Assignment On

Anticancer

Antimetabolites

antifungal

Course Title: pharmacology II,

Course Code: BPH-3013

Submitted To:

Dr.Md. Siddiqul islam

Associate professor

Department of Pharmacy

Southeast university

Submitted By:

Nargish sultana mimi

ID:2018100300002
 Anticancer

Cancer  An abnormal growth of cells which tend to proliferate in an uncontrolled way and, in
some cases, to metastasize. Cancer cells can spread to other parts of the body through the blood
and lymph systems, this process is called metastasis.

Cancer  is not one disease. It is a group of more than 100 different and distinctive diseases.

Cancer can involve any tissue of the body and have many different forms in each body area.
Most cancers are named for the type of cell or organ in which they start. If a cancer spreads
(metastasizes), the new tumor bears the same name as the original (primary) tumor.

Categorized based on the functions/locations of the cells from which they originate:

Carcinoma - skin or in tissues that line or cover internal organs. E.g., Epithelial cells. 80-90%
reported cancer cases are carcinomas.

Sarcoma - bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue.

Leukemia - White blood cells and their precursor cells such as the bone marrow cells, causes
large numbers of abnormal blood cells to be produced and enter the blood.

Lymphoma - cells of the immune system that affects lymphatic system.

Myeloma - B-cells that produce antibodies- spreads through lymphatic

System.Central nervous system cancers - cancers that begin in the tissues of the brain and
spinal cord.
 Cancer Therapeutic Modalities (classical)

1. Surgery
Surgery is often the first line of choice for solid tumors, whenever possible.  Surgery may/may
not be combined with other modalities. The size, type, location of tumor and factors such as age,
comorbid conditions of a patient are key determinant factors in choosing surgery.

surgery may also be used to relieve symptoms of pain or alleviate symptoms caused due to
obstruction to an adjacent organ, duct or vital structures from tumor and improve the quality of
life (Palliative Surgery). In the case of some cancers such as head and neck cancer or breast
cancer, reconstructive surgery may also be performed after tumor resection surgery.

2.Radiation
High energy waves such as x-rays, gamma rays or electron beams may be used to destroy or
shrink tumor cells. You may be offered radiation therapy prior to or following surgery or
chemotherapy.  It can also be used for palliation to relieve symptoms of pain caused by tumor
lesions that are inoperable.  

In order to minimize side effects and be effective, you will receive radiation therapy in small
doses called fractions, spread across weeks. As radiation does not bifurcate between the normal
and malignant cells, you may experience side effects depending on the area of irradiation.

3.Chemotherapy
Also referred to as “Chemo”, uses drugs that destroy or kill cancerous cells. A wide variety of
chemotherapeutic drugs are available and may be delivered by various modes (Intravenous,
intramuscular,  intrathecal, intraperitoneal, etc) depending on individual cancer cases. You may
receive chemotherapy in combination with surgery and radiation.

50% patients will undergo chemotherapy,to remove micrometastasis. However,chemotherapy is

able to cure only about 10-15% of all cancer patients.
 New types of cancer treatment

Hormonal Treatments:

These drugs are designed to prevent cancer cell growth by preventing the cells from receiving
signals necessary for their continued growth and division. Hormone therapy may be used to
reduce or prevent symptoms in men with prostate cancer who are not able to
have surgery or radiation therapy.

Targeted Therapy
Targeted therapy is a type of cancer treatment that targets the changes in cancer cells that help
them grow, divide, and spread. Learn how targeted therapy works against cancer and about
common side effects that may occur

Stem Cell Transplant

Stem cell transplants are procedures that restore blood-forming stem cells in cancer patients who
have had theirs destroyed by very high doses of chemotherapy or radiation therapy. Learn about
the types of transplants, side effects that may occur, and how stem cell transplants are used in
cancer treatment

Vaccines: Stimulate the body's defenses against cancer. Vaccines usually contain proteins found
on or produced by cancer cells. By administering these proteins,the treatment aims to increase
the response of the body against the cancer cells.

Antibodies: The antibodies used in the treatment of cancer have been manufactured for use as
drugs. E.g., Herceptin,
 Cancer Chemotherapy

Chemotherapy was first developed at the beginning of the 20th century, although it was not
originally intended as a cancer treatment.

During World War II, it was discovered that people exposed to nitrogen mustard developed
significantly reduced white blood cell counts. This finding led researchers to investigate whether
mustard agents could be used to halt the growth of rapidly dividing cells such as cancer cells

Most of the recent progress using antineoplastic therapy is based on:

1.Development of new combination therapy of using existing drugs.

2. Better understanding of the mechanisms of antitumor activity.

3. Development of chemotherpeutic approaches to destroying micrometastases

4. Understanding the molecular mechanisms concerning the initiation of

5. tumor growth and metastasis.

6. Recognition of the heterogeneity of tumors

Malignancies which respond favorably to chemotherapy:

A.choriocarcinoma,

B.Acute leukemia,

C.Hodgkin's disease,

D.Burkitt's lymphoma,

E.Wilms' tumor,

F.Testicular carcinoma,

G.Ewing's sarcoma,

H.Retinoblastoma in children,

I.Diffuse histiocytic lymphoma and

J.Rhabdomyosarcoma.

D. Antineoplastic drugs are most effective against rapidly dividing tumor cells.

E. The Main Goal of Antineoplastic Agents

IS to eliminate the cancer cells without affecting normal tissues (the concept of differential
sensitivity). In reality, all cytotoxic drugs affect normal tissues as well as malignancies - aim for
a favorable therapeutic index (aka therapeutic ratio).

A therapeutic index is the lethal dose of a drug for 50% of the population (LD50) divided by the
minimum effective dose for 50% of the population (ED50).
The effects of tumor burden, scheduling, dosing, and initiation/duration of treatment on
patient survival.

General rules of chemotherapy

 Aggressive high-dose chemotherapy

 Dose- limiting is toxicity towards normal cells

 Cyclic regimens - repeated administrations with appropriate intervals for regeneration of

normal cells (e.g., bone marrow cells)

 Supportive therapy - to reduce toxicity

Hematotoxicity – bone marrow transplantation, hematopoietic growth factors

Specific antagonists: antifolate (methotrexate) – folate (leucovorin)

MESNA - donor of –SH groups, decreased urotoxicity of cyclophosphamide. Detoxifying agent.

dexrazoxane: chelates iron, reduced anthracycline cardiotoxicity

amifostine: reduces hematotoxicity, ototoxicity and neurotoxicity of alkylating agents

Combination of several drugs with different mechanisms of action, different resistance

mechanisms, different dose-limiting toxicities.

Adjuvant therapy: Additional cancer treatment given after the primary treatment to lower the
risk that the cancer will come back. Adjuvant therapy may include chemotherapy, radiation
therapy, hormone therapy, targeted therapy, or biological therapy.

Neoadjuvant therapy: Treatment given as a first step to shrink a tumor before the main
treatment, which is usually surgery, is given. Examples of neoadjuvant therapy include
chemotherapy, radiation therapy, and hormone therapy. It is a type of induction therapy.

Supportive therapy:

-Antiemetics (5-HT3 -antagonists)

-Antibiotic prophylaxis and therapy (febrile neutropenia)

-Prophylaxis of urate nephropathy (allopurinol)

-Enteral and parenteral nutrition

-Pain – analgesic drugs

-Psychological support
 Antimetabolites

Antimetabolites are drugs that interfere with one or more enzymes or their reactions that are
necessary for DNA synthesis. Antimetabolites are a form of chemotherapy drug. They're one of
the most commonly used therapies to treat cancer.

Antimetabolites are called a “cytotoxic” type of drug because they kill cells. They work by
mimicking the molecules that a cell needs to grow. Cells are tricked into taking in the drugs and then
using the antimetabolites instead of their normal building blocks of genetic material: RNA and DNA.
With the drugs on board, the cells can no longer copy their DNA, so they can’t divide into new cells.
Because antimetabolites target cells only as they are dividing, these medications are most effective
against tumors that are growing quickly.
 Methotrexate
Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-
system suppressant.It is used to treat cancer, autoimmune diseases, ectopic pregnancy, and for
medical abortions.Types of cancers it is used for include breast cancer, leukemia, lung
cancer, lymphoma, gestational trophoblastic disease, and osteosarcoma.Types of autoimmune
diseases it is used for include psoriasis, rheumatoid arthritis, and Crohn's disease.

Clinical application

Choriocarcinoma,

Acute lymphoblastic leukemia(children),

osteogenic

Sarcoma.

 Burkitt's and other

non-Hodgkin‘s

lymphomas, cancer

of breast, ovary, bladder, head & neck

The Mechanism of Action of the Folate Antagonists 

Methotrexate is an antimetabolite of the antifolate type. It is thought to affect cancer and

rheumatoid arthritis by two different pathways. For cancer, methotrexate competitively
inhibits dihydrofolate reductase (DHFR), an enzyme that participates in
the tetrahydrofolate synthesis.The affinity of methotrexate for DHFR is about 1000-fold that of
folate. DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate. Folic acid
is needed for the de novo synthesis of the nucleoside thymidine, required for DNA
synthesis.Also, folate is essential for purine and pyrimidine base biosynthesis, so synthesis will
be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates,
and proteins
 Route of administration

It can be given by mouth or by injection.

Side effects
 dizziness.
 drowsiness.
 headache.
 swollen, tender gums.
 decreased appetite.
 reddened eyes.
 hair loss.

Drug interaction

Penicillins may decrease the elimination of methotrexate, so increase the risk of toxicity While

they may be used together, increased monitoring is
recommended. The aminoglycosides, neomycin and paromomycin, have been found to reduce
gastrointestinal (GI) absorption of methotrexate.Probenecid inhibits methotrexate excretion,
which increases the risk of methotrexate toxicityLikewise, retinoids and trimethoprim have been
known to interact with methotrexate to produce additive hepatotoxicity and haematotoxicity,
respectively.Other immunosuppressants like cyclosporins may potentiate methotrexate's
haematologic effects, hence potentially leading to toxicity
 Pyrimidine Analogs:Cytosine Arabinoside

The Mechanism of Action

pyrimidine antagonists belong to the group of antimetabolite anticancer drugs and show

structural resemblance with naturally occurring nucleotides . Their action is accomplished
through incorporation as false precursor in DNA or RNA or through inhibition of proteins
involved in nucleotide metabolism

Clinical application

most effective agent for induction of remission in acute myelocytic leukemia; also used for
induction of remission acute lymphoblastic leukemia,non-Hodgkin's lymphomas; usually used in
combination chemotherapy
Route of administration

It can be given by mouth. Orally effective

Side effects

bone marrow depression,anorexia,nausea,vomiting.

Purine analogs:6-Mercaptopurine(6-MP) and Thioguanine

the purine antagonists function by inhibiting DNA synthesis in two different ways:
1.They can inhibit the production of the purine containing nucleotides, adenine and guanine. If a
cell doesn't have sufficient amounts of purines, DNA synthesis is halted and the cell cannot
divide.
2.They may be incorporated into the DNA molecule during DNA synthesis. The presence of the
inhibitor is thought to interfere with further cell division
Clinical application

most effective agent for induction of remission in acute myelocytic leukemia; also used for
induction of remission acute lymphoblastic leukemia,non-Hodgkin's lymphomas; usually used in
combination chemotherapy
Route of administration

It can be given by mouth. Orally effective

Side effects

bone marrow depression,anorexia,nausea,vomiting.

Antifungal
An antifungal medication, also known as an antimycotic medication, is a pharmaceutical
fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm,
candidiasis (thrush), serious systemic infections such as cryptococcal meningitis, and others.

Mycosis

A disease caused by infection with a fungus, such as ringworm or thrush.

Major Types of Mycoses

 superficial

 cutaneous

 subcutaneous

 systemic

 Opportunistic

 Symptoms vary from cosmetic to life threatening

Antifungal Agents
 Polyene antibiotic

 Imidazole and triazole

 Allylamines

 Echinocandin

 Flucytosine is an antimetabolite.

 Griseofulvin binds to polymerized microtubules and inhibits fungal mitosis; It is derived

from the mold Penicillium griseofulvum.

 Fluocinonide

 Salicylic Acid (topical)

 Tinactin or Tolnaftate

 Potassium Iodide

Polyene antibiotic

The polyene antibiotics bind with sterols in the fungal cell membrane, principally ergosterol.
This causes the cell's contents to leak out and the cell dies. Animal cells contain cholesterol
instead of ergosterol and so they are much less susceptible.

 Nystatin

 Amphotericin B (may be administered liposomally)

 Natamycin

 Rimocidin

 Filipin

 Pimaricin

Nystatin
History

Like many other antifungals and antibiotics, nystatin is of bacterial origin. It was isolated
from Streptomyces noursei in 1950 by Elizabeth Lee Hazen and Rachel Fuller Brown, who were
doing research for the Division of Laboratories and Research of the New York State Department
of Health. Hazen found a promising micro-organism in the soil of a friend's dairy farm. She
named it Streptomyces noursei, after Jessie Nourse, the wife of the farm's owner.Hazen and
Brown named nystatin after the New York State Health Department in 1954.

The two scientists donated the royalties from their invention, over $13million dollars, to the
nonprofit Research Corporation for theadvancement of academic scientific study. Elizabeth Lee
Hazen and Rachel Fuller Brown were inducted into the National Inventors Hall of Fame in 1994.

MEDICAL USE

Nystatin, sold under the brandname Mycostatin among others, is an antifungal medication. It is

used to treat Candidainfections of the skin including diaper rash, thrush, esophageal candidiasis,
and vaginal yeast infections.It may also be used to prevent candidiasis in those who are at high
risk. Nystatin may be used by mouth, in the vagina, or applied to the skin.

side effects
Common side effects when applied to the skin include burning, itching, and a rash.[1] Common
side effects when taken by mouth include vomiting and diarrhea.

Imidazole and triazole

The imidazole and triazole groups of antifungal drugs inhibit the enzyme cytochrome P450 14α-
demethylase. This enzyme converts lanosterol to ergosterol, and is required in fungal cell
membrane synthesis. These drugs also block steroid synthesis in humans.
Imidazoles:

 Miconazole Bifonazole

 Ketoconazole Butoconazole

 Clotrimazole Econazole

 Mebendazole Fenticonazole

 Isoconazole Oxiconazole

 Sertaconazole Sulconazole

 Thiabendazole Tiaconazole

The triazoles are newer, and are less toxic and more effective:

 Fluconazole

 Itraconazole

 Ravuconazole

 Posaconazole

 Voriconazole
 Allylamines

Allylamines inhibit the enzyme squalene epoxidase, another enzyme required for

ergosterol synthesis:

 Terbinafine - marketed as Lamisil

 Amorolfine

 Naftifine

 Butenafine

Echinocandin

Echinocandins inhibit the synthesis of glucan in the cell wall, probably via the enzyme 1,3-β

glucan synthase:

 Anidulafungin

 Caspofungin

 Micafungin