Anticancer agents

1. ANTINEOPLASTIC AGENTS

2. Introduction #1
• Normal cells…
• Differentiate, grow, mature, divide
– Regulated, balanced; cell birth=cell death
• Regulation: intracell 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

3. Introduction #2
– Dysplasia: replacement cells disordered in
size, shape
• Incr’d mitosis rate
• Somewhat reversible, often precancerous
– Neoplasia: abnormal growth/invasion of cells
• “New growth”
• Neoplasm = tumor
• Irreversible
• Cells replicate, grow w/out control

4. 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

5. Cancer (Neoplastic)
• Cancer occurs after normal cells have been
transformed into neoplastic cells through
alteration of 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

6. Oncogenesis = Process of Tumor
Development
• Probably multi-step process
• Initation = important change introduced into cell
– Probably through DNA alteration
– >1 event probably needed for tumor production
– Reversible unless and until:
• Promotion = biochem event encourages tumor form’n
• Gen’ly need both initiation and promotion
– Initiators, promoters may be toxins OR radiation OR viruses)

7. 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 toxicity
– Increased survival and improved quality of life
• Adjuvant therapy
– Attempt to eradicate microscopic cancer after surgery
– e.g. breast cancer & colorectal cancer

8. Six Established Rx Modalities
1. Surgery
2. Radiotherapy
3. Chemotherapy
4. Endocrine therapy
5. Immunotherapy
6. Biological therapy

9. The Basic Concept of
Cell Generation Cycle
18_01_cell_cycle.jpg
Cell Cycle = Growth, Division

10. Cell Cycle Phases
18_02_four_phases.jpg
Synth DNA precursors,
proteins, etc.
Premitotic synth of
structures, mol’s

11. Cycle Checkpoints
18_04_Feedback.jpg

12. • 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)
• Growth fraction - at any particular time some cells are going
through the cell cycle whereas other cells are resting.
• The ratio of proliferating cells to cells in G0, is called the
growth fraction.
• A tissue with a large percentage of proliferating cells & few
cells in G0 has a high growth fraction.
• Conversely, a tissue composed of mostly of cells in G0 has a
low growth fraction

13. Apoptosis Review
• In healthy cells, survival factors signal
activation anti-apoptotic mechanisms
– Cytokines, hormones, cell contact factors
• Programmed cell death
• Cascade of proteases initiate process
• Second pathway activated d by intracell
signals, e.g. DNA damage
– Players are p53 gene & prot; mitochondrial
cytochrome c; Apaf-1 (prot); caspase 9

14. Uncontrolled Proliferation
• Result of activation proto-oncogenes or
inactivation of tumor suppressor genes
– Change in growth factors, receptors
• Incr’d growth factors prod’d
– Change in growth factor pathways
• 2nd messenger cascades (esp tyr-kinase receptor
cascades)
– Change in cell cycle transducers
• Cyclins, Cdk’s, Cdk inhibitors
– Change in apoptotic mech’s
– Change in telomerase expression
– Change in local blood vessels  angiogenesis

15. Anticancer Drugs
• Alkylating Agent
• Antimetabolite
• Antibiotics
• Alkaloid
• Hormones
• Others（cis-platinum，carboplatin，
lobaplatin etc ）

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

17. 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.

18. 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.

19. Classification of Alkylating Agents
 Bis Chloroethyl Amines：
Cyclophosphamide, Chlormethine,
Chlorambucil, Sarcolysine
 Nithrosoureas：
Carmustine，Lomustine
 Ethyeneammonium or Aziridines：
Thiotepa，triethylene melamine
 Alkysulfonates：Busulfan

20. Resistance of Alkylating Agents
Resistance to alkylating agents has several
causes:
 Membrane transport may be decreased.
 The drug may be bound by glutathione (GSH)
via GSH-S-transferase or metallothioneins in
the cytoplasm and inactivated.
 The drug may be metabolized to inactive
species.

21. Adverse Effects of Alkylating Agents
• Myelosuppression is the dose-limiting adverse
effect for alkylating agents.
• Nausea and vomiting are common as are
teratogenesis and gonadal atrophy, although in
the latter cases these are variable, according to
the drug, its schedule, and route of
administration.
• Treatment also carries a major risk of
leukemogenesis and carcinogenesis.

22. 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.

23. Alkylating Agents——Nitrosoureas
Carmustine, Lomustine, Semustine
Pharmacokinetics:
• Nitrosoureas are highly lipophilic and reach
cerebrospinal fluid concentrations that are
about 30% of plasma concentrations.
Indications:
• Because of their excellent CNS penetration,
carmustine and lomustine have been used to
treat brain tumors.

24. Alkylating Agents——
Phenylalanine Nitrogen Mustard
• Melphalan is a nitrogen mustard that is
primarily used to treat multiple myeloma
(plasma cell myeloma), breast cancer, and
ovarian cancer.

25. lkylating Agents——
Alkysulfonates
Busulfan
Indications:
• Busulfan is administered orally to treat chroic
granulocytic leukemia and other myeloproliferative
disorders.
Adverse Effects:
• Busulfan produces advers effects related to
myelosuppression. It only occasionally produces
nausea and vomitting. In high doses, it produces a rare
but sometimes fatal pulmonary fibrosis, ”busulfan
lung”.

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

27. Antimetabolites
General Characteristics：
Antimetabolites are S phase-specific drugs
that are structural analogues of essential
metabolites and that interfere with DNA
synthesis.
Myelosuppression is the dose-limiting toxicity
for all drugs in this class.

28. Classification of Antimetabolites
 Folic acid Antagonists: MTX
 Purine Antagonists: 6MP
6TG
 Pyrimidine Antagonists：5FU
araC
HU

29. Antimetabolites——
Folic Acid Antagonist
Methotrexate （MTX）
Mechanism of Action：
 The structures of MTX and folic acid are similar. MTX
is actively transported into mammalian cells and
inhibits dihydrofolate reductase, the enzyme that
normally converts dietary folate to the
tetrahydrofolate form required for thymidine and
purine synthesis.

30. Antimetabolites——
Folic Acid Antagonist
Methotrexate （MTX）
Indications：
• The use of MTX in the treatment of choriocarinoma, a
trophoblastic tumor, was the first demonstration of curative
chemotherapy.
• It is especially effective for treating acute lymphocytic leukemia
and for treating the meningeal metastases of a wide range of
tumors.
Adverse Effects：
 MTX is myelosuppressive, producing severe leukopenia, bone
marrow aplasia, and thrombocytopenia.
 This agent may produce severe gastrointestinal disturbances.
 Renal toxicity may occur because of precipitation (crystalluria) of
the 7-OH metabolite of MTX.

31. Antimetabolites——
Purine Antagonists
6-Mercapapurine（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
thioguanine.Long-term mercaptopurine use may cause
hepatotoxicity.

32. Antimetabolites——
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. It has two active
metabolites: 5-FdUMP and 5-FdUTP. 5-FdUMP inhibits
thymidylate synthetases and prevents the synthesis of thymidine,
a major building block of DNA. 5-FdUTP is incorporated into RNA
by RNA polymerase and interferes with RNA function.

33. Antimetabolites——
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, and oral and gastrointestinal
ulceration. Nausea and vomitting are usually mild.
• With fluorouracil, myelosuppression is more problematic
after bolus injections, whereas mucosal damage is dose-
limiting with continuous infusions.

34. Antimetabolites——
Pyrimidine Antagonists
Cytarabine
Indications：
• Cytarabine has a narrow clinical spectrum and
is primarily used in combination with
daunorubicin or thioguanine for the treatment
of acute nonlymphocytic leukemia.
Adverse Effects:
• High doses of cytarabine can damage the liver,
heart, and other organs.

35. • Anthracyclines:
– Doxorubicin (Adriamycin)
– Daunorubicin
• Bleomysin
• Dactinomycin
• Mitomycin
Antibiotics

36. Doxorubicin & Daunorubicin
These drugs
intercalate
between base
pairs, inhibit
topoisomerase II
and also generate
free radicals
They block RNA
and DNA synthesis
and cause strand
scission

37. ADR
• Cardiac toxicity (due to generation of free radicals)
• Acute form: arrthythmias, 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
• Radiation recall reaction

38. 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 delays and prolonged
myelosuppression that preferentially affects
platelets and leukocytes

39. 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.

40. 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.

41. Anti-Cancer Plant Allaloids
• 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).

42. Anti-Cancer Plant Allaloids
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

43. Anti-Cancer Plant Allaloids
Paclitaxel & Docetaxel (Taxans)
• These drugs act by interfering with mitotic spindle
• They prevent micotubule disassembly into tubulin
monomers
• 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

44. Platinum Compound
Cisplatin:
Mechanism of Action:
• Cisplatin binds to guanine in DNA and RNA, and the
interaction is stabilized by hydrogen bonding. The
molecular mechanism of action is unwinding and
shortening of the DNA helix.
Cisplatin:
Indications:
• Cisplatin has efficacy against a wide range of neoplasms.
It is given intravenously as a first-line drug for
testicular, ovarian, and bladder cancer, and it is also
useful in the treatment of melanoma and a number of
other soild tumors.
Adverse Effect:
• Cisplatin produces relatively little myelosuppression but
can cause severe nausea, vomiting, and nephrotoxicity.

45. Carboplatin:
Indication:
• Carboplatin has a similar spectrum of
activity, but it is approved only as a
second-line drug for ovarian cancer.

46. 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.

47. Hormones
Estrogens:
• Estrogens inhibit the effects of endogenous
androgens and androgen-dependent
metastatic prostatic carcinoma.
Diethylstilbestrol is usually the agent of
choice.
• Cardiac and cerebrovascular complications
and carcinoma of the male breast are
potential adverse effects.

48. Hormones
Androgens:
• Androgen activity in breast cancer is
similar to that of estrogens, perhaps for
the same mechanistic reasons.
• Virilizing effects and hepatic toxicity
make them unacceptable to most
patients.
• Fluoxymesterone is the most widely used
agent.
• Danazol has use in hematology in aplastic
anemia and congenital anemias.

49. Hormones
• GnRH analogs
• Leuprolide, gosarelin and naferelin
• 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

50. Hormones
Glucocorticoids:
• They are integral components of curative
therapy for acute lymphoblastic leukemia,
non-Hodgkin’s lymphoma, and Hodgkin’s
disease.
• Glucocorticoids have essential roles in the
prevention of allergic reaction, emesis control,
relief of intracranial hypertension or spinal
cord compression in neurologic complications,
and pain relief.

51. Sex hormone antagonists
Tamoxifen
• It is a SERM
• Blocks the binding of estrogen to receptors of estrogen
sensitive cancer cells in bresat tissue
• It is used in receptor positive breast carcinoma
• Also useful in progestin resistant endometrial
carcinoma
ADR:
• Hot flushes, vaginal bleeding and venous thrombosis
Other drugs
• Flutamide: androgen receptor antagonist used in
prostatic carconima
• ADR for flutamide includes: gynecomastia, hot flushes

52. 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
• 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

53. Miscellaneous agents
• Asparaginase, imatinib, interferons, monoclonal antibodies
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

54. Imatinib
• Example of a drug, whose development was
guided by knowledge of a specific oncogene
• Used for the treatment of chronic myeloid
leukemia
• Acts by inhibiting tyrosine kinase activity of
the protein product of the Bcr-Abl oncogene

55. Interferons
• Human interferons have been classified into three
types—α, β, and —on the basis of their antigenicity.
• The α interferons are primarily leukocytic, whereas the
β and  interferons are produced by connective tissue
fibroblasts and T lymphocytes, respectively.
• Recombinant DNA techniques in bacteria have made it
possible to produce two species designated interferon-
α-2a and -2b used in Tx of neoplastic diseases.
• ***Interferon-α-2a is presently approved for the
management of hairy-cell leukemia, chronic myeloid
leukemia, and acquired immunodeficiency syndrome
(AIDS)–related Kaposi sarcoma.
• ***Interferon-α-2b is approved for the treatment of
hairy-cell leukemia, melanoma, AIDS-related Kaposi's
sarcoma, and follicular lymphoma.

56. 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.
• Recombinant technology has led to the creation of
“humanized” antibodies that overcome the
immunologic problems previously observed following
administration of mouse (murine) antibodies.
• Currently, several monoclonal antibodies are available
for the treatment of cancer.
• Trastuzumab, rituximab, bevacizumab, and cetuximab

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