Cancer Chemotherapy-2

Dr. R. Senthil Kumar

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 Cell Cycle–Specific (CCS) Agents Cell Cycle–Nonspecific (CCNS)
Agents
Antimetabolites (S phase) Alkylating agents
Capecitabine Altretamine

Classification Cladribine
Clofarabine
Bendamustine
Busulfan
Cytarabine (ara-C) Carmustine
Fludarabine Chlorambucil
5-Fluorouracil (5-FU) Cyclophosphamide
Gemcitabine Dacarbazine
6-Mercaptopurine (6-MP) Lomustine
Methotrexate (MTX) Mechlorethamine
6-Thioguanine (6-TG) Melphalan
Epipodophyllotoxin (topoisomerase II Temozolomide
inhibitor) (G1–S phase) Thiotepa

Etoposide Anthracyclines
Taxanes (M phase) Daunorubicin
Albumin-bound paclitaxel Doxorubicin
Docetaxel Epirubicin
Paclitaxel Idarubicin
Vinca alkaloids (M phase) Mitoxantrone
Vinblastine Antitumor antibiotics
Vincristine Dactinomycin
Vinorelbine Mitomycin
Antimicrotubule inhibitor (M phase) Camptothecins (topoisomerase I
inhibitors)
Ixabepilone Irinotecan
Antitumor antibiotics (G2–M phase) Topotecan
Platinum analogs
Bleomycin Carboplatin
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Cisplatin
 Alkylating agents
• Cyclophosphamide
• Cisplatin
• Procarbazine
• Busulfan
• Mechlorethamine

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 MOA
• Alkylating agents

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 Alkylating Agents- Used in wide variety of
hematologic and solid tumors
• Thiotepa – ovarian cancer
• Busulfan – DOC in CML (***Important ADR-Pulmonary
fibrosis).
• ***Nitrosoureas (Carmustine and lomustine ) - brain
tumors
– Highly lipid soluble drugs hence reach high concentration in the
brain and CSF.
• Streptozocin – insulin-secreting islet cell carcinoma of
the pancreas
• Mechlorethamine – Prodrug. Component of MOPP
regimen for Hodgkin’s disease. It is a highly irritant drug
so care should be taken to avoid extravasation during IV
administration
• Chlorambucil (Leukeran): DOC for CLL. Slow acting and5
least toxic nitrogen mustard.
 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
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 Mechanism of resistance
• *** The mechanisms mentioned below are
common for all the alkylyting agents
• Increased DNA repair
• Decreased drug permeability
• Production of “trapping” agents (thiols)

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 Uses
• Non-Hodgkin’s lymphoma
• Breast Ca
• Ovarian Ca
• Neuroblastoma

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 ADR
• Acrolein is the metabolite
• Responsible for causing hemorrhagic
cystitis
– Suprapubic pain
– Hematuria
– Cyctoscopic findings
• ***This is prevented/treated by
MESNA (mercaptoethanesulfonate)
• Rarely cyclophosphamide can cause
SIADH and pulmonary toxicity 11
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 Cisplatin
• Platinum analog
• Same MOA as cyclophosphamide
• **Used in testicular carcinoma
• Also used for Ca of bladder, lung and ovary
• Carboplatin is new drug with better safety profile
ADR
• Nephrotoxicity (prevented by Amifostine***)
• ***Ototoxicity (acoustic nerve damage)
• Peripheral neuritis
• Severe nausea and vomiting

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 Procarbazine
• MOA: forms hydrogen peroxide, which
generates free radicals that cause DNA
damage
• Important component of regimens
especially for Hodgkin’s lymphoma
ADR
• ***Disulfiram like reactions

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 Blood in the urine!!!
• A 30-year-old man is seen at the ER complaining about
severe suprapubic pain, fever and signs of passing blood
in the urine. He is currently in treatment for non-
Hodgkin’s lymphoma (four drug regimen).
1. What is your preliminary diagnosis?
2. If it is drug induced, who is “the culprit”?
3. What is the mechanism behind the latest complication?
4. How to treat the complication?
5. Which drug we covered until now has serious
nephrotoxic effects?
6. How to prevent that particular drug induced renal
damage?
7. ADR of:
1. Procarbazine
2. Busulfan 15
 Legend
Drug Class
Sub-class
Prototype Drug

Antimetabolites
Folic Acid Analogs Purine Analogs Pyrimidine Analogs

Methotrexate Mercaptoguanine Fluorouracil

Trimetrexate Thioguanine Cytarabine

Fludarabine Phosphate Gemcitabine
Pemetrexed Capecitabine
Cladribine

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 Antimetabolites
• They are structurally similar to
endogenous compounds
• They act as antagonists of:
– Folic acid (methotrexate)
– Purines (Mercaptopurine and thioguanine)
– Pyrimidine (fluorouracil, cytarabine)

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Antimetabolits: sites of drug action

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Methotrexate

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 Methotrexate (MTX)
• MTX is a folic acid analog that binds with high
affinity to the active catalytic site of dihydrofolate
reductase (DHFR)
• Thus it interferes with the synthesis of
tetrahydrofolate (THF)
• THF serves as the key one-carbon carrier for
enzymatic processes involved in de novo
synthesis of thymidylate, purine nucleotides, and
the amino acids serine and methionine.
• Inhibition of these various metabolic processes
thereby interferes with the formation of DNA,
RNA, and key cellular proteins.
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 Mechanism of Resistance

1. Decreased drug
transport
2. Altered DHFR
3. Decreased
polyglutamate
formation
4. Increased levels
of DHFR

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 Contd..
• Most commonly used anticancer drug.
• Cell cycle specific (CCS) drug and acts during S phase
of the cell cycle.
• Antineoplastic, immunosuppressant and
antiinflammatory
• Used in RA, psoriasis
• Well absorbed orally; can also be given IM, IV or
intrathecally**.
• It is bound to plasma proteins, does not cross the BBB
and most of the drug is excreted unchanged in urine.
• It is a weak acid and so is excreted better at high urine
pH. Appropriate hydration and alkalinizing the urine is
important to prevent renal tox with MTX

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 ADR
• Bone marrow suppression (BMS)
• Mucositis
• Folic acid deficiency
• The toxic effects of MTX on normal cells is
reduced by administering folinic acid
(leucovorin)
– This is called leucovorin rescue ****
– Higher the dose of MTX more the leucovorin
you give**
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 Leucovorin Rescue

Mechanism of action of
methotrexate and the effect of
administration of leucovorin.
• FH2 = dihydrofolate
• FH4 = tetrahydrofolate
• dTMP = deoxythymidine
monophosphate
• dUMP = deoxyuridine mono
phosphate.

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6-Mercaptopurine (6-MP) &
Thioguanine
• Both 6-MP and Thioguanine are
activated by HGPRT to toxic
nucleotides that inhibit several
enzymes involved in purine
metabolism
• ***Resistance is due to cancer
cells having d activity of
HGPRT
• Cancer cells also es alkaline
phosphatase that inactivate toxic
nucleotides
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 6-MP & Allopurinol
• 6-MP is metabolized in the liver by xanthine
oxidase and the inactive metabolites are
excreted in the urine
• ***Allopurinol is used frequently to treat/prevent
hyperuricemia caused by many anticancer
drugs.
• If Allopurinol is used with 6-MP then the dose of
6-MP is reduced by more than 75%
– Why??

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 Cytarabine (Ara-C)
• Cytarabine arabinoside is a pyrimidine
antimetabolite
• The drug is activated by kinases to AraCTP
– This acts as an inhibitor of DNA polymerase
• ***of all antimetabolites, this is the most specific
for S phase of tumor cell cycle
• It is an important component in acute lukemia
regimens
• ADR: at high doses cause neurotoxicity
(cerebellar dysfunction and peripheral neuritis)
– Hand-foot syndrome***

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 5-FU
Mechanism of the cytotoxic action of 5-FU
• 5-FU is converted to 5-FdUMP, which
competes with deoxyuridine
monophosphate (dUMP) for the enzyme
thymidylate synthetase.
• 5-FU = 5-fluorouracil
• 5-FUR = 5-fluorouridine
• 5-FUMP = 5-fluorouridine
monophosphate
• 5-FUDP = 5-fluorouridine diphosphate
• 5-FUTP = 5-fluorouridine triphosphate
• dUMP = deoxyuridine monophosphate
• dTMP = deoxythymidine
monophosphate
• 5-FdUMP = 5-fluorodeoxyuridine
monophosphate. 28
 Contd..
• 5-FU causes, “thymidineless death” of cells
• Resistance is due to d activation of 5-FU and d
thymidylate synthase activity
Uses and ADR
• Metastatic carcinomas of the breast and the GI tract,
hepatoma
• Carcinomas of the ovary, cervix, urinary bladder,
prostate, pancreas, and oropharyngeal areas
• Combined with levamisole for Rx of colon cancer
• ADR: nausea, mucositis, diarrhea, ***hand and foot
syndrome, Alopecia, hyperpigmentation, neurologic
deficits, bone marrow depression
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 Megaloblastic anemia
• A 50-year-old man is undergoing chemotherapy with a
multi-drug regimen after being diagnozed to have a
malignant tumor. Soon after the first cycle of
chemotherapy, he develops symptoms of severe
fatigue and pallor. His Hb is very low and the
peripheral smear shows presence of megaloblasts.
1. What is your prelim. Diagnosis?
2. Which of the drugs we discussed can be most likely
responsible for this complication?
3. Which compound (and how) administered soon after
chemotherapy could have prevented the toxicity?
4. Which are the anticancer drugs which can cause
tingling, feeling of warmth, redness, flaking and blisters
(what is this)?
5. MOA and Mech of resistance to 6-MP and TG? 30
6. MOA of 5-FU
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 Plant Alkaloids
Vinca Alkaloids Podophyllotoxins Camptothecins Taxanes

Vinblastine Etoposide Topotecan Paclitaxel

Vinblastine Teniposide Irinotecan Docetaxel

Vincristine
Vinorelbine

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Vinka alkaloids (Vinblastine,
vincristine)
• These drugs block the
formation of mitotic
spindle by preventing
the assembly of tubulin
dimers into microtubules
• ***They act primarily on
the M phase of cancer
cell cycle
• Resistance is due to d
efflux of drugs from tumor
cells
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 Vinka alkaloids (animation and
ADR)
• Microtubule Synthesis animation
• Inhibition of spindle function
ADR
• Severe neurotoxicity
– Paresthesias
– Loss of reflexes
– Foot drop
– Ataxia
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 VinBlastine VinCristine (oncovan)
Uses ; (ABVD) Uses: (MOPP)
Hodgkin’s disease Childhood leukemias
Lymphomas Childhood tumors-Wilm’s
Carcinoma Breast tumor, Neuroblastoma,
Testicular tumors Hodgkin’s disease
Toxicity: Toxicity:
Bone marrow Peripheral neuritis with
suppression, anorexia, Paresthesia, Muscle
nausea, vomiting & weakness
Diarrhea, Alopecia ***Vincristine has
marrow sparing effect
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 Etoposide & Teniposide
• Acts by inhibiting topoisomerase II
• These drugs are most active in late S and
early G2 phase
• Used in combination Tx of small cell
carcinoma of lung, prostrate and testicular
carcinomas
Other topoisomerase inhibitors:
• Topotecan, Irinotecan
– Both act by inhibiting topoisomerase-I
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Topoisomerase inhibitors

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Paclitaxel & Docetaxel
• These drugs act by interfering with
mitotic spindle
• They prevent micotubule
disassembly into tubulin monomers
• Taxanes animation
ADR
• Neutropenia
• Peripheral neuropathy

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 Questions
• What is the diff between MOA of taxanes and Vinca
alkaloids
• Which is the marrow sparing anticancer drug
• Topoisomerase-1 inhibitors
• Topoisomerase-2 inhibitors

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

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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
• *These are CCNS drugs
• Used as a component in
ABVD regimen in Hodgkin’s
lymphoma
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 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

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Bleomycin
• Acts through binding to DNA, which
results in single and double strand
breaks following free radical formation
and inhibition of DNA synthesis
• The DNA fragmentation is due to
oxidation of a DNA-bleomycin-Fe(II)
complex and leads to chromosomal
aberrations
• CCS drug that causes accumulation of
cells in G2
Uses
• ABVD regimen for Hodgkin’s
• Intracavitary therapy in ovarian and
breast cancers (Sclerosing agent)
ADR
• ***Pulmonary fibrosis
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 Questions
• ADR of anthracyclines? (clinical
symptoms)
• Why ADR with anthracyclines?
• How to treat it?
• ADR of bleomycin?

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 Hormonal agents
• Glucocorticoids
• Sex hormone antagonists
• GnRH analogs
• Aromatase inhibitors

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 Glucocorticoids (Prednisone)
• Because of their marked lympholytic action, they
are used in acute leukemias and lymphomas.
• Have anti-inflammatory effect
• Increase appetite
• Produce euphoria (feeling of well being)
• Increase body weight
• Suppress hypersensitivity reaction due to certain
anticancer drugs
• Control hypercalcemia
• Control bleeding
• Have non-specific antipyretic effect
• Increase the antiemetic effect of
ondansetron/granisetron/ metoclopramide 46
Sex hormone antagonists

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 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 48
MOA of drugs

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 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

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 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.

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Contd..

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 Contd..
• 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

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 Miscellaneous agents

Asparaginase, imatinib,
interferons, monoclonal antibodies

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 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***** 55
Contd..

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 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
• This gene is expressed in CML
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MOA of imatinib
• Imatinib MOA

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 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.
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 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 in
the United States for the treatment of cancer.
• Trastuzumab, rituximab, bevacizumab, and cetuximab
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 Trastuzumab
• In patients with metastatic breast cancer,
overexpression of transmembrane human
epidermal growth factor–receptor protein 2
(HER2) is seen in 25 to 30 % of patients.
• Trastuzumab is a recombinant DNA–produced,
humanized monoclonal antibody, specifically
targets the extracellular domain of the HER2
growth receptor that has intrinsic tyrosine kinase
activity.
• Trastuzumab binds to HER2 sites in breast
cancer tissue and inhibits the proliferation of
cells that overexpress the HER2 protein, thereby
decreasing the number of cells in the S phase.
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FDA approved MAb

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 Questions???
• What are Flutamide and Leuprolide and mention
their uses?
• MOA of tamoxifen?
• MOA of anastrozole and letrozole?
– Important clinical indication for these drugs?
• Important ADR of L-asparaginase?
– Clinical symptoms of ADR (including lab)
• MOA and use of imatinib?
• MABs used in cancer chemotherapy (know four
of them circled above)
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 Treatment of Specific cancers
Hodgkin’s disease:
• ABVD regimen
(doxorubicin,bleomycin,vinblastine,dacarbazine)
• MOPP regimen
(mechorethamine,vincristine,procarbazine,prednisone)
• NHL: CHOP regimen
(cyclophosphamide,doxorubicin,vincristine,prednisone)
• Multiple myeloma : MP protocol (melphalan and
prednisone)
Breast ca:
• CMF protocol (cyclophosphamide-MTX-fluorouracil)
• Tamoxifen
• Anastrozole, letrozole

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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
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