CANCER

Cancer develops when cells grow, or divide, and form more cells without control or order
Survival from cancer depends on the tumor stage at time of diagnosis.
Can originate in almost any body organ
Most common site for women is the breast
Most common site for men is the prostate gland

Tumors that have progressed to a greater degree are usually slower growing and thus are
more difficult to treat. Thus the chances of survival are less than with the smaller more
rapidly growing tumors. Also the longer a tumor has been growing the more likelihood of
metastasis. Since metastases are more disseminated than the primary tumors they are
difficult to treat without inducing much toxicity to normal tissues. Thus the chances of
survival are less

Normal Tissue

Beginning of Abnormal Growth

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 Increasing number of dividing cells

Growing mass of tissues
(Tumor)

 
Benign Malignant

Malignant versus Benign Tumors

Depending on whether or not they can spread by invasion and metastasis, tumors are
classified as being either benign or malignant. Benign tumors are tumors that cannot
spread by invasion or metastasis; hence, they only grow locally. Malignant tumors are
tumors that are capable of spreading by invasion and metastasis. By definition, the term
"cancer" applies only to malignant tumors.
Benign tumors are not cancer
Do not spread to other parts of the body; remain within the tissue of origin
Are usually not threats to life.

Malignant tumors are cancer.

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Cells in malignant tumors can grow without control and invade or damage other parts of
the body. When cancer (malignant tumor) spreads from the original site to another part of
the body it is called metastasis.
Characteristics of cancer cells
 Proliferate in a disregulated manner
 invade surrounding tissues probably through secretion of certain proteolytic
enzymes
 Metastasize or spread to secondary sites throughout the body.
 Also fail to differentiate normally.
 Also show alterations of cell surface components such as antigens, enzymes and
oncogenes. Some of these may be shed into the blood and are detectable by
immunologic techniques as tumor markers.
 Cancers growing in the body also occupy space and crowd out normal cells.
 They produce nutritional deficits and weight loss due to their high metabolic rate.
 They metastasize to distant organs (e.g., liver, brain, lungs, bone) and destroy
these tissues.
 Cancer cells also decrease host defense mechanisms against infection.

Types of Cancer
There are over 100 different types of cancer
Treatment decisions are based on knowing the type of cancer involved

1. Solid Tumors
2. Carcinomas
3. Sarcomas
4. Cancers of the Blood & Bone Marrow
5. Leukemia
6. Lymphoma
7. Myeloma

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Cancers are divided into five main groups:
1. Carcinomas: Solid tumors that originate from epithelial tissue, Tissue that covers
external and internal body surfaces, the lining of vessels, body cavities, glands, and
organs
2. Sarcomas Originate from supportive and connective tissue, Bone, fat, muscle, and
cartilage
3. Lymphomas are cancers that start in lymph nodes or lymphoid tissues.
4. Leukemias are cancers of the white blood cells.
5. Myelomas are cancers that start in plasma cells found in the bone marrow.

Types of Effective Treatment of Cancers

1. Surgery is the most effective treatment of cancer but it is ineffective for
metastasized or disseminated tumors
2. Radiation is the next most effective treatment after surgery. Rapidly dividing cells
are the most sensitive. It is useful primarily in cancers that are not widely
disseminated. It is often combined with surgery and chemotherapy.
3. Immunotherapy and Biological Response Modifiers (BRMs) is effective against
small number of tumor cells. Its most important role is in combination with other
agents.
4. Chemotherapy is useful mostly for disseminated cancers and is often used in
combination with other types of therapy such as surgery, radiation or
immunotherapy.
5. Immunotherapy has been becoming more and more important in recent years due
to improved knowledge as to how they work and through molecular biologic
techniques their is a greater availability of agents that play a role in anticancer
activity.

Grading of cancer cells

Grading: Measures the extent to which tumor cells differ from their parent tissue
Grade 1 = well-differentiated cells, function most like the parent tissue. Least malignant
Grade 4 = least differentiated cells, not like the parent tissue. Most rapidly increasing in
number

American Joint Commission on Cancer recommends:

Grade GX - Grade cannot be assessed (Undetermined grade)
G1 - Well-differentiated (Low grade)
G2 - Moderately differentiated (Intermediate grade)
G3 - Poorly differentiated (High grade)
G4 - Undifferentiated (High grade)

Staging of Cancer
Staging is the process that tells how far the cancer has spread in the body.
The staging of cancer is important for the following reasons:

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Determines extent of the disease
Treatment is determined by the stage
Determines patient’s prognosis
TNM Staging Classification System
For example, in stomach cancer:
T-1 means the primary tumour is still in the stomach wall. T-3 means the primary tumour
has grown right through the stomach wall and T-4 means it is invading nearby structures
such as the pancreas.
N-0 means there is no spread to lymph nodes. N-1 means that some local lymph nodes
are affected. N-2 means more extensive spread to local lymph nodes.
M-0 means there are no metastases. M-1 means that there are metastases to some other
area of the body such as the liver or brain.
So, for a certain case of stomach cancer, a doctor may say something like "the stage is T-
3, N-1, M-0" which means "the cancer has spread through the stomach wall, there is
some spread to local lymph nodes, but no metastases in other parts of the body".
There are other staging classifications which are sometimes used

Stage 0—precancer
Stage 1 —small cancer found only in the organ where it started
Stage 2 —larger cancer that may or may not have spread to the lymph nodes
Stage 3 —larger cancer that is also in the lymph nodes
Stage 4 —cancer in a different organ from where it started

Risk factors
Lifestyle and Environmental Risk Factors
 Tobacco
 Alcohol
 Diet
 Sunlight
 Radiation
 Industrial agents and chemicals: benzopyrene diol epoxide, bisbenzimide,
aflatoxin, or ethidium bromide.

Warning Signs of Cancer

Need for Immediate Follow-Up
C = Change in bowel or bladder habits
A = A sore that does not heal
U = Unusual bleeding or discharge
T = Thickening or lump in breast or elsewhere
I = Indigestion or difficulty in swallowing
O = Obvious change in a wart or mole
N = Nagging cough or hoarseness

Cancer treatment
Surgery: Removal of the cancerous tumor and possibly the surrounding tissue and lymph
nodes near the tumor. Very effective in treating localized cancer.

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Radiation therapy: The use of high-energy rays to kill cancer cells
Types - external (outside the body) and/or internal (implanted in the body)

The radiation used for cancer treatment comes from special machines or from radioactive
substances. Radiation therapy equipment aims specific amounts of the radiation at tumors
or areas of the body where there is disease.
Radiation in high doses kills cells or keeps them from growing and dividing. Because
cancer cells grow and divide more rapidly than most of the normal cells around them,
radiation therapy can successfully treat many kinds of cancer. Normal cells are also
affected by radiation but, unlike cancer cells, most of them recover from the effects of
radiation. To protect normal cells, doctors carefully limit the doses of radiation and
spread the treatment out over time. They also shield as much normal tissue as possible
while they aim the radiation at the site of the cancer.

Chemotherapy: The use of drugs to kill cancer cells. Can be given intravenously (through
a vein), by mouth (pills), through shot (an injection in the skin tissue or muscle), or
topical (applied on the skin)

Hormone Therapy: Used against certain cancers (Breast cancer, Prostate cancer) that
depends on hormones for their growth
Anti-hormone treatment can cause these cancers to go away or be controlled for a time

Immunotherapy: Helps the body’s natural ability (immune system) to fight disease or
protects the body from some of the side effects of cancer treatment

Radiation therapy:
 About 50 to 60 percent of cancer patients are treated with radiation at some time
during their disease.
 Radiation therapy is the careful use of high-energy radiation to treat cancer. A
radiation oncologist may use radiation to cure cancer or to relieve a cancer
patient's pain.
 Radiation therapy works because the radiation destroys the cancer cells' ability to
reproduce and the body naturally gets rid of these cells.
 Radiation also may be given externally by a machine outside a patients body
(Teletherapy)
 It can be given with radioactive sources that are put inside the body
(brachytherapy).
A cancer patient may be treated with radiation alone. Prostate cancer and larynx cancer
are often treated in this manner.
Sometimes radiation therapy is only part of a patient's treatment. For example, a woman
may have radiation therapy after breast conserving surgery. She can be cured of her
cancer and still keep her breast. When radiation therapy is only part of a patient's
treatment it is called adjuvant treatment.
Patients can be treated with radiation therapy and/or chemotherapy before surgery. This
may allow a patient to have less radical surgery than would otherwise be required. For

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example, some bladder cancer patients can keep their bladder if they are treated with all
three treatments rather than only one treatment.

Teletherapy (External beam radiation therapy): It is a method for delivering a beam of

high-energy x-rays to the location of the patient's tumor. The beam is generated outside
the patient and is targeted at the tumor site. These x-rays can destroy the cancer cells and
careful treatment planning allows the surrounding normal tissues to be spared.

Use of gamma rays with Cobalt-60 and Cesium-137

It can be used for:
 Breast Cancer
 Colorectal Cancer (Bowel Cancer)
 Head and Neck Cancer
 Lung Cancer
 Prostate Cancer
Administered:
 In the hospital
 5-10 minutes, 5 days a week for about 6 weeks
 Linear accelerators & cobalt machines

Brachytherapy (internal radiation therapy): radiation source (Iodine-125, Palladium-103)
is placed in or near the tumor itself, giving a high radiation dose to the tumor while
reducing the radiation exposure in the surrounding area. This method is used for many
gynecological or oral neoplasms. Brachytherapy is used to treat cancers throughout the
body, including: Prostate, Cervix, Head and neck, Ovary, Breast, Gallbladder, Uterus,
Vagina

Radioactive “seeds” are carefully placed inside of the cancerous tissue and positioned in
a manner that will attack the cancer most efficiently.
In the treatment of prostate cancer, the radioactive seeds are about the size of a grain of
rice, and give off radiation that travels only a few millimeters to kill nearby cancer cells.
With permanent implants (for example, prostate) the radioactivity of the seeds decays
with time while the actual seeds permanently stay within the treatment area. There are 2
different kinds of brachytherapy: permanent, when the seeds remain inside of the body,
and temporary, when the seeds are inside of the body and then removed. Diseases treated
with temporary implants include many gynecologic cancers.
The types of seed also vary and may include Iodine-125, Palladium-103, and echnogenic
Iodine-125 seeds.

Radiation given in combination with chemotherapy may improve long term disease
control.
Side effects of radiation therapy:
Malaise, fatigue, Nausea, anorexia, vomiting, Skin reactions, Bone marrow suppression
Temporary dysphagia, diarrhea, tenesmus, production of mucus per rectum: irradiation of
git

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Principle of Chemotherapy
1. In cancer chemotherapy, analogy is drawn with bacterial chemotherapy; the malignant
cell being viewed as an invader. However, there are two main differences –

 Bacterial metabolism differs markedly from that of the host, while malignant cells
are in fact host cells with only minor differences. Therefore selectivity of drugs is
limited.
 Infecting orgs are amenable to immunological and other host defense
mechanisms. This is absent or minimal in cancer cells.

2. A single clonogenic malignant cell is capable of producing progeny that can kill
the host. To affect cure, all malignant cells must be killed or removed. Survival time is
related to the no. of cells that escape chemotherapeutic attack.

3. In any cancer, subpopulation of cells differs in their rate of proliferation and

susceptibility to cytotoxic drugs. A certain fraction of cells present are killed by one
treatment.

4. Whenever possible, complete remission should be the goal of cancer chemotherapy:

drugs are often used in maximum tolerated doses. Intensive regimens used early yield
better results.

5. Cancers are treated with a combination of 2 – 6 drugs, given in intermittent pulses to

achieve total tumor cell kill, giving time in between for normal cell to recover.

6. Synergistic combinations and rational sequences are devised by utilizing:

 Drugs which are effective when used alone
 Drugs with different mechanism of action
 Drugs with different toxicities
 Empirically by trial and error

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 Pre (nucleic acid) synthesis interval (G1 Phase)

Synthesis of DNA occurs (S Phase)

Post synthetic interval (G2 Phase)

Mitosis occurs (M Phase)

Two G1 cells are produced which can pass into next cycle or to
nonproliferatible cells G0 phase

Nonproliferating cells (G0 Phase)

Cell cycle nonspecific: kill resting as well as dividing cells e.g. nitrogen mustard,
cyclsophosphamide, chlorambucil, carmustine, 5-FU, Cisplatin, L-asparginase,
Actonomycin D.

Cell cycle specific: kill only actively dividing cells.

G1: Vinblasin
S: Mtx, Cytarabin, 6-TG, 6-MP, hydroxyurea, mitomycin, doxorubicin, daunorubicin
G2: Daunorubicin, Doxorubicin
M: Vincristine, vinblasin, paclitaxel

Drug resistance
 One of the most important problems with cancer chemotherapy.
 As many as 40-45% of patients' cancers may have or may develop resistance to
anticancer drugs.

Mechanisms of Resistance to Anticancer Drugs include:

1. Decreased intracellular drug levels. This could result from increased drug efflux or
decreased inward transport. Among the drugs which become resistant by this mechanism
are the anthracyclines, dactinomycin, vinca alkaloids, and epidopodophyllotoxins.

2. Increased drug inactivation. Included in this group are the alkylating agents,
antimetabolites and bleomycin.

3. Deceased conversion of drug to an active form. This mechanism is most common

among the antimetabolites which must be converted to the nucleotide before they are
active.

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4. Altered amount of target enzyme or receptor (gene amplification): Methotrexate is a
classic example here as often in methotrexate resistant tumors there is amplification in
the target enzyme dihydrofolate reductase.

5. Decreased affinity of target enzyme or receptor for drug. Examples, here are the
antimetabolites and hydroxyurea.

6. Enhanced repair of the drug-induced defect. The alkylating agents typically show
resistance by this mechanism although other mechanisms are also important with these
drugs.

7. Decreased activity of an enzyme required for the killing effect (topoisomerase II) .
This is a newly recognized target but decreased activity is important for resistance to
doxorubicin and the epipodophyllotoxins.

Multidrug Resistance (MDR):

 This is a phenomenon whereby tumors become resistant to several drugs,

simultaneously.
 The multidrug Resistance (MDR1) gene encodes an ATP-dependent 170 Kda
transmembrane efflux pump, called p-glycoprotein on tumor cells. This protein
facilitates drug efflux from the tumor cells and maintains a lower intracellular
drug level, hence promotes drug resistance.
 MDR activity may be reversed by drugs such as calcium channel blockers (e.g.,
verapamil), cyclosporin, or tamoxifen.
 Multidrug resistance occurs between several different structurally unrelated
antitumor agents that apparently have different mechanisms of action.

Alkaloids
A. Microtubule inhibitors:

1. Vinca alkaloids:
Microtubules are protein polymers that are responsible for various aspects of cellular
shape and movement. The major component of microtubules is the polymer tubulin, a
protein containing two nonidentical subunits (alpha and beta). These drugs act by
affecting the equilibrium between free tubulin dimers and assembled polymers.

Mechanism of action: The vinca alkaloids are cell specific agents and block cells in
mitosis. Their biological activity is explained by their specific binding to tubulin. Upon
binding to vinca alkaloids, tubulin dimers are unable to aggregate to form microtubules.
This effectively decreases the pool of free tubulin dimers available for microtubule
assembly, resulting in a shift of the equilibrium toward disassembly. Formation of
paracrystalline aggregates by vinca-bound tubulin dimers shifts the equilibrium even
further toward disassembly and microtubule shrinkage. They block mitosis with
metaphase arrest.

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Toxicity: Like the therapeutic uses the toxicities of these drugs is different. The dose
limiting toxicity of vincristine is mainly peripheral neuropathy and other neurological
toxicities. The most common symptom is a depressed Achilles tendon reflex which is
usually followed by paresthesias in the extremities. Autonomic neuropathy often occurs
early in the course of therapy resulting in abdominal pain, constipation, paralytic ileus,
urinary retention and orthostatic hypotension. Unlike most antineoplastic agents
vincristine usually does not cause significant bone marrow supression therefore
vincristine is often found in combination therapies with other drugs that are
myelosuppressive. Gastointestinal symptoms also are common with this vinca alkaloid.

Unlike vincristine the other vinca alkaloids produce mainly bone marrow depression.
Myelosuppression (primarily neutropenia) is the major toxicity of vinblastine while
lymphopenia is the dose limiting toxicity of vindesine but neurotoxicity also occurs s
frequently.The neurotoxicity produced by these drugs is similar to vincristine but less
common and less severe.

Therapeutic Uses: Despite close similarity in structure the different vinca alkaloids have
quite different therapeutic uses. Vincristine is used mainly in combination therapy for the
induction of remission in childhood acute leukemias. Vincristine together with prednisone
is the main therapy for induction of acute lymphocytic leukemia. Complete remissions
are obtained in 80 to 90 % of patients. It is also used for the treatment of Hodgkin's and
non-Hodgkin's lymphoma where it is part of several complex protocols. Here again
vincristine therapy is very successful.
On the other hand the most important clinical use of vinblastine is in the therapy of
metastatic testicular tumors where it is combined with bleomycin and cisplatin.
Beneficial responses have also been obtained in the treatment of Hodgkin's and non-Hod
gkin's lymphoma. In Hodgkins disease it has been used in place of vincristine providing
similar antitumor activity with less neurotoxicity. Vindesine the newest of the vinca
alkaloids has significant activity in the treatment of acute leukemia, blast cris is of
chronic myelogenous leukemia and Hodgkins and non Hodgkins lymphomas.

Pharmacology: Their absorption is unpredictable and they usually are given by i.v.
infusion. They are very irritating to tissues. Both are rapidly cleared from the plasma and
excreted predominantly by the liver by a combination of hepatic metabolism and biliary
excretion. Caution should be used with decreased hepatic function. Many vinca
metabolites have been found in humans and animals. It is believed that a number of these
are active cytotoxic agents and that the Pharmacological effects of these drugs are still
felt long after the parent drug is gone. Vincristine is eliminated much more slowly than
the other two vinca alkaloids.

2. Taxols:
Mechanism of action In contrast to other microtubule antagonists, taxol disrupts the
equilibrium between free tubulin and microtubules by shifting it in the direction of

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assembly, rather than disassembly. As a result, taxol treatment causes both the
stabilization of microtubules and the formation of abnormal bundles of microtubules.
Toxicity The major toxicity of these drugs is bone marrow depression with neutropenia
the common dose limiting toxicity. Hypersensitivity reactions are also common. They are
characterized by dyspnea, urticaria and hypotension. It is not clear at this time whether
they are due to the vehicle in which taxol is given or the drug itself. Avoidance of bolus
injections and short infusions can minimize this toxicity as can pretreatment with steroids
or antihistamines. Mucositis is also common and is manifested as ulcerations of the
mouth and throat. Taxol also causes some reversible neurotoxicities most often numbness
and paresthesias in the hands and feet.

Therapeutic Uses: It has significant activity against ovarian cancer, breast cancer,
carcinoma of the lung and head and neck carcinoma. Response rates in these cancers are
fairly high.

Pharmacology: It is usually given i.v.preferably in 24 hr infusions in order to prevent

certain severe hypersensitivity reactions from occurring. Taxol binds extensively to
plasma proteins. It undergoes significant P-450 mediated hepatic metabolism to
hydroxylated metabolites and this is believed to be the major mechanism of elimination.

B. Chromatin Function Inhibitors

2. Topoisomerase II inhibibitors
Epipodophyllotoxins
 Etoposide
 Teniposide
(These drugs are semi synthetic glycosidic derivatives of podophyllotoxin)
This class of drugs owes their antitumor effects to disruption of chromosomal dynamics.
Drugs that interfere with the protein s responsible for these changes are selectively toxic
to proliferating cells.

Mechanism of action: DNA in eukaryotic cells must be packed very efficiently to be able
to fit into the nucleus. As a result, chromosomal DNA is twisted extensively and the
activities of enzymes called topoisomerases are needed to permit selected regions of
DNA to become sufficiently untangled and relaxed to allow transcription, replication, and
other essential functions to proceed. To do this topoisomerases have the ability to break
DNA strands and then to reseal these breaks after the topological changes have occurred.
The clinically useful drugs in this class are inhibitors of topoisomerase II as they break
both strands of DNA teniposide is taken up by cells more rapidly and retained to a greater
extent than etoposide. This may be because teniposide is more lipophilic than etoposide.
These drugs form complexes with the topoisomerase II enzyme. This complex produces
inhibition of the enzyme along with production of double stranded breaks in the DNA.
Removal of the drug results in a rapid return of normal topoisomerase function. Arrest of
cells occurs during the G2 phase of the cell cycle.

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Pharmacology: They are usually given i.v. as oral administration usually results in
variable absorption. Approximately 30-50 % of etoposide is recovered as unchanged
drug. Almost all of this is found in the urine with all amount excreted in the bile. Both
drugs are extensively bound to plasma proteins.

Clinical uses : Etoposide has shown activity against a variety of tumor types. Its greatest
effectiveness is in the treatment of testicular tumors where it is effective against tumors
resistant to treatment of other drugs. I t is most effective when combined with bleomycin
and cisplatin. Etoposide also has an important role in the treatment of small cell lung
carcinomas where it is often combined with cisplatin. Teniposide has been studied
clinically much less than etoposide. It appears to be effective for the treatment of acute
lymphoblastic leukemia and childhood neuroblastomas as well as brain tumors in adults.

Toxicity: The principal dose-limiting toxicity of these drugs is BONE MARROW

DEPRESSION primarily leukopenia and thrombocytopenia. Nausea and diarrhea are
common but not severe. Mucositis can be severe at higher doses. Other toxic effects seen
include fever, chills, erythema. Allergic reactions have been noted in some patients.

3. Topoisomerase I inhibibitors
Camptothecin: The camptotecins are a new class of chemotherapeutic agents with a novel
mechanism of action targeting the nuclear enzyme topoisomerase I. This compound was
isolated from the bark of a Chinese tree. This drug and its derivatives are inhibitors of
topoisomerase I. Camptothecin itself is poorly soluble and causes significant toxicity.
Several more soluble and less toxic derivatives are now available. One derivative with a
lot of promise is irinotecan (CPT-11). It is one of the most active compounds available for
the treatment of non small cell lung cancer. Leucopenia and diarrhea were the most
severe toxicities seen. Nausea and vomiting were common but manageable

Alkylating agents
Covalent DNA-binding Drugs
Nitrogen Mustards
1. Mechlorethamine (mustine HCL)
2. Cyclophosphamide
3. Ifosfamide
4. Chlorambucil
5. Melphalan
6. Thio-Tepa
7. Busulfan
8. Nitrosoureas
9. Dacarbazine

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Antimetabolites
 Structural analogs of naturally occurring compounds. These are analogues related
to normal components of DNA or of coenzymes involved in nucleic acid
synthesis. They competitively inhibit utilization of normal substrate or get
themselves incorporated forming dysfunctional macromolecules.
 Antimetabolites interfere with the production of nucleic acids. They work through
a variety of mechanisms including competition for binding sites on enzymes and
incorporation into nucleic acids. Antimetabolites inhibit the growth of the most
rapidly proliferating cells in the body (e.g., bone marrow, G.I. tract, etc.).
 There are three categories of antimetabolites:
1. Antifolates
2. Purine analogs and
3. Pyramidine antimetabolites.

Antifolates:
Methotrexate:
 Inhibits dihydrofolate reductase, blocking the conversion of dihydrofolic acid to
tetrahydrofolic acid which is essential coenzyme required for purine synthesis.
 It has cell cycle specific action - kills cells in S phase; primarily inhibits DNA
synthesis, but also affects RNA and protein synthesis.
 Methotrexate can be administered by several different routes including chronic
oral, intermittent oral or i.v.high-dose intravenous and intrathecal.

Toxicity: The primary toxic effects are against the rapidly dividing cells of the bone
marrow and gastrointestinal epithelium. The severity of the clinical effects depends
largely on the duration of exposure to inhibitory levels of the drug. All of the stem-cell
types of the marrow can be affected to produce leukopenia, thrombocytopenia and with
long-term administration, anemia. Methotrexate therapy must therefore be modified
according to the patient’s hematological status and leukocyte and platelet counts must be
carefully monitored.
Mucositis is one of the earliest signs of toxicity and its appearance indicates that the dose
must be reduced or other serious toxicities will occur. If diarrhea and ulcerative stomatitis
occur therapy with the drug must be stopped.
Methotrexate causes kidney damage which is a frequent complication of high dose
therapy. It is manifested by elevated serum creatinine and decreased creatinine clearance.
Crystalline deposits of methotrexate and methotrexate derived material have been found
in the renal tubule which seems to account for most of the nephrotoxicity. Alkalinizing
the urine to increase the solubility and ensuring good urine flow minimizes most of the
nephrotoxicity due to high-dose methotrexate.
Both low and high dose therapy can cause hepatotoxicity. High dose therapy results in
elevated liver enzymes and low dose therapy produces a different type of hepatotoxicity
which includes cirrhosis.
Methotrexate can cause a reversible pulmonary syndrome which has been observed
primarily in children undergoing maintenance therapy.

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Intrathecal and high-dose administration is accompanied by several types of
neurotoxicity. These range from acute manifestations to long-term delayed toxicity in the
form of encephalopathy.
Nausea and anorexia frequently occur as acute side effects of methotrexate therapy.
High dose MTX-rescue therapy
Administration of high doses of methotrexate plus folinic acid (leucovorin) can be very
beneficial in certain types of cancer. This therapy involves administration of methotrexate
at high doses along with leucovorin to rescue host tissues from the effects of the intense
methotrexate therapy. The leucovorin provides the normal tissues with the reduced folate
leucovorin which circumvents the inhibition of DHFR. The protection seems to be
selective in that it does not alter the antitumor effect of the methotrexate. Apparently only
the host cells are able to utilize the leucovorin. A more recent explanation is that of
differential reactivation of DHFR in host and tumor cells. Beneficial effects have been
observed in patients with osteosarcoma as well acute leukemia.

Purine antagonist:

 Converted in the body to corresponding monoribonucleotides which inhibits the

conversion of inosine monophosphate to adenine and guanine nocleotides.
 Therapeutic Uses Both drugs are used primarily in the treatment of leukemias.
Response rates are higher in children than adults. 6-MP is used in the maintenance
therapy of acute lymphocytic leukemia and 6-TG in the treatment of acute
nonlymphocytic leukemia.

Toxicity: Bone marrow depression is dose limiting with both drugs.

Other major toxicities include nausea and vomiting and stomatitis.
Hepatotoxicity is seen as jaundice in about 33% of the patients treated with 6-MP

Antibiotics
These drugs interact with DNA in a variety of different ways including intercalation,
DNA strand breakage and inibition with the enzyme topoisomerase II. Most of these
compounds have been isolated from natural sources and antibiotics.

Dactinomycin (actinomycin D):

Mechanism of action: At low concentrations dactinomycin inhibits DNA directed RNA
synthesis and at higher concentrations DNA synthesis is also inhibited.
Actinomycin D is usually given i.v. and can cause severe local necrosis if extravasation
occurs. Therefore, it should be administered into the tubing of a rapidly flowing i.v.
infusion.
Actinomycin is used mainly in the treatment of pediatric solid tumors ( e.g.Wilm's tumor,
rhabdomyosarcoma). It also is an alternative drug used to treat choriocarcinoma when
methotrexate can't be used because of resistance. The treatment of several solid tumors
utilizes combination therapy with actinomycin and radiotherapy.
The primary and dose limiting toxicity of actinomycin is bone marrow depression

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Also nausea, vomiting, malaise, ulceration of the oral mucosa and gastointestinal tract
and acneiform eruptions of the skin occurs.

Anthracycline antibiotics:
Mechanism of action: The anthracyclines all bind to DNA and their cytotoxicity largely
results from this binding. They bind to double stranded DNA.

 All three anthracyclines are administered i.v.

 The anthracyclines are very irritating to tiss ue and should not be extravasated
 Daunorubicin has limited clinical activity. It is very useful for the treatment of
acute lymphocytic and especially acute myelocytic leukemia. Doxorubicin has a
very broad range of clinical usefulness in contrast to daunorubicin. It is most
active against solid tumors, particularly breast cancer. Other solid tumors against
which it has good activity are ovary, bladder, and lung carcinomas. It is also
active in the treatment of Non-Hodgkin's lymphoma and Hodgkin's disease.
 The toxic effects of all three anthracyclines are similar. They frequently cause
nausea and vomiting and patients may experience anorexia and diarrhea. These
drugs and their metabolites may color the urine red for one or two days after
administration. Bone marrow depression is dose-limiting and occurs in 60%-80%
of patients.
 Cardiac toxicity is a peculiar adverse effect observed with these agents in both
adults and children. The total dose should not exceed 550 mg/m2 as the risk of
cardiotoxicity increases markedly at that level.

Anthracenediones (mitoxantrone):
 Analogs of the anthracyclines
 Mitoxanthone is given by i.v. infusion
 Mitoxanthone has a much narrower range of therapeutic activity that the
anthracyclines. It is used mainly for treatment of the leukemias (mainly acute
myelogenous leukemia) and lymphomas as well as advanced breast cancer.
 Toxicity Patients should be warned of a possible blue-green coloration of the
sclerae and nails as well as the urine. It causes less nausea and vomiting and
alopecia than does doxorubicin. Its major toxicities are bone marrow depression
and mucositis.
 Bleomycin: Bleomycin is MARROW SPARING and is NOT
IMMUNOSUPPRESSIVE and is therefore a useful compound to use in
combination drug protocols. In the usual doses the gastrointestinal tract, liver,
kidneys and CNS are also not affected. Despite these advantages bleomycin is
quite toxic. The most common toxicity involves the skin and mucous membranes
Oral mucositis is dose related and common in the more aggressive regimens.
Alopecia occurs in about 10 - 20% of patients. Toxic reactions of the skin include
hyperpigmentation, sclerotic changes with collage infiltration, edema and
erythema of the hands and feet. These cutaneous changes are reversible when the
drug is discontinued. As mentioned above the skin contains very little if any of the

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 bleomycin inactivating enzymes. Bleomycin is given parenterally most commonly
i.v. or i.m.

Enzymes
L-asparaginase:
Hydrolyzes L-asparagine to L-aspartate. The enzyme is effective because a few
neoplastic cells have low levels of asparagine synthetase activity and require L-
asparagine for growth. The use of L-asparaginase in cancer chemotherapy is limited to
acute lymphocytic leukemia to induce remission.

Hydroxyurea:
Hydroxyurea inhibits DNA synthesis by inhibiting conversion of ribonucleotides to
deoxyribonucleotide by inhibiting ribonucleotide reductase thus interferes DNA
synthesis. The drug is well absorbed from the gastrointestinal tract and is routinely given
orally.

Hormones
Tamoxifen
Tamoxifen is a competitive inhibitor of estradiol binding to the estrogen receptor.It acts
as a complete antagonist in some systems and as an antagonist with partial agonist
activity in other systems. By binding to the receptor it competes with the binding of
endogenous estradiol and its major therapeutic effect reflects this antiestrogenic
mechanism. It induces a change in the 3 dimensional shape of the receptor inhibiting its
binding to the estrogen response element on DNA.
Pharmacology Tamoxifen is administered orally
It is used in the treatment of metastatic breast cancer. It is used alone for palliation of
advanced breast cancer in women with estrogen receptor -positive tumors
Tamoxifen is very well tolerated. The most frequent side effect is acute nausea and
vomiting. This usually disappears after a few weeks and it can be reduced by taking the
drug with meals. More chronic side effects include hot flashes, transient and mild
thrombocytopenia and leukopenia; vaginal bleeding; skin rashes; hypercalcemia;
retinopathy and corneal opacities with high dose long-term therapy

Flutamide:
This is a nonsteroidal antiandrogen. It is used in combination with gonadotropin releasing
hormone analogs in therapy for patients with cancer of the prostate
Toxicity: Occasional diarrhea, nausea, vomiting and reversible liver function
abnormalities are the significant toxicities of this drug.

Platinum compounds
A platinum compound that is hydrolyzed intracellularly to produce a highly reactive
moiety which causes cross linking of DNA: favorable site being N7 of guanine residue.

Cisplatin: a platinum compound that is hydrolyzed intracellularly to produce a highly

reactive moiety which causes cross linking of DNA: favourable site being N7 of guanine
residue.

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Both cisplatin and carboplatin must be given parenterally often by i.v. injection. Cisplatin
is given i.v. and by local introduction into the bladder and into the peritoneal space.
Cisplatin is one of the most frequently used anticancer drugs. It is an effective component
of several different combination drug protocols used to treat a variety of solid tumors.
These drugs are used in the treatment of testicular cancer (with bleomycin and
vinblastine), bladder cancer, head and neck cancer (with bleomycin and fluorouracil) ,
ovarian cancer (with cyclophosphamide or doxorubicin) and lung cancer (with
etoposide). Cisplatin has been found to be the most active single agent against most of
these tumors.
Toxicity: The dose limiting toxicity with cisplatin is nephrotoxicity.
Other toxic effects associated with this drug include bone marrow depression, severe
nausea and vomiting, anaphylactic reactions and peripheral neuropathy. Highly emetic
drug
Cisplatin also causes a neurotoxicity that most commonly is seen as a peripheral
neuropathy with sensations of numbness in the hands, feet, arms, and legs.
With carboplatin the dose limiting toxicity is bone marrow depression. Other toxic effects
include moderate nausea and vomiting and a low potential for ototoxicity and peripheral
neuropathy.

New approaches to cancer therapy

Monoclonal antibody-drug, -toxin, or -radionuclide conjugates:
These antibodies recognize specific antigenic determinants on cancer cells. Their
potential is very far reaching. Monoclonal antibodies that recognize tumor associated
surface components can inhibit tumor cell proliferation in culture and whole animals.

Biological response modifiers:

These include agents e.g., interferons, interleukins that affect the patient's biological
response to a neoplasm beneficially. Some of the agents in this category act directly on
the tumor cells while most of them act indirectly by enhancing the hosts’ immunological
response to the neoplastic cells.

Interferons: These compounds were originally discovered as natural anti-viral

compounds. Human interferons are classified into three groups: alpha, beta, and gamma.
only interferon presently used clinically for anticancer activity is alpha. They are acid
stable polypeptides. IFNalpha has demonstrated activity in a broad range of malignant
disorders. Its best activity has been in the treatment of hairy cell leukemia. In the
treatment of other neoplasms it is still in the early stages of clinical development.

Interleukin-2: Human IL-2 is a glycoprotein with a M.W. of 17.2 kD. It is now known to
stimulate B lymphocytes also as well as having several other effects. It is being studied in
the treatment of acute myelogenous leukemia where it has been shown to induce
remission in relapsed patients. When used alone toxicity is related to the activation and
expansion of lytic lymphocytes has occurred. This has produced inflammation and
vascular leak as well as the secondary release of other cytokines. It also has been used in
adoptive immunotherapy to stimulate clonal expansion of lymphokine- activated killer
(LAK) cells and tumor infiltrative lymphocytes (TIL).

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Hematopoietic growth factors:
Several growth factors have recently been found to be very useful in reducing some of
the bone marrow toxicity associated with the use of the anticancer agents. These are a
subset of regulatory polypeptides of the cytokine family that are involved in the
proliferation and differentiation of granulocytes and monocyte/macrophages.The ones
most commonly used are granulocyte-macrophage stimulating, and granulocyte
stimulating factor. Both of these have been shown to replenish peripheral blood.
neutrophils after high dose chemotherapy followed by autologous bone-marrow
transplantation. Positive benefits include decreasing the frequency of infections and
shortening the stay in the hospital. Erythropoietin has been used to replenish red blood
cells in aplastic anemia and after cancer chemotherapy

Gene therapy:
Alteration of a cell's gene dosage for specific genes could significantly affect the
outcome of a malignant growth.. For example, if a tumor suppresser gene could be
delivered to leukemic cells the malignant process may be able to be stopped or reversed.
On the other hand if the DNA coding for a particular gene were incorporated into the
cells genetic apparatus a permanent reprogramming of the cell might be achieved. This
might be achieved in cells removed from a patient or by a viral vector. It might also be
achieved in vivo by injection of a viral vector targeted to the desired cell type.

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