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منتديات طلاب وطالبات جامعة الملك عبد العزيز منتديات طلاب وطالبات جامعة الملك عبد العزيز
قديم 10-08-2011, 12:23 AM   #16

سلطان حكمي

جامعي

 
تاريخ التسجيل: Feb 2011
كلية: كلية الاقتصاد والادارة
نوع الدراسة: إنتظام
المستوى: متخرج
البلد: جــــدة
الجنس: ذكر
المشاركات: 2,572
Skaau.com (4) Anti-Cancer Drugs

Anti-Cancer Drugs
Introduction
The available anticancer drugs have distinct mechanisms of action which may vary in their effects on different types of normal and cancer cells. A single "cure" for cancer has proved elusive since there is not a single type of cancer but as many as 100 different types of cancer. In addition, there are very few demonstrable biochemical differences between cancerous cells and normal cells. For this reason the effectiveness of many anticancer drugs is limited by their toxicity to normal rapidly growing cells in the intestinal and bone marrow areas. A final problem is that cancerous cells which are initially suppressed by a specific drug may develop a resistance to that drug. For this reason cancer chemotherapy may consist of using several drugs in combination for varying lengths of time.
Cancer Chemotherapy:
Chemotherapy drugs, are sometimes feared because of a patient's concern about toxic effects. Their role is to slow and hopefully halt the growth and spread of a cancer. There are three goals associated with the use of the most commonly-used anticancer agents.
1. Damage the DNA of the affected cancer cells.
2. Inhibit the synthesis of new DNA strands to stop the cell from replicating, because the replication of the cell is what allows the tumor to grow.
3. Stop mitosis or the actual splitting of the original cell into two new cells. Stopping mitosis stops cell division (replication) of the cancer and may ultimately halt the progression of the cancer.
Unfortunately, the majority of drugs currently on the market are not specific, which leads to the many common side effects associated with cancer chemotherapy. Because the common approach of all chemotherapy is to decrease the growth rate (cell division) of the cancer cells, the side effects are seen in bodily systems that naturally have a rapid turnover of cells iincluding skin, hair, gastrointestinal, and bone marrow. These healthy, normal cells, also end up damaged by the chemotherapy program.
Catagories of Chemotherapy Drugs:


In general, chemotherapy agents can be divided into three main categories based on their mechanism of action.
Stop the synthesis of pre DNA molecule building blocks:


These agents work in a number of different ways. DNA building blocks are folic acid, heterocyclic bases, and nucleotides, which are made naturally within cells. All of these agents work to block some step in the formation of nucleotides or deoxyribonucleotides (necessary for making DNA). When these steps are blocked, the nucleotides, which arethe building blocks of DNA and RNA, can not be synthesized. Thus the cells can not replicate because they can nnot make DNA without the nucleotides.
Examples of drugs in this class include 1) methotrexate (Abitrexate®),2) fluorouracil (Adrucil®), 3) hydroxyurea (Hydrea®), and 4) mercaptopurine (Purinethol®).
Directly damage the DNA in the nucleus of the cell:


These agents chemically damage DNA and RNA. They disrupt replication of the DNA and either totally halt replication or cause the manufacture of nonsense DNA or RNA (i.e. the new DNA or RNA does not code for anything useful).
Examples of drugs in this class include cisplatin (Platinol®) and 7) antibiotics - daunorubicin (Cerubidine®), doxorubicin (Adriamycin®), and etoposide (VePesid®).
Effect the synthesis or breakdown of the mitotic spindles:


Mitotic spindles serve as molecular railroads with "North and South Poles" in the cell when a cell starts to divide itself into two new cells. These spindles are very important because they help to split the newly copied DNA such that a copy goes to each of the two new cells during cell division. These drugs disrupt the formation of these spindles and therefore interrupt cell division.
Examples of drugs in this class of 8) miotic disrupters include: Vinblastine (Velban®), Vincristine (Oncovin®) and Pacitaxel (Taxol®).
1) Methotrexate:
Methotrexate inhibits folic acid reductase which is responsible for the conversion of folic acid to tetrahydrofolic acid. At two stages in the biosynthesis of purines (adenine and guanine) and at one stage in the synthesis of pyrimidines (thymine, cytosine, and uracil), one-carbon transfer reactions occur which require specific coenzymes synthesized in the cell from tetrahydrofolic acid.
Tetrahydrofolic acid itself is synthesized in the cell from folic acid with the help of an enzyme, folic acid reductase. Methotrexate looks a lot like folic acid to the enzyme, so it binds to it thinking that it is folic acid. In fact, methotrexate looks so good to the enzyme that it binds to it quite strongly and inhibits the enzyme. Thus, DNA synthesis cannot proceed because the coenzymes needed for one-carbon transfer reactions are not produced from tetrahydrofolic acid because there is no tetrahydrofolic acid. Again, without DNA, no cell division.

2) 5-Fluorouracil:
5-Fluorouracil (5-FU; Adrucil®, Fluorouracil, Efudex®, Fluoroplex®) is an effective pyrimidine antibolite. Fluorouracil is synthesized into the nucleotide, 5-fluoro-2-deoxyuridine. This product acts as an antibolite by inhibiting the synthesis of 2-deoxythymidine because the carbon - fluorine bond is extremely stable and prevents the addition of a methyl group in the 5-position. The failure to synthesize the thymidine nucleotide results in little or no production of DNA.
Two other similar drugs include: gemcitabine (Gemzar®) and arabinosylcytosine (araC). They all work through similar mechanisms.
3) Hydroxyurea:
Hydroxyurea blocks an enzyme which converts the cytosine nucleotide into the deoxy derivative. In addition, DNA synthesis is further inhibited because hydroxyurea blocks the incorporation of the thymidine nucleotide into the DNA strand
4) Mercaptopurine:
Mercaptopurine, a chemical analog of the purine adenine, inhibits the biosynthesis of adenine nucleotides by acting as an antibolite.
In the body, 6-MP is converted to the corresponding ribonucleotide. 6-MP ribonucleotide is a potent inhibitor of the conversion of a compound called inosinic acid to adenine Without adenine, DNA cannot be synthesized.
6-MP also works by being incorporated into nucleic acids as thioguanosine, rendering the resulting nucleic acids (DNA, RNA) unable to direct proper protein synthesis.
5) Thioguanine:
Thioguanine is an antibolite in the synthesis of guanine nucleotides.
6) Alkylating Agents:
Alkylating agents involve reactions with guanine in DNA. These drugs add methyl or other alkyl groups onto molecules where they do not belong. This in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA.
In the first mechanism an alkylating agent attaches alkyl groups to DNA bases. This alteration results in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases.
A second mechanism by which alkylating agents cause DNA damage is the formation of cross-bridges, bonds between atoms in the DNA. In this process, two bases are linked together by an alkylating agent that has two DNA binding sites. Cross-linking prevents DNA from being separated for synthesis or tranion.
The third mechanism of action of alkylating agents causes the mispairing of the nucleotides leading to mutations.
There are six groups of alkylating agents: nitrogen mustards; ethylenimes; alkylsulfonates; triazenes; piperazines; and nitrosureas.
Cyclosporamide is a classical example of the role of the host bolism in the activation of an alkylating agent and is one or the most widely used agents of this class. It was hoped that the cancer cells might posses enzymes capable of accomplishing the cleavage, thus resulting in the selective production of an activated nitrogen mustard in the malignant cells. Compare the top and bottom structures in the graphic on the left.
7) Antibiotics:
A number of antibiotics such as anthracyclines, dactinomycin, bleomycin, adriamycin, mithramycin, bind to DNA and inactivate it. Thus the synthesis of RNA is prevented.
General properties of these drugs include: interaction with DNA in a variety of different ways including intercalation (squeezing between the base pairs), DNA strand breakage and inhibition with the enzyme topoisomerase II. Most of these compounds have been isolated from natural sources and antibiotics. However, they lack the specificity of the antimicrobial antibiotics and thus produce significant toxicity.
The anthracyclines are among the most important antitumor drugs available. Doxorubicin is widely used for the treatment of several solid
tumors while daunorubicin and idarubicin are used exclusively for the treatment of leukemia.
These agents have a number of important effects including: intercalating (squeezing between the base pairs) with DNA affecting many functions of the DNA including DNA and RNA synthesis. Breakage of the DNA strand can also occur by inhibition of the enzyme topoisomerase II.
Dactinomycin (Actinomycin D):
At low concentrations dactinomycin inhibits DNA directed RNA synthesis and at higher concentrations DNA synthesis is also inhibited. All types of RNA are affected, but ribosomal RNA is more sensitive. Dactinomycin binds to double stranded DNA , permitting RNA chain initiation but blocking chain elongation. Binding to the DNA depends on the presence of guanine.

8) Mitotic Disrupters:
Plant alkaloids like vincristine prevent cell division, or mitosis. There are several phases of mitosis, one of which is the phase. During phase, the cell pulls duplicated DNA chromosomes to either side of the parent cell in structures called "spindles". These spindles ensure that each new cell gets a full set of DNA. Spindles are microtubular fibers formed with the help of the protein "tubulin". Vincristine binds to tubulin, thus preventing the formation of spindles and cell division
Side effects

Tamoxifen

The anticancer drug tamoxifen (Nolvadex) increases the risk of cancer of the uterus in some women. It also causes cataracts and other eye problems. Women taking this drug may have hot flashes, menstrual changes, genital itching, vaginal discharge, and weight gain. Men who take tamoxifen may lose interest in sex or become impotent. Health care providers should keep in close contact with patients to assess the individual risks associated with taking this powerful drug.
Other anticancer drugs

These side effects are not common, but could be a sign of a serious problem. Health care providers should immediately be consulted if any of the following occur:
black, tarry, or bloody stools
blood in the urine
diarrhea
fever or chills
cough or hoarseness
wheezing or shortness of breath
sores in the mouth or on the lips
unusual bleeding or bruising
swelling of the face
red "pinpoint" spots on the skin
redness, pain, or swelling at the point where an inject-able anticancer drug is given
pain in the side or lower back
problems urinating or painful urination
dizziness or faintness
fast or irregular heartbeat
Other side effects do not need immediate care, but should have medical attention. They are:
joint pain
skin rash
hearing problems or ringing in the ears
numbness or tingling in the fingers or toes
trouble walking or balance problems
swelling of the feet or lower legs
unusual tiredness or weakness
loss of taste
seizures
dizziness
confusion
agitation
headache
dark urine
yellow eyes or skin
flushing of the face
Anti Cancer Drugs
Generic (Brand Name)
Clinical Uses
Common Side
Effects To Drug
Altretamine (Hexalen)
Treatment of
advanced ovarian
cancer
Bone marrow
depression, nausea
and vomiting
Asparaginase (Elspar)
Commonly used in
combination with
other drugs; refrac-
tory acute lymphocy-
tic leukemia
Liver, kidney,
pancreas, CNS
abnormalities,
Bleomycin (Blenoxane)
Lymphomas,
Hodgkin's disease,
testicular cancer
Hair loss, stomatitis,
pulmonary toxicity,
hyperpigmentation
of skin
Busulfan (Myleran)
Chronic granulocytic
leukemia
Bone marrow
depression,
pulmonary toxicity
Carboplatin (Paraplatin)
Pallilation of ovarian
cancer
Bone marrow
depression, nausea
and vomiting
Carmustine
Hodgkin's disease,
brain tumors, multi-
ple myeloma, malig-
nant melonoma
Bone marrow
depression, nausea
and vomiting, toxic damage to liver
Chlorambucil (Leukeran)
Chronic lymphocytic
leukemia, non-
Hodgkin's
lymphomas, breast
and ovarian cancer
Bone marrow
depression, excess
uric acid in blood
Cisplatin (Platinol)
Treatment of bladder,
ovarian,
uterine, testicular,
head and neck
cancers
Renal toxicity and
ototoxicity
Cladribine (Leustatin)
Hairy cell leukemia
Bone marrow
depression, nausea
and vomiting, fever
Cyclophosphamide
(Cytoxan)
Hodgkin's disease,
non-Hodgkin's lym-
phomas, neuroblas-
toma. Often used
with other drugs for
breast, ovarian, and
lung cancers; acute
lymphoblastic leuke-
mia in children; mul-
tiple myeloma
Bone marrow
depression, hair loss,
nausea and vomiting,
inflammation of the
bladder
Cytarabine (Cytosar-U)
Leukemias occurring
in adults and children
Bone marrow
depression, nausea
and vomiting,
diarrhea, stomatitis
Dacarbazine (DTIC-
Dome)
Hodgkin's disease,
malignant melanoma
Bone marrow
depression, nausea
and vomiting
Diethylstilbestrol (DES)
(Stilbestrol)
Breast cancer in
post-menopausal
women, prostate
cancer
Hair loss, nausea and
vomiting, edema,
excess calcium in
blood; feminizing
effects in men
Ethinyl
estradiol (Estinyl)
Advanced breast
cancer in post-
menopausal women,
prostate cancer
Excess calcium in
blood, anorexia,
edema, nausea and
vomiting; feminizing
effects in men
Etoposide (VePesid)
Acute leukemias,
lymphomas, testicu-
lar cancer
Bone marrow
depression, nausea
and vomiting, hair loss

Anti Cancer Drugs (continued)
Generic (Brand Name)
Clinical Uses
Common Side
Effects to Drug
Mitomycin (Mutamycin)
Bladder, breast,
colon, lung,
pancreas, rectum
cancers, head and
neck cancer, malig-
nant melanoma
Bone marrow
depression, nausea
and vomiting,
diarrhea, stomatitis,
possible tissue
damage
Mitotane (Lysodren)
Cancer of the adrenal
cortex (inoperable)
Damage to adrenal
cortex, nausea,
anorexia
Mitoxantrone (Novantrone)
Acute nonlymphocy-
tic leukemia
Cardiac arrhythmias,
labored breating,
nausea and vomiting,
diarrhea, fever,
congestive heart
failure
Paclitaxel (Taxol)
Advanced ovarian
cancer
Bone marrow
depression, hair loss,
nausea and vomiting,
hypotension, allergic
reactions, slow heart
action, muscle and
joint pain
Pentastatin (Nipent)
Hairy cell leukemia
unresponsive to
alpha-interferon
Bone marrow
depression, fever,
skin rash, liver
damage, nausea and
vomiting
Pipobroman (Vercyte)
Chronic granulocytic
leukemia
Bone marrow
depression
Plicamycin (Mithracin)
Testucular tumors
Toxicity/damage
to bone marrow,
kidneys, and liver
Prednisone (Meticorten)
Used in adjunct ther-
apy for palliation of
symptoms in lympho-
mas, acute leukemia
Hodgkin's disease
May be toxic to all
body systems
Procarbazine (Matulane)
Hodgkin's disease
Bone marrow
depression, nausea
and vomiting
Streptozocin (Zanosar)
Islet cell carcinoma of
pancreas
Nausea and vomiting,
toxicity to kidneys
Tamoxifen (Nolvadex)
Advanced breast can-
cer in post
menopausal
Nausea and vomiting,
ocular toxicity, hot
flashes
Teniposide (Vumon)
Acute lymphocytic
leukemia in children
See Etoposide
Vinblastine (Velban)
Breast cancer,
Hodgkin's disease,
static testicular
cancer
Bone marrow
depression,
neurotoxicity
Vincristine (Oncovin)
Acute leukemia,
Hodgkin's disease,
lymphomas
Constipation,
neurotoxicity,
possible tissue
necrosis



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