a terminal t1/2 of ~6-
a dose is excreted in the urine intact. 8 hours in patients with normal renal function.
- The taxanes have become central components of the - Approximately 40% of an administered dose is excreted
regimens for treating metastatic ovarian, breast, lung, GI, intact in the urine.
genitourinary, and head and neck cancers. - In patients with advanced liver disease, increased toxicity
- In current regimens, these drugs are administered once may result from a low serum albumin (decreased drug
weekly or every 3 weeks. binding) and elevated bilirubin (which displaces etoposide
- Paclitaxel exerts its primary toxic effects on bone marrow. from albumin).
Neutropenia usually occurs 8-11 days after a dose and - The intravenous dose of etoposide (VEPESID, others) for
reverses rapidly by days 15-21. testicular cancer in combination therapy is 50-100 mg/m2
- Docetaxel causes greater degrees of neutropenia than for 5 days, or 100 mg/m2 on alternate days for three doses
paclitaxel but less peripheral neuropathy and asthenia and - For small cell carcinoma of the lung, the dosage in
less frequent hypersensitivity. combination therapy is 35 mg/m2/day intravenously for 4
days or 50 mg/m2/day intravenously for 5 days. The oral
Antibiotics: Anthracyclines dose for small cell lung cancer is twice the IV dose. Cycles
of therapy usually are repeated every 3-4 weeks.
- The anthracycline antibiotics have a tetracyclic ring structure
- When given intravenously, the drug should be
attached to an unusual sugar, daunosamine.
administeredslowly over a 30- to 60-minute period to avoid
- Cytotoxic agents of this class all quinone and hydroquinone
hypotension and bronchospasm, which likely result from the
moieties on adjacent rings that permits the gain and loss of
additives used to dissolve etoposide, a relatively insoluble
electrons.
compound.
- These compounds can intercalate with DNA, directly
- A disturbing complication of etoposide therapy has emerged
affecting transcription and replication.
in long-term follow-up of patients with childhood acute
- A more important action is the ability to form a tripartite
lymphoblastic leukemia, who develop an unusual form
complex with topoisomerase II and DNA.
ofacute nonlymphocytic leukemia with a translocation in
- Anthracyclines, by virtue of their quinone groups, also
chromosome 11q23
generate free radicals in solution and in both normal and
- The dose-limiting toxicity of etoposide is leukopenia, with a
malignant tissues.
nadir at 10-14 days and recovery by 3 weeks.
- Daunorubicin, doxorubicin, epirubicin, and idarubicin usually
are administered intravenously and are cleared by a
complex pattern of hepatic metabolism and biliary excretion. Drugs of Diverse Mechanism of Action
Doxorubicin Bleomycin
- Doxorubicin is available for intravenous use. - A unique group of DNA-cleaving antibiotics.
- The recommended dose is 60-75 mg/m2, administered as a - Cytotoxicity from its ability to cause oxidative damage to the
single rapid intravenous infusion that is excreted after 21 deoxyribose of thymidylate and other nucleotides leading to
days. single and double stranded DNA breaks.
- Care should be taken to avoid extravasation, because severe - Cleaves DNA by generating free radicals.
local vesicant action and tissue necrosis may result. - In the presence of O2 and reducing agents, such as
- Doxorubucin is effective in malignant lymphomas.
dithiothreitol, metal-drug complex becomes cleaved and
- The toxic manifestations of doxorubicin are similar to those
function as ferrous oxidase, transferring electrons from
of daunorubicin. Myelosuppression is a major dose-limiting
complication, with leukopenia usually reaching a nadir Fe2+ to molecular oxygen to produce oxygen radicals.
during the second week of therapy and recovering by the - Administered IV, IM, or SC, or instilled into the bladder for
fourth week; thrombocytopenia and anemia follow a similar local treatment of bladder cancer.
pattern but usually are less pronounced. Stomatitis, - After IV infusion, relatively high drug concentrations are
mucositis, diarrhea, and alopecia are common but detected in skin and lungs of experimental animals and
reversible. these organs become major sites of toxicity.
- Having high molecular mass, bleomycin crosses BBB poorly.
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- After IV administration of bolus dose of 15 mg/m2, peak

concentrations of 1-5 mg/mL are achieved in plasma.
- Elimination half time: ~3hrs
- About ⅔ excreted intact in urine
- Plasma concentrations are greatly elevated if usual doses
are given to patients with renal impairment and if such
patients are at high risk of developing pulmonary toxicity.
- Decreased doses if CrCl <60 mL/min
- Recommended dose 10-20 units/m2 given weekly or twice
weekly by IV, IM, or SC.
- Highly effective against germ cell tumors of testis and ovary.
- Testicular cancer - curative when used with Cisplatin and
Vinblastine or Cisplatin and Etoposide
o It is a component of standard curative ABVD regimen
(Doxorubicin/Adriamycin, Bleomycin, Vinblastine,
Dacarbazine) for Hodgkin’s lymphoma.
- Causes little myelosuppression → significant advantages in
combination with other cytotoxic drugs.
- However, it causes constellation of cutaneous toxicities
o Hyperpigmentation
o Hyperkeratosis
o Erythema
o Ulceration
- Rarely may experience Raynaud’s phenomenon
- Most serious adverse reaction: Pulmonary Toxicity
o Begins with dry cough, fine rales, diffuse basilar
infiltrates on X-Ray and may progress to life-threatening
pulmonary fibrosis.
- Other toxic reactions: Hyperthermia, Headache, Nausea and
vomiting, Peculiar acute fulminant reaction observed in
patients with lymphomas.

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[PHARMACOLOGY] Chemotherapy of Neoplasms

APPENDIX

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