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Anticancer Drugs PDF
Anticancer Drugs PDF
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.
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.
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
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
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.
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
9. Progestins
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
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
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
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.
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.
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::
Cytrarabine:
pyraramidine antagonist.
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:
Stomatits.
Resistance of methotrexate:
12-
3. Plant alkaloids
Vinca alkaloids:
Vinblastine & Vincristine:
Mechanism of action:
Inhibition of tubulin polymeraization mitotic arrest leading to cell death. [Stop at metaphaselysis&death
Podophyllotoxins:
Etoposide(VP-16), Teniposide(VM-26)
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
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:
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:
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:
5. Hormonal Agents
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
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.
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
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
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
I. ALKYLATING DRUGS
A. Nitrogen Mustards
Chlorambucil (Leukeran)
Cyclophosphamide (Cytoxan)
Estramustine (Emcyt)
Ifosfamide (Iflex)
Mechlorethamine HCl
Melphalan (Alkeran)
temozolomide (Temodal)
Brain tumor
Uracil mustard
B. Nitrosoureas
Carmustine (BiCNU)
Lomustine (CeeNu)
Streptozocin (Zanosar)
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)
Cisplatin (Platinol)
Decarbazine (DTIC)
Pipobroman (Vercyte)
Thiotepa
(triethylenethiophosphoramide)
D. Alkyl Sulfonates
Busulfan (Myleran)
Anticancer/Antineoplastic
Drugs
II. ANTIMETABOLITES
A. Folic Acid Antagonist
Methotrexate (MTX),
Amethopterin
B. Pyrimidine Analogues
Capecitabine (Xeloda)
Cytarabine HCl (Cytosar-U,
ARA-C)
Floxuridine (FUDR)
5-Fluorouracil (5-FU,
Adrucil)
Gemcitabine HCl (Gemzar)
Procarbazine HCl (Matulane)
C. Purine Analogues
Cladribine (Leustatin)
Vinorelbine (Navelbine)
B. Antimicrotubule or Taxanes
Docetaxel (Taxotere)
Paclitaxel (Taxol)
C. Topoisomerase I Inhibitors
Irinotecan HCl (Camptosar)
Metastatic cancer of the colon and rectum, breast cancer, small-cell lung
cancer, leukemia.
Metastatic cancer of the ovaries, cancer of the head/ neck, colon, rectum,
malignant glioma.
D. Topoisomerase II Derivatives
Etoposide (VePesid)
Anticancer/Antineoplastic
Drugs
Testicular cancer, cancer of the skin, cervix, penis, squamous cellcarcinoma of the head/neck, Hodgkin's disease.
Dactinomycin (Actinomycin D,
Cosmegen)
Daunorubicin (Actinomycin)
Doxorubicin (Adriamycin)
Epirubicin (Ellence)
Idarubicin (Idamycin)
Mitomycin (Mutamycin)
Mitoxantrone (Novantrone)
Plicamycin (Mithracin)
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)
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
VI. MISCELLANEOUS
Anastrozole (Arimidex)
Bexarotene (Targretin)
Transtuzumab (Herceptin)
Dr.Yasser
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