CANCER CHEMOTHERAPY

INTRODUCTION
Cancer is a class of diseases characterized by out-of-control cell growth. There are over 100 different types of
cancer, and each is classified by the type of cell that is initially affected.
Cancer harms the body when damaged cells divide uncontrollably to form lumps or masses of tissue called tumors
(except in the case of leukemia where cancer prohibits normal blood function by abnormal cell division in the blood
stream). Tumors can grow and interfere with the digestive, nervous, and circulatory systems and they can release
hormones that alter body function. Tumors that stay in one spot and demonstrate limited growth are generally
considered to be benign.
More dangerous, or malignant, tumors form when two things occur:
1. a cancerous cell manages to move throughout the body using the blood or lymph systems, destroying healthy
tissue in a process called invasion
2. That cell manages to divide and grow, making new blood vessels to feed itself in a process called
angiogenesis.
When a tumor successfully spreads to other parts of the body and grows, invading and destroying other healthy
tissues, it is said to have metastasized. This process itself is called metastasis, and the result is a serious condition
that is very difficult to treat.

What causes cancer?

Cancer is ultimately the result of cells that uncontrollably grow and do not die. Normal cells in the body follow an
orderly path of growth, division, and death. Programmed cell death is called apoptosis, and when this process
breaks down, cancer begins to form. Unlike regular cells, cancer cells do not experience programmatic death and
instead continue to grow and divide. This leads to a mass of abnormal cells that grows out of control.

Genes - the DNA type

Cells can experience uncontrolled growth if there are damages or mutations to DNA, and therefore, damage to the
genes involved in cell division. Four key types of gene are responsible for the cell division process: oncogenes tell
cells when to divide, tumor suppressor genes tell cells when not to divide, suicide genes control apoptosis and tell
the cell to kill itself if something goes wrong, and DNA-repair genes instruct a cell to repair damaged DNA.
Cancer occurs when a cell's gene mutations make the cell unable to correct DNA damage and unable to commit
suicide. Similarly, cancer is a result of mutations that inhibit oncogene and tumor suppressor gene function, leading
to uncontrollable cell growth.

Carcinogens
Carcinogens are a class of substances that are directly responsible for damaging DNA, promoting or aiding cancer.
Tobacco, asbestos, arsenic, radiation such as gamma and x-rays, the sun, and compounds in car exhaust fumes
are all examples of carcinogens. When our bodies are exposed to carcinogens, free radicals are formed that try to
steal electrons from other molecules in the body. Theses free radicals damage cells and affect their ability to
function normally.

Genes - the family type

Cancer can be the result of a genetic predisposition that is inherited from family members. It is possible to be born
with certain genetic mutations or a fault in a gene that makes one statistically more likely to develop cancer later in
life.

Other medical factors

As we age, there is an increase in the number of possible cancer-causing mutations in our DNA. This makes age an
important risk factor for cancer. Several viruses have also been linked to cancer such as: human papillomavirus (a
cause of cervical cancer), hepatitis B and C (causes of liver cancer), and Epstein-Barr virus (a cause of some
childhood cancers). Human immunodeficiency virus (HIV) - and anything else that suppresses or weakens the
immune system - inhibits the body's ability to fight infections and increases the chance of developing cancer.

What are the symptoms of cancer?

Cancer symptoms are quite varied and depend on where the cancer is located, where it has spread, and how big
the tumor is. Some cancers can be felt or seen through the skin - a lump on the breast or testicle can be an
indicator of cancer in those locations. Skin cancer (melanoma) is often noted by a change in a wart or mole on the
skin. Some oral cancers present white patches inside the mouth or white spots on the tongue.
Other cancers have symptoms that are less physically apparent. Some brain tumors tend to present symptoms
early in the disease as they affect important cognitive functions. Pancreas cancers are usually too small to cause
symptoms until they cause pain by pushing against nearby nerves or interfere with liver function to cause a
yellowing of the skin and eyes called jaundice. Symptoms also can be created as a tumor grows and pushes
against organs and blood vessels. For example, colon cancers lead to symptoms such as constipation, diarrhea,
and changes in stool size. Bladder or prostate cancers cause changes in bladder function such as more frequent or
infrequent urination.
As cancer cells use the body's energy and interfere with normal hormone function, it is possible to present
symptoms such as fever, fatigue, excessive sweating, anemia, and unexplained weight loss. However, these
symptoms are common in several other maladies as well. For example, coughing and hoarseness can point to lung
or throat cancer as well as several other conditions.
When cancer spreads, or metastasizes, additional symptoms can present themselves in the newly affected area.
Swollen or enlarged lymph nodes are common and likely to be present early. If cancer spreads to the brain, patients
may experience vertigo, headaches, or seizures. Spreading to the lungs may cause coughing and shortness of
breath. In addition, the liver may become enlarged and cause jaundice and bones can become painful, brittle, and
break easily. Symptoms of metastasis ultimately depend on the location to which the cancer has spread.

Metastasis: The Formation of Secondary Tumours

Cells in an invasive tumour can separate off, digest a pathway through the extracellular matrix and enter the
bloodstream. When they reach a permissible site, they can exit (extravasation) the blood stream and set up shop
as secondary tumours (metastases).

Events of Metastasis
1. Detachment from the primary site
o Mutations in cell-to-cell adhesion (homotypic binding)
o E.g. loss of E-cadherin expression
o Individual tumour cells break loose from primary mass
2. Invasion into circulatory vessel
o Cells must penetrate basement membrane (heterotypic binding) and degrade ECM
o Secrete high levels of extracellular proteases including matrix metalloproteinases (MMPs)
o Cells must penetrate basement membrane of circulatory vessel
o Involves heterotypic binding via integrin and laminin receptors
3. Mobility through circulatory system
o Mobile cells vulnerable in blood stream
o 1 in 10,000 survive
4. Establishment of a new colony
o Most common site of distant metastases are lungs or liver
o Some cancers show organ preference
o Local concentrations of growth factors and hormones

How is cancer classified?

There are five broad groups that are used to classify cancer.
1. Carcinomas are characterized by cells that cover internal and external parts of the body such as lung, breast,
and colon cancer.
2. Sarcomas are characterized by cells that are located in bone, cartilage, fat, connective tissue, muscle, and
other supportive tissues.
3. Lymphomas are cancers that begin in the lymph nodes and immune system tissues.
4. Leukemias are cancers that begin in the bone marrow and often accumulate in the bloodstream.
5. Adenomas are cancers that arise in the thyroid, the pituitary gland, the adrenal gland, and other glandular
tissues.
Cancers are often referred to by terms that contain a prefix related to the cell type in which the cancer originated
and a suffix such as -sarcoma, -carcinoma, or just -oma. Common prefixes include:

Adeno- = gland
Chondro- = cartilage
Erythro- = red blood cell
Hemangio- = blood vessels

Hepato- = liver
Lipo- = fat
Lympho- = white blood cell
Melano- = pigment cell
Myelo- = bone marrow
Myo- = muscle
Osteo- = bone
Uro- = bladder
Retino- = eye
Neuro- = brain

How is cancer diagnosed and staged?

Early detection of cancer can greatly improve the odds of successful treatment and survival. Physicians use
information from symptoms and several other procedures to diagnose cancer. Imaging techniques such as X-rays,
CT scans, MRI scans, PET scans, and ultrasound scans are used regularly in order to detect where a tumor is
located and what organs may be affected by it. Doctors may also conduct an endoscopy, which is a procedure that
uses a thin tube with a camera and light at one end, to look for abnormalities inside the body.
Extracting cancer cells and looking at them under a microscope is the only absolute way to diagnose cancer. This
procedure is called a biopsy. Other types of molecular diagnostic tests are frequently employed as well. Physicians
will analyze your body's sugars, fats, proteins, and DNA at the molecular level. For example, cancerous prostate
cells release a higher level of a chemical called PSA (prostate-specific antigen) into the bloodstream that can be
detected by a blood test. Molecular diagnostics, biopsies, and imaging techniques are all used together to diagnose
cancer.
After a diagnosis is made, doctors find out how far the cancer has spread and determine the stage of the cancer.
The stage determines which choices will be available for treatment and informs prognoses. The most common
cancer staging method is called the TNM system. T (1-4) indicates the size and direct extent of the primary tumor, N
(0-3) indicates the degree to which the cancer has spread to nearby lymph nodes, and M (0-1) indicates whether
the cancer has metastasized to other organs in the body. A small tumor that has not spread to lymph nodes or
distant organs may be staged as (T1, N0, M0), for example.
TNM descriptions then lead to a simpler categorization of stages, from 0 to 4, where lower numbers indicate that the
cancer has spread less. While most Stage 1 tumors are curable, most Stage 4 tumors are inoperable or
untreatable.

How is cancer treated?

Cancer treatment depends on the type of cancer, the stage of the cancer (how much it has spread), age, health
status, and additional personal characteristics. There is no single treatment for cancer, and patients often receive a
combination of therapies and palliative care. Treatments usually fall into one of the following categories: surgery,
radiation, chemotherapy, immunotherapy, hormone therapy, or gene therapy.

Surgery
Surgery is the oldest known treatment for cancer. If a cancer has not metastasized, it is possible to completely cure
a patient by surgically removing the cancer from the body. This is often seen in the removal of the prostate or a
breast or testicle. After the disease has spread, however, it is nearly impossible to remove all of the cancer cells.
Surgery may also be instrumental in helping to control symptoms such as bowel obstruction or spinal cord
compression.

Radiation
Radiation treatment, also known as radiotherapy, destroys cancer by focusing high-energy rays on the cancer cells.
This causes damage to the molecules that make up the cancer cells and leads them to commit suicide.
Radiotherapy utilizes high-energy gamma-rays that are emitted from metals such as radium or high-energy x-rays
that are created in a special machine. Early radiation treatments caused severe side-effects because the energy
beams would damage normal, healthy tissue, but technologies have improved so that beams can be more
accurately targeted. Radiotherapy is used as a standalone treatment to shrink a tumor or destroy cancer cells
(including those associated with leukemia and lymphoma), and it is also used in combination with other cancer
treatments.

Chemotherapy
Chemotherapy utilizes chemicals that interfere with the cell division process - damaging proteins or DNA - so that
cancer cells will commit suicide. These treatments target any rapidly dividing cells (not necessarily just cancer
cells), but normal cells usually can recover from any chemical-induced damage while cancer cells cannot.
Chemotherapy is generally used to treat cancer that has spread or metastasized because the medicines travel
throughout the entire body. It is a necessary treatment for some forms of leukemia and lymphoma. Chemotherapy
treatment occurs in cycles so the body has time to heal between doses. However, there are still common side
effects such as hair loss, nausea, fatigue, and vomiting. Combination therapies often include multiple types of
chemotherapy or chemotherapy combined with other treatment options.

Immunotherapy
Immunotherapy aims to get the body's immune system to fight the tumor. Local immunotherapy injects a treatment
into an affected area, for example, to cause inflammation that causes a tumor to shrink. Systemic immunotherapy
treats the whole body by administering an agent such as the protein interferon alpha that can shrink tumors.
Immunotherapy can also be considered non-specific if it improves cancer-fighting abilities by stimulating the entire
immune system, and it can be considered targeted if the treatment specifically tells the immune system to destroy
cancer cells. These therapies are relatively young, but researchers have had success with treatments that introduce
antibodies to the body that inhibit the growth of breast cancer cells. Bone marrow transplantation (hematopoetic
stem cell transplantation) can also be considered immunotherapy because the donor's immune cells will often
attack the tumor or cancer cells that are present in the host.

Hormone therapy
Several cancers have been linked to some types of hormones, most notably breast and prostate cancer. Hormone
therapy is designed to alter hormone production in the body so that cancer cells stop growing or are killed
completely. Breast cancer hormone therapies often focus on reducing estrogen levels (a common drug for this is
tamoxifen) and prostate cancer hormone therapies often focus on reducing testosterone levels. In addition, some
leukemia and lymphoma cases can be treated with the hormone cortisone.

Gene therapy

The goal of gene therapy is to replace damaged genes with ones that work to address a root cause of cancer:
damage to DNA. For example, researchers are trying to replace the damaged gene that signals cells to stop
dividing (the p53 gene) with a copy of a working gene. Other gene-based therapies focus on further damaging
cancer cell DNA to the point where the cell commits suicide. Gene therapy is a very young field and has not yet
resulted in any successful treatments.

How can cancer be prevented?

Cancers that are closely linked to certain behaviors are the easiest to prevent. For example, choosing not to smoke
tobacco or drink alcohol significantly lower the risk of several types of cancer - most notably lung, throat, mouth, and
liver cancer. Even if you are a current tobacco user, quitting can still greatly reduce your chances of getting cancer.
Skin cancer can be prevented by staying in the shade, protecting yourself with a hat and shirt when in the sun, and
using sunscreen. Diet is also an important part of cancer prevention since what we eat has been linked to the
disease. Physicians recommend diets that are low in fat and rich in fresh fruits and vegetables and whole grains.
Certain vaccinations have been associated with the prevention of some cancers. For example, many women
receive a vaccination for the human papillomavirus because of the virus's relationship with cervical cancer. Hepatitis
B vaccines prevent the hepatitis B virus, which can cause liver cancer.
Some cancer prevention is based on systematic screening in order to detect small irregularities or tumors as early
as possible even if there are no clear symptoms present. Breast self-examination, mammograms, testicular selfexamination, and Pap smears are common screening methods for various cancers.

Resistance to Cytotoxic Drugs

The efflux pumps shown schematically at the
plasma membrane include MDR1, MRP
family members, and MXR (ABC G2), which
is presumed to function as a dimer.

Anticancer Chemotherapeutic Agents

They may be divided into different groups as follows

Alkylating Agents
Tyrosine Kinase Inhibitors
Antimetabolites
Plant Alkaloids
Antibiotics
Monoclonal Antibodies
Hormones
Miscellaneous

Alkylating Agents
1. Nitrogen Mustard

1. Anthracyclines

1. Vinca Alkaloids
(Microtubule Inhibitors)

1. Androgens

hosphamid,
Propionate

Plant Alkaloids
Antibiotics

Hormones

2. Antiandrogens
2. Nitrosoureas

3. Estrogens
2. Posophyllotoxins

3. Platinum Complex
4. Antiestrogens

2. Bleomycins

5. Aromatase Inhibitors
3. Actinomycins

3. Taxanes
4. Triazenes

4. Metomycins

5. Azridines
Antimetabolites
6. Adrenocorticoids

1. Folate Antagonists

Miscellaneous

6. Alkyl Sulpphonates

2. Purine Antagonists

7. Hydrazine

7. Gonadotropin
Releasing Hormone
Agonists

Tyrosine Kinase Inhibitors

8. Peptide Hormone
Inhibitors
Monoclonal Antibodies
3. Pyranidine
Antagonists

9. Progestins

The cell cycle 2 key events:

I. S phase: Synthesis of DNA
II. M phase: Division of parent cell into two daughter cells during mitosis.
G1 (gap): Synthesis of cellular components needed for DNA synthesis.
G2: Synthesis of cellular components for mitosis
IMPORTANCE OF CELL CYCLE KINETICS
Based on information of cell cycle cytotoxic drugs are divided into two classes.
1. Cell cycle - specific agents = CCS agents CCS drugs most effective in:
- Hematologic malignancies
- Solid tumors which are proliferating or are in growth fraction.
2. Cell cycle- Nonspecific agents=CCNS agents CCNS drugs are useful in:
- Low growth fraction solid tumors
Note: Growth fraction = the ratio of the number of cells that are proliferating to the total
number of cells in the tumor.
General principles in the use:

Cytostatic interfere with several different stages of the cell cycle and so open the way to the
rational use of drug combinations.
Cycle non-specific drugs act at all stages in the proliferating cell cycle (but not in the G0 resting
phase)
Phase-specific drugs act only at a specific phase:
The more rapid the cell turnover the more effective they are.
CANCER CHEMOTHERAPY
A. Concepts
1. Cell cycle kinetics: Cell cycle-specific (CGS) drugs act on tumor cells during the mitotic cycle
and are usually phase specific. Most anticancer drugs are cell cycle-nonspecific (CCNS), killing
tumor cells in both resting and cycling phases.
2. Log kill: Antitumor drug treatment kills a fixed proportion of a cancer cell population rather
than a constant number of cells. A 3-log-kill dose of a drug reduces cancer cell numbers by
three orders of magnitude.
3. Resistance: Established mechanisms of tumor cell resistance to anticancer drugs.
4. Toxicities: Drug-specific toxicities.
B. Principles of chemotherapy

Action sites of cytotoxic agents

1. A L K Y L A T I N G AGENTS:

Alkylsulfonates: Busulfan
Ethylenimines: Thiotepa and Hexamethylamine
Hydrazines and Triazines: Altretamine, Procarbazine, Dacarbazine, Temozolomide
Metal salts: Carboplatin, Cisplatin, and Oxaliplatin
Mustard gas derivatives: Mechlorethamine, Cyclophosphamide, Chlorambucil, Melphalan, and Ifosfamide
Nitrosureas: Carmustine, Lomustine, and Streptozocin

Cell- cycle-nonspecific drugs

Combine with DNA of both malignant and normal cells and thus damage not only malignant cells but also dividing normal cells (the
bone marrow and the GIT)
Mechanisms: the alkyl groupings (ethyleneimine ions and positively charged carbonium ions) are highly reactive, so that combine with
susceptible groups in cells and in tissue fluids (SH, PO4)
The alkylating action on DNA leads to abnormal base pairing or intra and interstrand links with DNA molecule
Cytotoxic, mutagenic and teratogenic effects may result from interaction with DNA

Cyclophosphamide

an inactive prodrug
can be given orally
Is activated by the CYP450 in liver as well as in tumors.
With time, the active metabolite and also acrolein are formed. The latter compound is responsible for bladder toxicity
(chemical hemorrhagic cystitis).
A wide spectrum antitumor and immunosuppressive activity that used as a part of combination therapy regimens to
treat lymphoma, breast cancer, bladder cancer, ovarian cancer and various children malignancies

T o x i c i t i e s:

Bone marrow depression, granulocytopenia, and thrombocytopenia. urotoxicity appears with chronic therapy - M e s n a
dimesna
(2-mercaptoethane sulfonate sodium) protects the urinary tract against the irritant effects by supplying sulfhydryl groups to
form a stable thioether with acrolein. Mesna is given by IV injection or by mouth

Nitrosoureas:

alkylating agents used to treat cancers such as Hodgkin's disease and some solid tumours.
Examples include lomustine and carmustine. They are lipid soluble and so can enter the brain.

Streptozotocin is a naturally occurring nitrosourea obtained from Streptomyces acromogenes.

No cross resistance with other alkylating agent.
Carmustine and Lomustine are potent bone marrow toxins. Hepatotoxicity and nephrotoxicity. Broad spectrum
of activity (solid tumors, in particular brain tumors).
The nitrosourea moiety is shown in blue below.

streptozotocin

Carmestine
lomustine
IV
Orally
No active metabolite Active metabolite
Both readily penetrate into CNS
Undergoes extensive metabolism.
Urinary excretion is main route.
Cisplatin:

Kills cells in all stages of the cell cycle (not specific cell cycle)
Inhibits DNA synthesis & function.
Aggressive hydration with IV saline infusion significantly reduce the incidence of nephrotoxicity (b/c it wash the
kidney)
Effective against :
[Broad anticancer effect]
solid tumors includes (lung, esophagus, gastric)
Genitourinary cancer as testicular, ovarian & bladder.
Generally, the alkylating agents are used to treat hematological & solid tumors.

Drug resistance of the alkylating agents:

Increased capability to repair DNA lesions.
Decreased permeability of the cell to alkylating drugs.
Increased production of glutathione. [glutathione inactivate alkylating drugs]

2. ANTIMETABOLITE AGENTS:
antimetabolites

affect purine

6-mercaptopurine
6-thioguanine

affect pyrimidine

affect both

-methotrexate
*5- Flurouracil
*Cytarapine

Purine Antagonist:
6-mercaptopurine (6-MP) and 6-thioguanine (6-TG)
Metabolized by hypoxathine guanine phosphoribosyl transferase (HGPRT) to monophosphate 6-thioinosinic acid [active form]
which inhibites purine synthesis.

Mechanisms: 6-MP ribonucleotide inhibits purine nucleotide synthesis and metabolism. This alters the synthesis and
function of RNA and DNA. Mercaptopurine interferes with nucleotide interconversion and glycoprotein synthesis.
Therapeutic uses of 6MP:
In the treatment of childhood acute lymphoblastic leukemia.
Pharmacokinatics of 6MP:
Given orally.
Widely distributed except CNS
Metabolized by liver, excreted by kidney.
Toxicity of 6MP:
The common triad
Nephrotoxicity
Acute gout (hyperuricemia) b/c of uric acid metabolism defect so
give the pt. allopurinol as prophylactic, or to reduce the symptoms].

GI upset.
Drug interactions
Allopurinol inhibits xanthine oxidase, the enzyme that breaks down mercaptopurine. Those taking
allopurinol (often used to prevent gout) are at risk for mercaptopurine toxicity. The dose should be reduced
or allopurinol should be discontinued

Note: One of the best known purine antimetabolite is acyclovir, an antiviral agent used to treat herpesvirus infections. Purine
antagonists currently used to treat cancer patients include 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). These drugs are
similar to each other, and work in the same way. The structures the normal purines (adenine and guanine) with their antagonists
(6-MP and 6-TG)

Pyrimidine Antagonists:
Fluorouracil -S-phase, Cytarabine, Gemcitabine and Capecitabine
5-Flurouracil:

It is pro-drug converted to deoxyuridine monophosphate [active form], inhibits thymidylate synthase enzyme
inhibition of thymidylic acid, one of the essential precursors for DNA synthesis.

Mechanisms: 5-FU is first converted to fluorouridine monophosphate (FUMP) by orotate phosphoribosyltranferase

(OPRT). It is then phosphorylated to create fluorouridine diphosphate (FUDP), which is phosphorylated once again to
create fluoridine triphospate (FUTP). It is essentially equivalent to uridine triphosphate, but has a fluorine at carbon 5.
Hence, once incorporated, it leads to RNA damage. When FUTP is incorporated into RNA, tRNA and mRNA cannot be
translated. To be specific, pre-mRNA cannot be processed into mature mRNA. Polyadenylation and splicing cannot take
place. Therefore, rRNA, tRNA, mRNA and snRNA are never processed and the cell must go through apoptosis. FUDP

can also become fluorodeoxyuridine diphosphate by ribonucleotide reductase (RR), which makes a ribonucleotide become
a deoxyribonucleotide. Once dephosphorylated to become fluorodeoxyuridine monophosphate (FdUMP), it inhibits
thimydylate synthase. Thymidylate synthase is the only enzyme that can can create deoxythimidine monophosphate from
deoxyuridine monophosphate. Therefore, if there is a shortage of deoxythimidine monophosphate, no more can be made
when TS is inhibited. Hence, DNA synthesis is halted without deoxythimidine triphosphate. It has also been found that
UDG (urasil-DNA-glycosylase) is incapable of doing excision and repair during DNA synthesis when the ratio of dUTP to
dTTP is too high. Also, if fluorodeoxyuridine diphosphate is phosphorylated into fluorodeoxyuridine triphosphate, it can
be incorporated into DNA and damage the cell. All mechanisms listed essentially lead to cell death.

Pharmacokinetics of 5-Flurouracil:

Not given orally as 80-85% of the dose is catabolized by dihydropyrimidne dehydrogenase in gut mucosa.
So, Given IV
In cancer skin applied topically.
Penetrate well into all tissues including CNS.
Metabolized in liver& excreted in urine & lung.
Clinical uses of 5-Flurouracil::

Widely used to treat colorectal, breast, gastric, pancreatic carcinoma. [GI mainly)

Toxicity of 5-Flurouracil::

Common triad But bone marrow depression is severe

Severe ulceration of oral & GIT mucosa

neurotoxicity& Myleosupression [severe BM depression]

Cytrarabine:

pyraramidine antagonist.

Is converted to arabinose triphosphate which acts as pyrimidine antagonist.

It is incorporated into nuclear DNA & retard chain elongation.

Also, inhibits DNA polymerase & resulting in blockade of DNA synthesis & repair.

Mechanisms: Cytarabine (ara-C) is metabolized to araCTP which then competes with CTP (cytidine triphosphate) for DNA
polymerase. If araCTP ends up being incorporated into DNA, chain termination occurs as does cell death. Synergistic
effects involving cyclophosphamide and cytarabine occur most likely because of reduced DNA repair secondary to
cytarabine-mediated inhibition of DNA polymerase activity.

Pharmacokinetics of Cytrarabine:
Given IV route (inactivated orally by
cytidine deaminase in intestinal mucosa)
Poorly penetrate CNS, given intrathecaly in
meningeal tumor.
Metabolized to inactive metabolite &
excreted in urine.

Uses of Cytrarabine:

Treatment of hematologic cancer & non Hodgkin leukemia.

Adverse effects of Cytrarabine:

The common triad, with Severe BM

depression.

Stomatits.

Cerebral ataxia. [An example of

nurotoxicity, others:seizures, nuropathy.]

N.B some drugs cannot penetrate BBB in good concentration

cannot treat brain tumor,But this does not mean it will Not cause
neurotoxicity because some concentration can pass ]

Folic Acid Inhibitors:

Methotrexate
Mechanisms: inhibits folate synthesis through inhibition of dihydrofolate reductase
step in the formation of purine & nucleiac acids DNA or RNA.
pyramidine , as trimethoprim]

[Inhibits purine &

 Resistance of methotrexate:

Decreased drug transport into the cell. [cell wall permeability]

Decreased reductase enzyme.
Route of administration of methotrexate:

IV, intrathecal, oral. (intrathecal route used for brain tumor)

Does not penetrate BBB
Excreted mainly through kidney & less extent in feces.
Adverse effects of methotrexate:

12-

Common triad (VND, BM depression, alopecia)

Renal damage
Hepatic fibrosis or cirrhosis.
Neurologic (mainly with intrathecal route) [e.g headache, peripheral neuropathy,changes in mental concentration, seizures]
Pulmonary(cough, dysnea,cyanosis)
Headache, fever, seizures.
Contraindicated in pregnancy. [All the cytotoxic drugs. Not prove to be safe.]
The hematological toxic effect of methotrexate can be reversed by leucovorin. [only hematological effect, does
not prevent pulmonary or neurologic side effects

3. Plant alkaloids

Vinca alkaloids:
Vinblastine & Vincristine:

Mechanism of action:

Inhibition of tubulin polymeraization mitotic arrest leading to cell death. [Stop at metaphaselysis&death

Pharmacokinatics of Vinblastin & Vincristine:

IV concentrated & metabolized in liver by CytP450.
Excreted in bile / feces.
Toxicity :
Phlebitis or cellulitis.
(Wrong in technique)
Vinblastine more potent as myleosupressant.
Vincristine neurotoxicity (mainly peripheral neuropathy
Constipation.
Clinical uses of Vinblastine & Vincristine:
Several pediatric tumors.
Hematological malignancies such as Hodgkin & non Hodgkin lymphoma & multiple myeloma.

Podophyllotoxins:
Etoposide(VP-16), Teniposide(VM-26)

Semi-synthetic derivatives of podophyllotoxin extracted from the root of the mayapple.

Mechanism of action of VP-16:

Block cell division in the late S-G2 phase of cell cycle.
Inhibits topoisomerase 2 causing DNA damage
Pharmacokinatics of VP-16:
Given IV. Infusion, 90-95% bound to plasma protein.
Uses of VP-16:
1- In combination with bleomycin & cisplastin for testicular carcinoma.
2- Small cell & non-small lung cancer.
3- Hodgkin &NHL
4- gastric cancer
5- Breast cancer
Toxicity:
Hematopoietic and lymphoid toxicity

Camptothecins:
Topotecan, Irinotecan
Irinotecan-a prodrug that is metabolized to an active Top. I
inhibitor, SN-38
Mechanism of Action:
Interfere with the activity of Topoisomerase I
Resulting in DNA damage
Toxicity:
Topotecan: Neutropenia, thrombocytopenia,
anemia
Irinotecan: Severe diarrhea, myelosuppression
Therapeutic Uses:
Topotecan- metastatic ovarian cancer (cisplatin-resistant)
Irinotecan- colon and rectal cancer

Taxanes:
Paclitaxel (Taxol), Docetaxel

Alkaloid esters derived from the Western and European Yew

Mechanism of action of Paclitaxel:
Mitotic spindle poison.
Bind to microtubules stabilizing them in polymerized state causing inhibition of mitosis & cell division.
It resembles the plant alkaloids BUT it differs in that it allows polymerization then stabilizes it.]
Uses of Paclitaxel:
Advanced ovarian & metastatic breast cancer
Non-small cell &small cell lung cancer.
Pharmacokinetics of Paclitaxel:

Given IV
metabolized by hepatic CytP450
Excreted in feces.
Adverse effects of Paclitaxel:
The common triad
BM depression ( neutropenia)
Hypersensitivity reactions, 5% of patients characteristic]
Neurotoxicity
Edema in the legs

4. Antibiotics

Anthracyclines- Doxorubicin & Daunorubicin

Dactinomycin
Plicamycin
Mitomycin
Bleomycin

Anthracyclines:
Doxorubicin, Daunorubicin

Has a broad spectrum of clinical activity against hematological as

well as solid tumor. [Breast, lung, esophagus]
Mechanism of action of Doxorubicin:
1- inhibition of topoisomerase 2
2- high affinity binding to DNA causing blockade
of the synthesis of DNA
3- generation of free radicals (causing
cardiotoxicity)
4- Binding to celluar membrane to alter
permeability & ion transport.
Pharmacokinetics of Doxorubicin:
Given IVI (inactivated by GIT)
Metabolized in liver giving an active & inactive metabolite.
Do not penetrate BBB or testis.
Up to 50% is eliminated in the feces via biliary excretion.
Causes red color to the urine.
[As rifampicin]
Adverse effects of Doxorubicin:
Dose related cardiac damage leading to arrhythmias & heart failure.
Skin pigmentation

Dactinomycin:
Mechanism of action of Doxorubicin:
Binds to double stranded DNA through intercalation between adjacent guanine-cytosine base pairs
Inhibits all forms of DNA-dependent RNA synthesis
Uses:
Mainly used to treat Pediatric tumors eg. Willms tumor, soft tissue sarcoma & Ewings sarcoma.

Plicamycin:
Mechanism of action of Doxorubicin:
Liberates oxygen free radicals resulting in breaking of DNA strands & chromosomal aberrations.
Pharmacokinatics of bleomyicn:
SC, IM,IV
Most of the drug is excreted unchanged in urine.
Uses of bleomyicn:
Hodgkin & NHL.
Testicular tumors
Carcinoma
Toxicity of bleomyicn:
The common triad.
Pulmonary toxicity (pnumonaitis,cough,dysnea,fibrosis)
[we use Mensa]
Skin toxicity (hypertrophic skin changes& hyper pigmentation of the hands)

Mitomycin:
Mechanism of action of Doxorubicin:
Bioreductive alkylating agent that undergoes metabolic reductive activation through an enzyme-mediated
reduction to generate an alkylating agent that cross-links DNA
Uses of Mitomyicn:

Squamous cell carcinoma of the cervix

Adenocarcinomas of the stomach, pancreas, and lung
2 line in metastatic colon cancer
nd

Toxicity of Mitomyicn:

Severe myelosuppression
Renal toxicity
Interstitial pneumonitis

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.

Testicular cancer.
Squamous cell carcinomas of the head and neck, cervix, skin, penis, and rectum.
Lymphomas.
Intracavitary therapy in ovarian and breast cancers

Bleomycin:
Mechanism of action:

Uses of Bleomyicn:

Toxicity of Bleomyicn:

Lethal anaphylactoid reactions.

Blistering.
Pulmonary fibrosis

5. Hormonal Agents

Steroid hormones & Their antagonist

Hormone sensitive tumor
May be
1- Hormone responsive
2-hormone dependent [eg.breast ca depend on estrogen for growth, so we prevent the
hormone]
3-both in which treatment is only palliative

1-prednisone:
Potent, synthetic, anti-inflammatory corticosteroid.
Given orally
Activated in liver by 11- hydroxysteroid dehydrogenase to prednisolone.
Excretion is through urine
Mechanism of action:
Steroid hormones form an intracellular steroid receptor complex that binds directly to
chromatin, activating the transcription of specific genes causing production of specific
proteins that effect the cellular growth & proliferation of tumor cells.
Therapeutic uses:
Lymphoma & other hematological tumors.
Adverse effects:
Infections
Ulcers
Pancreatitis
Hyperglycemia
Osteoporosis
Change in mood

Estrogen & androgen inhibitors

Tamoxifen (SERMs), Raloxifene (SERMs) and FaslodexEstrogen stimulates the
growth of breast & endometrial cancer.
In prostate cancer, androgen stimulates growth but estrogen suppress.

Tamoxifen: anti-estrogen
Used for the treatment of both early stage & metastatic breast cancer.
Also, as chemopreventive agent in women at high risk for breast cancer.
Binds to estrogen receptors of estrogen sensitive tumors. [Occupy the receptor,
no place for the hormone to bind]
Pharmacokinetics:
Given orally
Half live is long 7-14 days
Metabolized in liver giving active metabolite
Excreted through bile

Side effects:

Menopausal symptoms
Fluid retention, edema.
Increase incidence of endometrial hyperplasia &cancer. Follow up is Very important

Flutamide :( anti-androgens)
Binds to androgen receptor that inhibits androgen effects.
In combination with radiation for treatment of early stage prostate cancer& metastatic prostate cancer.
Given orally.
Given IM once every 3 months transient release of FSH, LH, followed by inhibition of the release of
testosterone.

Side effects of anti-androgens:

Hot flushes, impotence, gynecomastia, GI upset.
Flutamide can cause liver failure.

Gonadotropins-Releasing Hormone Agonists:

Ex: Leuprolide & Goserelin
Mechanism of action:
Agents act as GnRH agonist, with paradoxic effects on the pituitary
Initially stimulating the release of FSH and LH, followed by inhibition of the release of these hormones
Resulting in reduced testicular androgen synthesis
Therapeutic uses:
Metastatic carcinoma of the prostate.
Hormone receptor-positive breast cancer.
Toxicity:
Gynecomastia.
Edema.
Thromboembolism

Aromatase Inhibitors
Aminogluthethimide
Mechanism of action:
Inhibitor of adrenal steroid synthesis at the first step, conversion of cholesterolof pregnenolone.
Inhibits the extra-adrenal synthesis of estrone and estradiol.
Inhibits the enzyme aromatase that converts androstenedione to estrone
Therapeutic uses:
ER-and PR-positive metastatic breast cancer.
Toxicity:
Dizziness.
Lethargy.
Visual blurring.
Rash

Anastrozole

A new selective no steroidal inhibitor of aromatase

Treats advanced estrogen and progesterone receptor positive breast cancer that is no longer responsive to tamoxifen.

6. Miscellaneous Anticancer Agents

Asparaginase:
An enzyme isolated from various bacteria.
Mechanism of action:
Hydrolyzes L-aspargine to aspartic acid & ammonia.
Effective inhibitor of protein synthesis.
Tumor cells lack aspargine synthetase, so they require an exogenous source of L-aspargine.
In contrast, normal cells can synthesize L-aspargine, so they are less susceptible to cytotoxic action of asparaginase.
Therapeutic uses:
Childhood acute lymphocytic leukemia.
Side effects:
Hypersensitivity reactions.
Alternation in clotting factor [increase or decrease]risk for bleeding or clotting.
Pancreatitis.
Neurologic toxicity.
Coma(ammonia)

Hydroxyurea

An analog of urea.
Inhibits the enzyme ribonucleotide reductase.
Resulting in the depletion of deoxynucleoside triphosphate pools.
Thereby inhibiting DNA synthesis.
S-phase specific agent.
Treats melanoma and chronic myelogenous leukemia

Mitoxantrone

Structure resembles the anthracyclines

Binds to DNA to produce strand breakage
Inhibits DNA and RNA synthesis
Treats pediatric and adult acute myelogenous leukemia, non-Hodgkins lymphomas, and breast cancer
Causes cardiac toxicity

7. Monoclonal antibody therapy

One possible treatment for cancer involves monoclonal antibodies that bind only to cancer cell-specific antigens and induce
an immunological response against the target cancer cell. Such mAb could also be modified for delivery of a toxin,
radioisotope, cytokine or other active conjugate; it is also possible to design bispecific antibodies that can bind with their Fab
regions both to target antigen and to a conjugate or effector cell. In fact, every intact antibody can bind to cell receptors or
other proteins with its Fc region.
MAbs approved by the FDA include
Bevacizumab
Cetuximab
Panitumumab
Trastuzumab

Anticancer Drugs Summary

Anticancer/Antineoplastic
Drugs

Uses of Anticancer Drugs

I. ALKYLATING DRUGS
A. Nitrogen Mustards
Chlorambucil (Leukeran)

Cancer of the breast, ovaries, testicles, malignant lymphomas,

lymphocytic leukemia, multiple myeloma.

Cyclophosphamide (Cytoxan)

Hodgkin's disease, lymphocytic leukemia, cancer of the breast, ovaries,

bladder, cervix, endometrium, prostate, lung, head, sarcomas, Wilm's
tumor, and many others.

Estramustine (Emcyt)

Progressive carcinoma of the prostate

Ifosfamide (Iflex)

Testicular cancer, lymphomas, lung cancer, and sarcomas.

Mechlorethamine HCl

Hodgkin's disease, solid tumors, lymphosarcoma, pleural effusion from

cancer of the lung, bronchogenic cancer and brain tumors.

Melphalan (Alkeran)

Multiple myeloma, melanoma, cancer of the breast, ovaries, testes and

thyroid.

temozolomide (Temodal)

Brain tumor

Uracil mustard

Chronic lymphocytic and myelocytic leukemis, non- Hodgkin's disease,

cancer of the cervix, ovaries, and lung.

B. Nitrosoureas
Carmustine (BiCNU)

Hodglin's disease, multiple myeloma, melanoma, brain tumors, cancers

of the colon, rectum, stomach, and liver.

Lomustine (CeeNu)

Advanced Hodgkin's disease, brain tumors, multiple myelomas,

melanoma, cancers of the lung, breast, colon, rectum, and kidney.

Streptozocin (Zanosar)

Pancreatic islet cell tumor, cancer of the lung, Hodgkin's disease,

carcinoid tumors.

C. Alkylating-like Drugs
Altretamine (Hexalen)

Primarily for ovarian cancer. Also cancer of the breast, cervix, colon,
endometrium, head/neck, and lung, lymphomas.

Carboplatin (Paraplatin)

Cancer of the ovaries, testes, head/neck and lung.

Cisplatin (Platinol)

Cancer of the ovaries, testes, bladder, head/neck, breast, endometrium,

cervix, uterus, brain, lung, esophagus, prostate, and stomach,
melanoma.

Decarbazine (DTIC)

Hodgkin's disease, metastatic melanoma, sarcomas, neuroblastoma, islet

cell carcinoma.

Pipobroman (Vercyte)

Chronic myelocytic leukemia.

Thiotepa
(triethylenethiophosphoramide)

Cancer of the breast, ovary, bladder, lung, Hodgkin's disease,

lymphomas.

D. Alkyl Sulfonates

Busulfan (Myleran)

Myelocytic leukemia, acute nonlymphocytic leukemia.

Anticancer/Antineoplastic
Drugs
II. ANTIMETABOLITES
A. Folic Acid Antagonist
Methotrexate (MTX),
Amethopterin

Uses of Anticancer Drugs

Solid tumors, sarcomas, choriocarcinoma, leukemia,

lymphomas, non-Hodkgin's lymphoma, cancer of the breast,
head/neck, lung, bladder, kidney, brain, esophagus, cervix,
ovaries, prostate, testes, and stomach.

B. Pyrimidine Analogues
Capecitabine (Xeloda)
Cytarabine HCl (Cytosar-U,
ARA-C)
Floxuridine (FUDR)
5-Fluorouracil (5-FU,
Adrucil)
Gemcitabine HCl (Gemzar)
Procarbazine HCl (Matulane)

Advanced metastatic breast cancer.

Acute leukemias and lymphomas, and non-Hodgkin's
lymphoma.
Metastatic colon cancer and hepatoma.
Cancer of the breast, bladder, ovaries, cervix, endometrium,
prostate, head/neck, esophagus, stomach, colon, recturm,
pancreas, lung.
Advanced or metastatic adenocarcinoma of the pancreas.
Advanced Hodgkin's disease, metastatic brain cancer, smallcell lung cancer.

C. Purine Analogues
Cladribine (Leustatin)

Hairy cell leukemia, chronic lymphocytic leukemia, acute

myelocytic leukemia.
Fludarabine (Fludara)
Chronic lymphocytic leukemia, non-Hodgkin's disease.
6-Mercaptopurine
Acute lymphatic leukemia, chronic myelocytic leukemia, non(Purinethol)
Hodgkin's lymphoma.
Thioguanine
Acute and chronic myelogenous leukemia.
D. Ribonucleotide Reductase Inhibitor
Hydroxyurea (Hydrea)
Melanoma, resistant chronic myelocytic leukemia, ovarian
cancer, head/neck cancer.
Trimetrexate glucuronate
Cancer of the colon and rectum, Pneumocystis carinii
(NeuTrexin)
pneumoniaAIDS.
E. Enzyme Inhibitor
Pentostatin (Nipent)
Hairy cell leukemia
Anticancer/Antineoplastic
Drugs

Uses of Anticancer Drugs

III. MITOTIC INHIBITORS

A. Vinca Alkaloids
Vinbastine sulfate (Velban)

Cancer of the breast, testes, and kidney, Hodgkin's disease,

lymphosarcoma, neuroblastoma, choriocarcinomas.

Vincristine sulfate (Oncovin)

Cancer of the breast, lungs, and cervix, multiple myelomas, sarcomas,

Wilms' tumor, Burkitt's lymphoma, Hodgkin's disease, neuroblastoma.

Vinorelbine (Navelbine)

Advanced non-small cell lung cancer.

B. Antimicrotubule or Taxanes
Docetaxel (Taxotere)

Advanced or metastatic breast cancer.

Paclitaxel (Taxol)

Metastatic ovarian and breast cancer, advanced non-small cell cancer,

cancer of the head/neck.

C. Topoisomerase I Inhibitors
Irinotecan HCl (Camptosar)

Metastatic cancer of the colon and rectum, breast cancer, small-cell lung
cancer, leukemia.

Topotecan HCl (Hycamtin)

Metastatic cancer of the ovaries, cancer of the head/ neck, colon, rectum,
malignant glioma.

D. Topoisomerase II Derivatives
Etoposide (VePesid)

Testicular cancer, small-cell lung cancer, Hodgkin's and non-Hodgkin's

lymphomas, acute myelogenous leukemia, Kaposi's sarcoma.

Teniposide (Vumon, VM26)

Acute lymphoblastic leukemia (ALL) in children.

Anticancer/Antineoplastic
Drugs

Uses of Anticancer Drugs

IV. ANTITUMOR ANTIBIOTICS

Bleomycin sulfate (Benoxane)

Testicular cancer, cancer of the skin, cervix, penis, squamous cellcarcinoma of the head/neck, Hodgkin's disease.

Dactinomycin (Actinomycin D,
Cosmegen)

Testicular cancer, Wilms' tumor, choriocarcinoma, rhabdomyosarcoma,

Kaposi sarcoma.

Daunorubicin (Actinomycin)

Acute lymphocytic leukemia, Ewing's sarcoma, Wilms' tumor,

neuroblastoma, and non-Hodgkin's lymphoma.

Doxorubicin (Adriamycin)

Cancers of the breast, ovary, endometrium, testes, prostate, lung, GU

tract, and stomach, leukemias, lymphomas, osteogenic sarcoma, Wilms'
tumor, neuroblastomas, Ewing's sarcoma.

Epirubicin (Ellence)

Node-positive breast cancer, in adjuvant with anticancer therapy.

Acute monocytic leukemia, solid tumors.

Idarubicin (Idamycin)
Mitomycin (Mutamycin)

Disseminated adenocarcinoma of the breast, stomach, and pancreas.

Also cancer of the head/ neck, cervix and lung.

Mitoxantrone (Novantrone)

Acute nonlymphocytic leukemia, may be used for breast cancer.

Plicamycin (Mithracin)

Hypercalcemia due to cancer metastasis, testicular tumor.

Valrubicin (Valstar)

Bladder cancer

Anticancer/Antineoplastic
Uses of Anticancer Drugs
Drugs
V. HORMONES, HORMONAL ANTAGONISTS, AND ENZYMES
A. Androgens
Testolactone (Teslac)
Breast carcinoma in postmenopausal women.
Progesterone (Gesterol 50)
Palliative treatment for endometrial and breast cancer.
B. Hormonal Antagonists and Enzymes
Aminoglutethimide (Cytadren)
Bicalutamide (Casodex)
Exemestane (Aromasin)

Adrenal carcinoma, ACTH-producing tumors, may be used

for breast cancer.
Advanced metastatic prostate carcinoma.
Advanced breast cancer.

Flutamide (Eulexin)
Goserelin acetate (Zoladex)
Letrozole (Femara)
Megestrol acetate
Mitotane (Lysodren)
Nilutamide (Nilandron)
Polyestradiol phosphate
(Estrdurin)
Tamoxifen citrate (Nolvadex)
Toremifene (Fareston)
C. Enzymes
L-Asparaginase (Elspar)
Pegaspargase (Oncaspar)
Anticancer/Antineoplastic Drugs

Metastatic prostatic carcinoma.

Metastatic prostatic carcinoma, may be used in breast cancer.
Advanced breast cancer in postmenopausal women.
Advanced carcinoma of the breast and endometrium
Inoperable adrenal cortical carcinoma.
Prostatic carcinoma
Palliative treatment for inoperable prostatic carcinoma.
Palliative treatment for advanced breast cancer with positive
lymph nodes in postmenopausal women.
Advanced breast cancer in postmenopausal women.
Acute lymphocytic leukemia especially in children.
Acute lymphocytic leukemia (ALL).
Uses of Anticancer Drugs

VI. MISCELLANEOUS
Anastrozole (Arimidex)

Advanced breast cancer.

Bexarotene (Targretin)

Early or advanced-stage refractory cutaneous T-cell lymphoma.

Transtuzumab (Herceptin)

Metastatic breast cancer.

Dr.Yasser
First FPGEE Online Lecturer
Unique Egyptian Syndicate Lecturer for all Foreign Pharmacy Boards
www.dryayooo.myfreeforum.org
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yasserallaa@yahoo.com
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