Study

1. Anti-neoplastic drugs
By: Muhammad Aurangzeb
Lecturer-INS/KMU

2. Objectives
By the end of this unit, students will be able to:
• Review the characteristics of normal and
malignant cells.
• Explain characteristics of anti-neoplastic drugs.
• Classify anti-neoplastic drugs.
• Discuss the nursing care of patients who are on
anti-neoplastic drugs.
• Calculate the drug dosage for Anti-neoplastic
drugs.

3. Introduction
• Normal cells…
• Differentiate, grow, mature, divide
– Regulated, balanced; cell birth=cell death
• Regulation: intracellular signaling
– Hyperplasia: new cells production with growth stimulus via hormones,
endogenous signals
• Ex: hyperplasia of endometrial tissue during menstrual cycle is normal
and necessary
– BUT if intense, prolonged demand
• May  cell structural, functional abnormalities
• – Metaplasia: replacement of one cell type by another

4. Introduction
– Dysplasia: replacement cells are disordered
in size, shape
• Increased mitosis rate
• Somewhat reversible, often precancerous
– Neoplasia: abnormal growth/invasion of cells
• “New growth”
• Neoplasm = tumor
• Irreversible
• Cells replicate, grow with /out control

5. Neoplasms
• Tumors = groups of neoplastic cells
• Two major types: benign, malignant
• Benign – “noncancerous”
– Local; cells cohesive, well-defined borders
– Push adjacent tissue away
– Doesn’t spread beyond original site
– Often has capsule of fibrous connective tissue
• Malignant– grow more rapidly; often called “cancer”
– Not cohesive; seldom have capsule
– Irregular shape; disrupted architecture
– Invade surrounding cells
– Can break away to form second tumor
• “Metastasis” from 1o to 2o site

6. Some basic Facts about Cancer
• Cancer cells have lost the normal regulatory mechanisms that
• control cell growth and multiplication
• Cancer cell have lost their ability to differentiate (that means to
specialize)
• Benign cancer cell stay at the same place
• Malignant cancer cells invade new tissues to set up secondary
tumors, a process known as metastasis
• Chemicals causing cancer are called mutagens
• Cancer can be caused by chemicals, life style (smoking), and
viruses
• genes that are related to cause cancer are called oncogenes.
Genes that become onogenic upon mutation are called proto-
oncogenes.

7. Cancer (Neoplastic)
been
• Cancer occurs
transformed
normal cells have
neoplastic cells through
alteration of
after
into
their genetic material and the
abnormal expression of certain genes.
• Neoplastic cells usually exhibit chromosomal
abnormalities and the loss of their differentiated
properties.
• These changes lead to uncontrolled cell division
and many result in the invasion of previously
unaffected organs, a process called metastasis

10. Cell Cycle Phases
Synth DNA precursors,
proteins, etc.

11. Cycle
Checkpoints
18_04_F eedback.jpg

12. Cont…
• After completion of mitosis, the resulting daughter
cells have two options:
(1) they can either enter G1 & repeat the cycle or
(2)they can go into G0 and not participate in the cell
cycle. (Quiescent phase outside cell cycle)

13. Phases of the Cell Cycle
• G1 phase (gap 1): Cell grows in size
and prepares to copy its DNA in
response to various growth factors
• S phase (synthesis): Replication of
DNA, copying of the chromosome
• G2 phase (gap 2): Preparation for
cell division. Check copied DNA
and repair damaged copies.
• M phase (mitosis): Formation of the
mitotic spindle, and separation into
two individual cells (cell division).

14. Control of Cell Cycle Progression by CDKs
• Progression through the cell cycle is controlled by
cyclin-dependent kinases (CDKs).
• Binding of cyclin with its associated kinase
triggers to move the cell cycle to another
phase
• inhibitory proteins are present that can modify the
effect of cyclins. These include p21, that is
controlled by the tumor suppressor protein p53.
• over-active cyclins or CDKs have been
associated with many tumors. Excessive
production of cyclins or CDKs or insufficient
production of CDK inhibitors leads to disruption of
the normal regulation of the cell cycle.

15. • Cancer cells are often called immortal
since there seems to be no limit for
how often they can divide
• Life-time of normal cells is limited to
50-60 cell divisions. This is regulated
by telomeres. The telomeres are at
the 3’ end of the chromosomes. After
each replication about 50-100 base
pairs are lost
• At some point telomeres are too short
to be effective and the DNA becomes
unstable thereby limiting replication.
Cancer cells possess an enzyme
called telomerase which maintains the
length of the telomeres and thereby
allows more DNA replications.
Telomeres
A few short
telomeres
Critically short
telomeres
Apoptosi
s
Cancer (1 in
10,000,000)

16. Intrinsic Tumor Suppression: p53
• In response to DNA damage, oncogene activation or
other harmful events the tumor suppressor gene p53
is induced
• Various kinases phosporylate p53 which help
stabilizing it. Activated p53 results in DNA binding
and transcriptional activation
• p53 triggers cell-cycle arrest in untransformed cells
via cell-cycle regulators such as CDKs
• It also triggers apoptosis in transformed cells
• In most tumor cells p53 is mutated and inactivated

17. Uncontrolled Proliferation
• Result of activation proto-oncogenes (Ras)
or inactivation of tumor suppressor genes
(p53)
– Change in growth factors, receptors
• Increased growth factors produced
– Change in cell cycle transducers
• Cyclins, CDK’s, CDK inhibitors (p21)
– Change in apoptotic mechanism
– Change in telomerase expression

18. Principles of cancer chemotherapy
• Cancer chemotherapy strives to cause a lethal cytotoxic event
or apoptosis in the cancer cells that can arrest a tumor’s
progression. The attack is generally directed toward DNA or
against metabolic sites essential to cell replication, for
example, the availability of purines and pyrimidines, which
are the building blocks for DNA or RNA synthesis.
• Ideally, these anticancer drugs should interfere only with
cellular processes that are unique to malignant cells.
Unfortunately, most currently available anticancer drugs do
not specifically recognize neoplastic cells but, rather, affect all
kinds of proliferating cells, both normal and abnormal.

20. Mechanisms of Action of Antineoplastic
Drugs
1.Prevent DNA synthesis
2.Disrupt DNA, prevent DNA repair, and/or
prevent RNA synthesis
3.Interrupt mitosis
4.Interfere with protein or hormone synthesis

21. Goal of Chemotherapy
The GOAL is to eradicate the cancer cells
without affecting normal tissues. The REALITY
is that all cytotoxic drugs affect normal
tissues as well as malignancies due to a
narrow therapeutic index

22. The Goal of Cancer Treatments
• Curative
– Total irradication of cancer cells
– Curable cancers include testicular tumors, Wills tumor
• Palliative
– Alleviation of symptoms
– Avoidance of life-threatening complications
– Increased survival and improved quality of life
• Adjuvant therapy
– Attempt to eradicate microscopic cancer after surgery
– e.g. breast cancer & colorectal cancer

23. Classification of cancer drugs
• Cancer drugs can be divided into two general classes:
• CELL CYCLE SPECIFIC DRUGS (CCS; esp. plant
alkaloids and antimetabolites), and
• CELL CYCLE NON-SPECIFIC DRUGS (CCNS; esp.
alkylating agents and some natural products).
• Antineoplastic agents can also be organized
according to their chemical class, mechanism of
action, therapeutic use or their toxicities.

25. Toxicity
• Toxicity: Therapy aimed at killing rapidly dividing
cancer cells also affects normal cells undergoing
rapid proliferation (for example, cells of the buccal
mucosa, bone marrow, gastrointestinal [GI] mucosa,
and hair follicles), contributing to the toxic
manifestations of chemotherapy.

26. Common adverse effects:
• Most chemotherapeutic agents have a narrow therapeutic
index. Severe vomiting, stomatitis, bone marrow suppression,
and alopecia occur to a lesser or greater extent during
therapy with all antineoplastic agents.
• Vomiting is often controlled by administration of antiemetics.
• Some toxicities, such as myelosuppression that predisposes to
infection, are common to many chemotherapeutic agents,
whereas other adverse reactions are confined to specific
agents, such as bladder toxicity with cyclophosphamide,
cardiotoxicity with doxorubicin, and pulmonary fibrosis with
bleomycin. The duration of the side effects varies widely. For
example, alopecia is transient, but the cardiac, pulmonary,
and bladder toxicities can be irreversible.

27. General problems with anticancer
drugs
• Side effects greatest in other rapidly-dividing cells
– Bone marrow toxicity
– Impaired wound healing
– Hair follicle damage
– GI epithelium damage
– Growth in children
– Gametes
– Fetus
• May themselves be carcinogenic

28. Anticancer Drugs
• Antimetabolite
• Antibiotics
• Alkylating Agent
• Microtubule inhibitors
• Topoisomerase inhibitors
• Tyrosine kinase inhibitors
• Hormones
• Monoclonal antibodies
• Platinum complex compounds etc.

29. ANTIMETABOLITES
• Antimetabolites are structurally related to normal compounds
that exist within the cell. They generally interfere with the
availability of normal purine or pyrimidine nucleotide
precursors, either by inhibiting their synthesis or by
competing with them in DNA or RNA synthesis.
• Their maximal cytotoxic effects are in S-phase and are,
therefore, cell cycle specific.
• Methotrexate (MTX), pemetrexed and pralatrexate
are antifolate agents

30. Classification of Antimetabolites
 Folic acid Antagonists: (Methotrexate) MTX
Purine Antagonists: 6-Mercaptopurine
Pyrimidine Antagonists：5 Fluorouracil (5-FU)

31. Mechanism of Action
• MTX is structurally related to folic acid and acts as an
antagonist of the vitamin by inhibiting dihydrofolate reductase
(DHFR), the enzyme that converts folic acid to its active,
coenzyme form, tetrahydrofolic acid (FH4) required for
thymidine and purine synthesis. MTX is specific for the S-
phase of the cell cycle.
• Pemetrexed is an antimetabolite similar in mechanism to
methotrexate. However, in addition to inhibiting DHFR, it also
inhibits thymidylate synthase and other enzymes
involved in folate metabolism and DNA synthesis.
• Pralatrexate is a newer antimetabolite that also inhibits DHFR

32. Therapeutic uses:
• MTX, usually in combination with other drugs, is
effective against acute lymphocytic leukemia, Burkitt
lymphoma in children, breast cancer, bladder cancer,
and head and neck carcinomas.
• Pemetrexed is primarily used in non–small cell lung
cancer.
• Pralatrexate is used in relapsed or refractory T-cell
lymphoma

33. Adverse Effects：
 MTX is myelosuppressive, producing severe
leukopenia, bone marrow aplasia (failure), and
thrombocytopenia.
 This agent may produce severe gastrointestinal
disturbances.
 Renal toxicity may occur because of precipitation
(crystalluria) of the 7-OH metabolite of MTX.

34. Purine Antagonists
• 6-Mercaptopurine（6-MP）
• The drugs are believed to act similarly to inhibit purine base
synthesis, although their exact mechanisms of action are still
uncertain.
• Indications: Mercaptopurine is used primarily for the
maintenance of remission in patients with acute lymphocytic
leukemia and is given in combination with MTX for this
purpose.
• Adverse Effects:
• Well tolerate.
• Myelosuppression is generally mild with this drug. Long-
term mercaptopurine use may cause hepatotoxicity.

35. Pyrimidine Antagonists: 5-Fluorouracil
(5-FU)
• Mechanism of Action：
• Fluorouracil is an analogue of thymine in which the methyl
group is replaced by a fluorine atom.
• 5-FU is converted to 5-fluorodeoxyuridine monophosphate (5-
FdUMP), which competes with deoxyuridine monophosphate
(dUMP) for the enzyme thymidylate synthetase and prevents
the synthesis of thymidine, a major building block of DNA.

36. Pyrimidine Antagonists
• 5-Fluorouracil (5-FU)
• Indications：
• Fluorouracil is exclusively used to treat solid tumors,
especially breast, colorectal, and gastric tumors and
squamous cell tumors of the head and neck.
• Adverse Effects： Fluorouracil may cause nausea and
vomiting, myelosuppression, oral and gastrointestinal
ulceration. Nausea and vomiting are usually mild.

37. Pyrimidine Antagonists: Cytarabine
Cytarabine acts as a pyrimidine antagonist.
Indications：
• Cytarabine has a narrow clinical spectrum and is primarily used
in combination with daunorubicin for the treatment of acute
nonlymphocytic leukemia.
Adverse Effects:
• High doses of cytarabine can damage the liver, heart, and other
organs.

38. Anti-tumor Antibiotics
• The antitumor antibiotics owe their cytotoxic action
primarily to their interactions with DNA, leading to
disruption of DNA function. In addition to
intercalation, their abilities to inhibit topoisomerases
(I and II) and produce free radicals also play a major
role in their cytotoxic effect. They are cell cycle
nonspecific with bleomycin as an exception

39. Antibiotics
• Anthracyclines:
– Doxorubicin (Adriamycin)
– Daunorubicin
• Bleomysin
• Actinomycin D
• Mitomycin

40. Doxorubicin & Daunorubicin Mechanism of
action
• These drugs intercalate
between base pairs,
inhibit topoisomerase
II and also generate
free radicals
• They block RNA and
DNA synthesis and
cause strand scission
Doxorubicin interacts with molecular
oxygen, producing superoxide ions
and hydrogen peroxide, which cause
single-strand breaks in DNA

42. Adverse Drug Reaction
• Cardiac toxicity (due to generation of free radicals)
• Acute form: arrhythmias, ECG changes, pericarditis,
myocarditis
• Chronic form: ***Dilated cardiomyopathy, heart
failure
• ****Rx with dexrazoxane
• – This is an inhibitor of iron mediated free radical
generation
• Bone marrow depression, Total alopecia

43. Mitomycin C:
• Mechanism:
• Mitomycin C is an antineoplastic antibiotic that
• alkylates DNA and thereby causes strand
breakage and inhibition of DNA synthesis.
• Indications:
• It is primarily used in combination with vinvristine
as salvage therapy for breast cancer.
• Adverse Effects:
• Mitomycin produces delayed and prolonged
myelosuppression that preferentially affects platelets
and leukocytes

44. Actinomycin D:
• Actinomycin D intercalates DNA
and thereby prevents DNA
transcription and messenger
RNA synthesis.
• The drug is given intravenously,
and its clinical use is limited to
the treatment of trophoblastic
(gestational) tumors and the
treatment of pediatric tumors,
such as Wilms’ tumor and
Ewing’s sarcoma.

45. Bleomycin:
Mechanism:
• The drug has its greatest effect on neoplastic
cell in the G2 phase of the cell replication
cycle. Although bleomycin intercalates DNA,
the major cytotoxicity is believed to result
from ironcatalyzed free radical formation and
DNA strand breakage.
Indications:
• It is useful in Hodgkin’s and non-Hodgkin’s
lymphomas, testicular cancer, and several
other solid tumors.
Adverse Effects:
• Bleomycin produces very little
myelosuppression. The most serious
toxicities of Bleomycin are pulmonary and
mucocutaneous reactions.

46. ALKYLATING AGENTS
• Alkylating agents exert their cytotoxic effects by covalently
binding to DNA. Alkylation of DNA is probably the crucial
cytotoxic reaction that is lethal to the tumor cells.
• Alkylating agents do not discriminate between cycling and
resting cells, even though they are most toxic for rapidly
dividing cells.
• They are used in combination with other agents to treat a
wide variety of lymphatic and solid cancers.
• In addition to being cytotoxic, all are mutagenic and
carcinogenic and can lead to secondary malignancies such
as acute leukemia.

48. Alkylating Agents
• One of the frightening developments of World War I
was the introduction of chemical warfare. These
compounds were known as the nitrogen mustard
gases.
• The nitrogen mustards were observed to inhibit cell
growth, especially of bone marrow.
• Shortly after the war, these compounds were
investigated and shown to inhibit the growth of
cancer cells.

49. Alkylating Agents
Mechanism of Action
• Nitrogen mustards inhibit cell reproduction by binding
irreversibly with the nucleic acids (DNA). The specific
type of chemical bonding involved is alkylation.
• After alkylation, DNA is unable to replicate and
therefore can no longer synthesize proteins and other
essential cell metabolites.
• Consequently, cell reproduction is inhibited and the cell
eventually dies from the inability to maintain its
metabolic functions.

50. ALKYLATING AGENTS
• Cyclophosphamide
• Busulfan
• Carmustine (BCNU) Lomustine (CCNU)
• Melphalan
• Thiotepa

51. Alkylating Agents—Cyclophosphamide
• It is a prodrug and is activated by the P-450 enzymes to its
active form phosphoramide mustard
• The active drug alkylates nucleophilic groups on DNA
bases – Particularly at the N-7 position of guanine
• This leads to cross linking of bases, abnormal base pairing
and DNA strand breakage
Indications：
 It is used in the treatment of chronic lymphocyctic
leukemia, non-Hodgkin’s lymphomas, breast and ovarian
cancer, and a variety of other cancers.
 It is also a potent immunosuppressant, it is used in the
management of rheumatoid disorders and autoimmune
nephritis.
Adverse Effects:
 Alopecia, nausea, vomiting, myelosuppression, and
hemorrhagic cystitis.

52. Alkylating Agents——Nitrosoureas
Carmustine, Lomustine,
• Carmustine and lomustine are closely related
nitrosoureas. Nitrosoureas are highly lipophilic and reach
cerebrospinal fluid concentrations that are about 30% of
plasma concentrations.
• Mechanism of action: The nitrosoureas exert cytotoxic
effects by an alkylation that inhibits replication and,
eventually, RNA
and protein synthesis.
• Indications:
• Because of their excellent CNS penetration, carmustine
and lomustine have been used to treat brain tumors.

53. Alkylating Agents— Phenylalanine
Nitrogen Mustard
• Melphalan an alkylating agent which is a
phenylalanine derivative of nitrogen mustard.
• Although melphalan can be given orally, the plasma
concentration differs from patient to patient due to
variation in intestinal absorption and metabolism.
• Melphalan is primarily used to treat multiple
myeloma (plasma cell myeloma), breast cancer, and
ovarian cancer.

54. Alkylating Agents: Alkysulfonates
Busulfan
• Indications: Busulfan is administered orally to treat
chronic granulocytic leukemia. In aged patients,
busulfan can cause pulmonary fibrosis (“busulfan
lung”). Like other alkylating agents, all of these
agents are leukemogenic.
Adverse Effects: Busulfan produces adverse effects
related to myelosuppression. It only occasionally
produces nausea and vomiting. In high doses, it
produces a rare but sometimes fatal pulmonary
fibrosis, ”busulfan lung”.

55. Alkylating Agents——Thiotepa
• Thiotepa is converted rapidly by liver to its active
metabolite triethylenephosphoramide (TEPA); it is
active in bladder cancer

56. Microtubule Inhibitors
• The mitotic spindle is part of a larger, intracellular skeleton
(cytoskeleton) that is essential for the movements of
structures occurring in the cytoplasm of all eukaryotic cells.
• The mitotic spindle consists of chromatin plus a system of
microtubules composed of the protein tubulin. The mitotic
spindle is essential for the equal partitioning of DNA into
the two daughter cells that are formed when a eukaryotic
cell divides.
• Several plant-derived substances used as anticancer drugs
disrupt this process by affecting the equilibrium between
the polymerized and depolymerized forms of the
microtubules, thereby causing cytotoxicity.

57. Microtubule Inhibitors
Tubulin-Binding Agents
• Vinca Alkaloids: The cellular mechanism of action
of vinca alkaloids is the prevention of microtubule
assembly, causing cells to arrest in the late G2
phase by preventing formation of mitotic
filaments for nuclear and cell division
• Vinblastine, vincristin, vindesine and vinorelbine
are all alkaloids derived from the periwinkle plant
(Vinca rosea).

58. Mechanism of action of the microtubule
inhibitors.

59. Vinca Alkaloids
• Indications:
• Vinblastine is used in combination with Bleomycin and
Cisplatin for metastatic testicular tumors.
• Vincristine is used in combination with prednisone to induce
remission in childhood leukemia.
• Vinorelbine is used to treat non-small-cell lung cancer and
breast cancer.
• ADR
• Severe neurotoxicity
– Paresthesias
– Loss of reflexes
– Foot drop
– Ataxia

60. Microtubule Inhibitors
Paclitaxel & Docetaxel (Taxans)
• These drugs act by interfering with mitotic spindle by preventing
microtubule disassembly into tubulin monomers
• Mechanism of action: Both drugs are active in the M-phase
of the cell cycle, but unlike the Vinca alkaloids, they promote
polymerization and stabilization of the polymer rather than
disassembly, leading to the accumulation of microtubules .
The overly stable microtubules formed are nonfunctional,
and chromosome desegregation does not occur. This results
in death of the cell
• Therapeutic Uses. Docetaxel and paclitaxel have become central
components of regimens for treating metastatic ovarian, breast,
lung, and head and neck cancers
• ADR: Neutropenia & Peripheral neuropathy

61. Paclitaxel stabilizes microtubules,
rendering them nonfunctional.

62. Hormones
• Several types of hormone-dependent cancer
(especially breast, prostate, and endometrial cancer)
respond to treatment with their corresponding
hormone antagonists.
• Estrogen antagonists are primarily used in the
treatment of breast cancer, whereas androgen
antagonists are used in the treatment of prostate
cancer. Corticosteroids are particularly useful in
treating lymphocytic leukemias and lymphomas.

63. Glucocorticoids:
• They are integral components of curative therapy
for acute lymphocytic leukemia, non-Hodgkin’s
lymphoma, and Hodgkin’s disease.
• Prednisone is a potent, synthetic, anti-inflammatory
corticosteroid (at high doses, lymphocytolytic and
leads to hyperuricemia due to the breakdown of
lymphocytes)
• Prednisone is primarily employed to induce remission in
patients with acute lymphocytic leukemia and in the
treatment of both Hodgkin and non-Hodgkin
lymphomas.

64. Tamoxifen
• Tamoxifen is an estrogen antagonist with some estrogenic
activity, and it is classified as a selective estrogen receptor
modulator (SERM). It is used for first-line therapy in the
treatment of estrogen receptor–positive breast cancer.
• Mechanism of action: Tamoxifen binds to estrogen
receptors in the breast tissue, but the complex is unable to
translocate into the nucleus for its action of initiating
transcriptions. That is, the complex fails to induce estrogen-
response, and RNA synthesis does not occur. The result is a
depletion of estrogen receptors, and the growth-promoting
effects of the natural hormone and other growth factors
are suppressed.
• ADR: Hot flushes, vaginal bleeding and venous thrombosis

66. Aromatase inhibitors
• The aromatase reaction is responsible for the extra-
adrenal synthesis of estrogen from androstenedione
• This takes place in liver, fat, muscle, skin, and breast
tissue, including breast malignancies.
• Peripheral aromatization is an important source of
estrogen in postmenopausal women.
• Aromatase inhibitors decrease the production of
estrogen in these women.
• Anastrozole and Letrozole are aromatase inhibitors
• These drugs inhibit the aromatase enzyme
• ****Used in Tx of postmenopausal women with
metastatic breast ca (1st line drug)
• ADR includes: bone pain and peripheral edema

67. Estrogens
• Estrogens had been used in the treatment of prostatic
cancer. Estrogens inhibit the growth of prostatic tissue
by blocking the production of LH, thereby decreasing
the synthesis of androgens in the testis. Thus, tumors
that are dependent on androgens are affected.
• Adverse effects: Estrogen treatment can cause serious
complications, such as thrombo-emboli, myocardial
infarction, strokes, and hypercalcemia. Men who are
taking estrogens may experience gynecomastia and
impotence.

68. GnRH analogs
• GnRH analogs: Leuprolide, gosarelin and triptorelin
• Effective in management of Prostatic carcinomas
• When given in constant doses they inhibit release of
pituitary LH and FSH
• These drugs suppress gonadal function due to
down regulation and desensitization of Gn-RH
receptors
• ADR
• Leuprolide may cause gynecomastia, hematuria,
impotence and testicular atrophy

69. Monoclonal Antibodies
• They are created from B lymphocytes (from immunized
mice or hamsters) fused with “immortal” B-lymphocyte
tumor cells.
• The resulting hybrid cells can be individually cloned,
and each clone will produce antibodies directed against
a single antigen type.
• Currently, several monoclonal antibodies are available
for the treatment of cancer.
• Trastuzumab, rituximab, bevacizumab, and cetuximab
• Monoclonal antibodies have become an active area of
drug development for anticancer therapy and other
non-neoplastic diseases, because they are directed at
specific targets and often have fewer adverse effects.

70. Platinum Coordination Complexes
Cisplatin, carboplatin, and oxaliplatin
• Cisplatin was the first member of the platinum
coordination complex class of anticancer drugs
• Mechanism of action: The mechanism of action for
this class of drugs is similar to that of the alkylating
agents. It binds to guanine in DNA, forming inter and
intrastrand crosslinks. The resulting cytotoxic lesion
inhibits both polymerases for DNA replication and RNA
synthesis. Cytotoxicity can occur at any stage of the cell
cycle, but cells are most vulnerable to the actions of
these drugs in the G1 and S-phases.

72. Cisplatin, carboplatin, and oxaliplatin
• Adverse effects: Severe, persistent vomiting occurs
for at least 1 hour after administration of cisplatin
and may continue for as long as 5 days.
• Premedication with antiemetic agents is required.
• The major limiting toxicity is dose-related
nephrotoxicity, involving the distal convoluted tubule
and collecting ducts.
• This can be prevented by aggressive hydration.

73. Topoisomerase Inhibitors
• These agents exert their mechanism of action via inhibition of
topoisomerase enzymes, a class of enzymes that reduce
supercoiling of DNA
• A. Camptothecins are plant alkaloids originally isolated from
the Chinese tree Camptotheca.
• MOA: These drugs are S-phase specific and inhibit
topoisomerase I
• Adverse effects: Bone marrow suppression, (neutropenia)
• B. Etoposide is a semisynthetic derivative of the plant
alkaloid,. It blocks cells in the late S- to G2 phase of the cell
cycle. Its major target is topoisomerase II.
• Dose-limiting myelosuppression (primarily leukopenia) is the
major toxicity

74. Tyrosine Kinase Inhibitor
• The tyrosine kinases are a family of enzymes that are
involved in several important processes within a cell,
including signal transduction and cell division.
• Many tyrosine kinase inhibitors are available, and
these agents have a wide variety of applications in
the treatment of cancer.

75. Tyrosine Kinase Inhibitor
Imatinib, dasatinib, and nilotinib
• Imatinib is used for the treatment of chronic
myelogenous leukemia (CML). It acts as a signal
transduction inhibitor, used specifically to inhibit tumor
tyrosine kinase activity.
• The ability of imatinib to occupy the “kinase pocket”
prevents the phosphorylation of tyrosine on the
substrate molecule and, hence, inhibits subsequent
steps that lead to cell proliferation.
• These agents are all available in oral formulations, and
they are associated with notable toxicities, such as fluid
retention and QT prolongation

76. Miscellaneous agents
Asparaginase,, interferons,
• Asparaginase: L-Asparaginase catalyzes the deamination of
asparagine to aspartic acid and ammonia.
• L- Asparaginase is used in combination therapy to treat
childhood acute lymphocytic leukemia
• Its mechanism of action is based on the fact that some
neoplastic cells require an external source of asparagine
because of their limited capacity to synthesize sufficient
amounts of that amino acid to support growth and function.
• L- Asparaginase hydrolyzes blood asparagine and, thus,
deprives the tumor cells of this amino acid, which is needed
for protein synthesis
• ADR: Acute pancreatitis

77. Interferons
• Human interferons are biological response modifiers.
• MOA: Interferons interact with surface receptors on other cells, at
which site they exert their effects. Bound interferons are neither
internalized nor degraded. As a consequence of the binding of
interferon, a series of complex intracellular reactions take place.
• These include synthesis of enzymes, suppression of cell
proliferation, activation of macrophages, and increased cytotoxicity
of lymphocytes.
• However, the exact mechanism by which the interferons are
cytotoxic is unknown.
• Interferon is presently approved for the management of hairy-cell
leukemia, chronic myeloid leukemia, and acquired
immunodeficiency syndrome (AIDS)–related Kaposi sarcoma.

78. Prevention/management of Cancer
Chemotherapy induced ADR
• Nausea and vomiting : 5-Ht3 antagonist
(ondansetron)
• Bone marrow suppression : Filgrastim
(colony stimulating factors)
• MTX toxicity : Leucovorin (folic acid)
• Cyclophosphamide toxicity : MESNA
• Cisplatin toxicity : Amifostine
• Anthracycline toxicity ; Dexaroxazone

79. References
• Lippincott Illustrated Reviews: Pharmacology
Sixth Edition