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Anticancer drugs


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Title: Anticancer drugs

Anticancer drugs
4th year, General MedicinePractical Ing. J.
Chládek, Ph.D.
The outcome of cancer therapy
  • 1900 survival rates for sarkoma, karcinoma and
    haematological cancers less than 10
  • 2000 more than 50
  • Childhood Acute lymphoblastic leukemia gt 70
  • Hodgkin disease gt 90
  • Survival rates remain low for pancreatic (4),
    liver (7), glioblastoma (5), lung (15) cancers
    and colon cancers
  • Prostate and breast cancers have 5-year survival
    rates better than 80, but respond poorly at
    later stages
  • Major improvment in diagnosis and therapy
    (chemotherapy and supportive therapy)

Pathogenesis of cancer
  • DNA mutations
  • Inborn mutations of cancer susceptibility genes
  • Acquired mutations
  • Other epigenetic factors
  • Chemical carcinogens
  • Virus-induced cancer
  • X-rays
  • Other risk factors

Pathogenesis of cancer
  • The abnormal behaviors demonstrated by cancer
    cells are the result of a series of mutations in
    key regulatory genes.
  • The cells become progressively more abnormal as
    more genes become damaged.
  • Often, the genes that control DNA repair become
    damaged themselves.

Pathogenesis of cancer
  • Most cancers are thought to arise from a single
    mutant precursor cell.
  • As that cell divides, the resulting 'daughter'
    cells may acquire different mutations and
    different behaviors over a period of time.
  • Those cells that gain an advantage in division or
    resistance to cell death will tend to take over
    the population.

The Genes of Cancer
  • The genes of cancer have been categorized into
    two broad categories, depending on their normal
    functions in the cell.
  • Proto-oncogenes (if mutated oncogenes) Genes
    whose protein products stimulate or enhance the
    division and viability of cells or genes that
    contribute to tumor growth by inhibiting cell
  • Tumor suppressors. Genes whose protein products
    can directly or indirectly prevent cell division
    or lead to cell death.

The Role of Mutation in Cancer
  • For almost all types of cancer studied to date,
    it seems as if the transition from a normal
    to a cancer cell is step-wise progression that
    requires genetic changes in several different
    oncogenes and tumor suppressors. This is one
    reason why cancer is much more prevalent in older

The Role of Mutation in Cancer
Colon cancer rates in the United States as a
function of age. The graph was obtained from the
National Cancer Institute of the USA.
Important Oncogenes
  • These genes contribute to unregulated cell
    division if they are present in a mutant
    oncogenic form.
    The mutant proteins often retain some
    of their capabilities but are no longer sensitive
    to the normal control mechanizms.
  • HER-2/neu (erbB-2) a growth factor receptor
  • ras a signal transduction molecule
  • myc a transcription factor
  • src a protein tyrosine kinase
  • hTERT an enzyme that functions in DNA
  • Bcl-2 a membrane associated protein that
    functions to prevent apoptosis.

Important Tumor Suppressors
  • Tumor suppressors produce products that inhibit
    the division of cells if conditions for growth
    are not met (DNA damage, a lack of growth
    factors or defects in the division apparatus).
    A key to
    understanding tumor supppressors is that it is
    the LOSS OF FUNCTION of these genes that leads to
  • p53 (TP53) a transcription factor that regulates
    cell division
  • Rb alters the activity of trancription factors
    and therefore controls cell division
  • APC controls the availability of a transcription
  • BRCA involved in DNA repair.

Cancer Types
  • categorized based on the functions/locations of
    the cells from which they originate
  • Carcinoma a tumor derived from epithelial cells,
    those cells that line the surface of our skin and
    organs (80-90 of all cancer cases reported)
  • Sarcoma a tumor derived from muscle, bone,
    cartilage, fat or connective tissues.
  • Leukemia a cancer derived from white blood cells
    or their precursors.
  • Lymphoma a cancer of bone marrow derived cells
    that affects the lymphatic system.
  • Myelomas a cancer involving the white blood
    cells responsible for the production of
    antibodies (B lymphocytes).

Characteristics of Cancer Cells
  • 1) Excessive autonomous cell growth
  • tumor cells produce growth factors that stimulate
    their own proliferation (i.e. autocrine
  • malfunction in cell regulatory systems (i.e.
    abnormal receptors signal cell division in
    absence of growth factor)
  • loss of growth inhibitory signals (i.e. contact
  • (2) Invasiveness
  • ability to grow into adjacent tissue
  • (3) Ability to metastasize
  • spread to new sites and form new growths
  • lack of cell-cell contact inhibition (i.e.
    disorderly migration over adjacent cells)
  • production of enzymes that degrade protein
  • production of growth factors that stimulate blood
    vessel ingrowth
  • (4) Defective differentiation and immortality
  • related to uncontrolled proliferation (i.e.
    differentiated cells don't divide)
  • failure of cancer cells to undergo programmed
    cell death
  • (5) Genetic instability

Characteristics of Cancer Cells
  • Cancer cells often secrete enzymes that enable
    them to invade neighboring tissues. These enzymes
    digest away the barriers to migration and spread
    of the tumor cells.
  • The tumor cells produce (or cause nearby cells to
    produce) growth factors that stimulate the
    formation of blood vessels (neoangiogenesis).

Cancer Detection and Diagnosis
  • One of the key problems in the treatment of
    cancer is the early detection of the disease.
  • Often, cancer is detected in its later stages,
    when it has compromised the function of one or
    more vital organ systems and is widespread
    throughout the body.

Tumor growth
Weight (mg) Dubling time (days) Fraction of cells which devide ()
2 0.02 100
25 0.7 61
250 1.2 40
5000 7.5 7
Tumor growth
Dubling No 10 20
30 40
Tumor growth
Letal size
Clinical dg.
Rtg. dg.,
Neoangiogenesis, risk of metastazes
Cell No. 103 106
109 1012 Weight 1 mcg
1 mg 1 g 1 kg
Cancer Cell Burden
  • Widespread cancer may correspond to a cell burden
    of 1012.
  • Clinical remission and symptomatic improvement
    may require killing 99.9 of tumor cells.
  • Even with 99.9 cell kill, 10 9 cells remain
    (nine "logs" remaining)
  • Some of these remaining cells may be resistant or
    may not be accessible to chemotherapeutic agents
    (central nervous system)
  • By comparison, a three "log" kill may be curative
    for bacterial infections, since host resistance
    factors can eliminate residual disease, unlike
    the situation in treating cancer.

An Introduction to Cancer Treatments
  • The treatment given for cancer is highly variable
    and dependent on the type, location and amount of
    disease and the health status of the patient.
  • The treatments are designed to either
  • directly kill/remove the cancer cells or
  • to lead to their eventual death by depriving them
    of signals needed for cell division or
  • the treatments work by stimulating the body's own

Classical types of cancer treatment
  • Often in combination, either simultaneously or
  • Surgery Often the first line of treatment for
    many solid tumors. If the cancer is detected at
    an early stage, surgery may be sufficient to cure
    the patient.
  • Radiation The goal of radiation is to kill the
    cancer cells directly by damaging them with high
    energy beams.
  • Chemotherapy A term used for a wide array of
    drugs used to kill cancer cells. Chemotherapy
    drugs work by damaging the dividing cancer cells
    and preventing their further reproduction.
  • 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.

New types of cancer treatment
  • Specific Inhibitors Drugs targeting specific
    proteins and processes that are limited primarily
    to cancer cells or that are much more prevalent
    in cancer cells.
  • Antibodies The antibodies used in the treatment
    of cancer have been manufactured for use as
  • Biological Response Modifiers The use of
    naturally occuring, normal proteins to stimulate
    the body's own defenses against cancer.
  • 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.

Tumour selectivity of chemotherapy
  • Most drugs used in cytostatic chemotherapy
    interfere with the synthesis of DNA and /or RNA,
    with the results that cell death occurs or cell
    multiplication ceases.
  • These effects are not confined to malignant cells
    - cytostatic agents are also toxic to normal
    dividing cells, particularly those in bone
    marrow, the GIT, gonads, hair folicles and skin
    (rapidly dividing cells).

Tumor sensitivity
  • High high probability of currative effect ALL
    in children, Hodgkin d., ca testes, ovarian ca,
    Ewing sa. etc.
  • Medium increased of survivors, significant
    prolongation of life, paliative therapy adult
    AML, multiple myeloma, lymphocyte lymphoma,
    neuroblastoma, prostate ca, breast ca,
    endometrial ca, osteosarkoma
  • Low paliative chemoterapy pancreatic ca,
    bile-duct and blader ca, Grawitz tu, colorectal
    ca., aj.

Resistanceof cancer cells to chemotherapy
  • primary non-responsive tumors
  • aquired
  • reduced cellular uptake of drugs
  • increased cellular efflux
  • deletion of enzyme which activate the drug
  • increased detoxication of the drug
  • increased concentration of the target enzyme
  • rapid repair of drug-induced lesion
  • decreased number of receptors for the drug

Mechanisms of resistance
? deletion of enzyme to activate drug
? increased detoxication of drug
? reduced uptake of drugs
active metabolite
inactivated cytotoxic drug
? increased efflux (multidrug resistance)
defective cellular target
rapid repair of drug-induced lesion
increased concentration of target molecules
T- cellular target T - gene amplification
General rules of chemotherapy
  • Agressive high-dose chemotherapy
  • Dose-limiting is toxicity towards normal cells
  • Cyclic regimens repeated administrations with
    appropriate intervals for regeneration of normal
    cells (bone marrow)
  • 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
  • dexrazoxane chelates iron, reduced anthracycline
  • amifostine reduces hematotoxicity, ototoxicity
    and neurotoxicity of alkylating agents

General rules of chemotherapy
  • Combination of several drugs with different
    mechanisms of action, different resistance
    mechanisms, different dose-limiting toxicities
  • Adjuvant therapy courses of cytostatic drugs are
    given when the cancer has apparently been
    destroyed by surgery or radiotherapy. Its
    objective is to eradicate micrometastases.
  • Neoadjuvant therapy is defined as a preoperative
    cytostatic treatment in patients with locally
    advanced solid tumors The aims of neoadjuvant
    chemotherapy radiotherapy are the potentiality
    of curative resection, the reduction of surgical
    measures, and an increase in life span.

General rules of chemotherapy
  • Supportive therapy
  • Antiemetics (5-HT3 -antagonists)
  • Antibiotic prophylaxis and therapy (febrile
  • Prophylaxis of urate nephropathy (allopurinol)
  • Enteral and parenteral nutrition
  • Pain analgesic drugs
  • Psychological support

Chemotherapy classification based on the
mechanism of action
  • Antimetabolites Drugs that interfere with the
    formation of key biomolecules including
    nucleotides, the building blocks of DNA.
  • Genotoxic Drugs Drugs that alkylate or
    intercalate the DNA causing the loss of its
  • Plant-derived inhibitors of mitosis These agents
    prevent proper cell division by interfering with
    the cytoskeletal components that enable the cell
    to divide.
  • Plant-derived topoisomerase inhibitors
    Topoisomerases unwind or religate DNA during
  • Other Chemotherapy Agents These agents inhibit
    cell division by mechanisms that are not covered
    in the categories listed above.

The cell-cycle and phase specificity of some
cytotoxic drugs
G0 resting phase G1 prereplicative phase G2
postoperative phase S DNA synthesis M mitosis
or cell division
Paclitaxel, Docetaxel
Actinomycin D
Actinomycin D
Purine antagonists
Cytosine arabinoside
Cytosine arabinoside
The cell-cycle and phase specificity
of anticancer drugs
  • Class 1 agents (non cell cycle specific)
    proliferation independent or nonspecific kill
    cells whether they are proliferating (G1 - M) or
    not (G0 )
    nonspecific cytotoxicity ie. kill both normal and
    malignant cells to same extent
    eg. alkylating agents mechlorethamine
    and carmustine
  • Class 2 agents (cell cycle specific - phase
    specific) only toxic to neoplastic cells in
    certain phase of cell cycle, reach a plateau in
    cell killing with increasing dosages, eg.
    hydroxyurea is toxic to cells in S-phase,
    bleomycin is toxic to cells in G2 and early
    M-phase, dosing continuous infusion or frequent
    small doses to increase number of cells exposed
    at sensitive phase
  • Class 3 agents (cell cycle specific - non-phase
    specific) proliferation dependent, cycle
    specific, kill proliferating neoplastic cells in
    preference to resting cells, single large doses
    eg. anthracycline antibiotics, chlorambucil,

  • Antimetabolites are structurally similar to
    metabolites (building blocks for the synthesis
    of nucleic acids), but they can not be used by
    the body in a productive manner.
  • In the cell, antimetabolites are mistaken for the
    metabolites they resemble, and are processed a
    manner analogous to the normal compounds.
  • The presence of the 'decoy' antimetabolites
    prevents the cells from carrying out vital
    functions and the cells are unable to grow and
  • Antimetabolites used in the treatment of cancer
    interfere with the production or function of the
    nucleic acids, RNA and DNA

  • Folate Antagonists
  • Purine Antagonists
  • Pyrimidine Antagonists

Folate antagonists Methotrexate
  • Second cytostatic drug (after the first
    alkylating agents) introduced in chemotherapy.
  • Structure pteridine
    heterocycle p-aminobenzooic acid glutamic
    acid (1 MTX, several
  • Polyglutamates are retained in cells.

Methotrexate discovery
  • 1945 folic acid identified as an essential
    growth factor for Lactobacillus casei, later
  • 1948 Sidney Farber (Children's Hospital Boston)
    used FA as a supportive therapy of
    children with leukemia their symptoms
  • Later he attempted folate deprivation. The
    numbers of leukemia cells decreased the idea of
    cytostatic drugs antifolates
  • 1-rst derivative aminopterine first succesfull
    short-term remissions of ALL in children,
    excesive toxicity
  • Discovery of the mechanism of action of
  • Methotrexate designed as an DHFR inhibitor.
  • Marketed in 1953.

Folate antagonists
  • Folic acid is a growth factor that provides
    single carbons to the precursors used
    to form the nucleotides used in the synthesis of
    DNA and RNA.
  • Antifolates act by blocking the active site of
    dihydrofolate reductase (DHFR), an enzyme that
    reduces folic acid to its active reduced form.
    Reduced folates are co-enzymes necessary for
    methylation in various metabolic processes,
    in which they deliver methyl groups (one-carbon
    units) to specific target molecules. Moreover,
    MTX directly inhibits thymidylate synthase.

Main intracellular targets
for methotrexate
Leukovorine (5-formyltetrahydro-folic acid) the
only reduced folate sufficiently stable to be
produced and marketed as a drug. It is used
as a rescue therapy to reduce /prevent excessive
toxicity of MTX towards normal cells.
Folic acid cycle
  • Indications for i.v. infusion (duration 8 24h)
    therapy (medium tohigh doses, 0.5 10 g/m2)
  • Choriocarcinoma
  • Acute lymphocytic leukemia
  • Large cell lymphoma
  • High grade lymphoma
  • Head and neck cancers
  • Breast cancers
  • Bladder cancers
  • Osteogenic Cancers
  • Low-dose oral MTX once a week (25 mg)
    6-mercaptopurine maintenance therapy of ALL (2
  • Low-dose MTX once a week (7.5-25 mg p.o., i.m.,
    s.c.) immunosuppressive therapy of psoriasis,
    rheumatoid arthritis, Crohn disease

Resistance to Methotrexate
  • There are three known ways in which a cell may
  • immunity to the effects of this folate
  • Decreased concentration of the drug in the cell
    (decreased influx, increased efflux, decreased
    polyglutamate synthesis/increased hydrolysis)
  • Amplification of the DHFR gene causes an increase
    in the amount of DHFR present and has been shown
    to correlate with reduced response to
    methotrexate treatment.
  • Mutations in DHFR that reduce DHFR-methotrexate

Purine Antagonists
  • 6- merkaptopurine
  • 6- thioguanine
  • fludarabine

Purine Antagonists
Mechanizm of action of 6-mercaptopurine
hypoxanthine-guanine phosphoribosyltransferase
Adenosine monophosphate
Guanosine monophosphate
Inosine monophosphate
Purine synthesis de novo
Metabolism of 6-mercaptopurine
6-thioxantine 6-thiouric acid
Metabolic inactivation Metabolic activation
Xanthine oxidase
6-thioinosine monophosphate
6-thioguanosine -monophosphate
Incorporated in DNA as a false nucleotide
Patients with an inactive enzyme TPMT (thiopurine
methyltransferase) due to genetic polymorphism
are at high risk of life-threatening toxicity
(myelosuppression). Genetic test for TPMT
mutation or evaluation of TPMT activity in
erythrocytes help to reduce risk (starting dose
is reduced 10-fold in poor metabolizers)
  • Oral 6-MP once daily (25 mg) MTX maintenance
    therapy of ALL (2 years)
  • Adverse effects myelosuppression (leukopenia,
    thrombocytopenia), GIT (diarrhea, vomiting,
    pain), reversible hepatotoxicity
  • Azathioprine (prodrug of 6-MP) immunosuppressive
    therapy (Crohn dis., after transplantation, lupus
    erythematodes, glomerulonephritis etc.)

  • Analog of the nucleotide adeninarabinoside
  • Ind. chronic lymphatic leukemia, non-Hodgkin
  • FLAG protocol fludarabine cytosinarabinoside
    growth factor for granulocyte colonies treatment
    of AML
  • Adverse effects hematotoxicity

Pyrimidine Antagonists
  • Act to block the synthesis of pyrimidine
    containing nucleotides (C and T in DNA C and U
    in RNA).
  • PA have structures that are similar to the
    natural compounds.
  • By acting as 'decoys', these drugs can prevent
    the production of the finished nucleotides.
  • They may exert their effects at different steps
    in that pathway and may directly inhibit crucial
  • The pyrimidine antagonist may also be
    incorporated into a growing DNA
    chain and lead to termination of the process.

Pyrimidine Antagonists
  • 5-fluorouracil

Cytosine arabinoside (Ara-C)
  • metabolized to the nucleotide fluorouridine
    monophosphate (5-FUMP)
  • 5-FUMP is further metabolized to
  • A/ the triphosphate 5-FUTP which is incorporated
    in DNA
  • B/ 5-fluorodeoxyuridine monophosphate a strong
    inhibitor of thymidilate synthetase

  • Malignancies for which 5-FU is used include
  • Breast cancer
  • Pancreatic cancer
  • Stomach cancer
  • Colon cancer
  • Rectal cancer
  • Genito-urinary tract cancers (anus, adrenal
    gland, bladder, cervix, endometrium, ovaries,
    penis, prostate, and vulva)
  • Esophageal cancer
  • Liver cancer
  • Skin cancer
  • 5-FU may be applied to the skin via a cream to
    treat actinic keratoses and basal cell carcinomas
    (a type of skin cancer) that arise on a the skin
    due to chronic, prolonged sun exposure and
    sun-damage. These keratoses often provide a
    warning flag for possible development of
    melanoma. For this reason, 5-FU may be used as a
    preventative measure in these cases.

  • Common side effects include
  • Nausea and diarrhea
  • Drop in bone marrow function-possibly leading to
  • Increased tendency to bruise
  • Mouth sores
  • Pigmentation changes in the skin
  • 5-FU/leucovorine increased cytotoxic activity

Cytosine Arabinoside (Cytarabine)
  • Cytidine analog (arabinose instead of ribose)
  • Cytarabine triphosphate is incorporated in DNA
    and blocks its function.
  • Inhibitor of DNA and RNA-polymerases and
    nucleotide reductase
  • Metabolized in liver, kidney and intestinal
    mucosa by cytidine deaminase, t1/2 10 min
    therefore given frequently in
    a continuous i.v. infusion.

  • Malignancies for which cytarabine is used
  • Acute non-lymphocytic leukemia
  • Acute lymphocytic leukemia
  • Chronic myelocytic leukemia
  • Common side effects include
  • Bone marrow suppression
  • Anorexia
  • Nausea and vomiting
  • Diarrhea
  • Oral/anal inflammation or ulceration
  • Rash
  • Fever

  • Drug Usage
  • Capecitabine is an antimetabolite that is changed
    to 5-fluorouracil inside the body. It inhibits
    cell division and interfere with RNA and protein
  • Malignancies for which capecitabine is used
  • Metastatic colorectal cancer
  • Metastatic and/or resistant breast cancer
  • Capecitabine is administered as an oral tablet.

  • Gemcitabine is an antimetabolite that acts as a
    pyrimidine analog. It is incorporated into a
    dividing cell's DNA which causes the cell to
    undergo apoptosis.
  • Malignancies for which gemcitabine is used
  • Non-small cell lung cancer (in combination with
  • Pancreatic cancer (advanced or metastatic)
  • Gemcitabine is administered as an intravenous

Alkylating agents (Covalent DNA binding drugs)
  • The first class of chemotherapy agents used.
  • They stop tumour growth by cross-linking guanine
    nucleobases in DNA double-helix strands -
    directly attacking DNA.
  • This makes the strands unable to uncoil and
  • As this is necessary in DNA replication, the
    cells can no longer divide.
  • Cell-cycle nonspecific effect
  • Alkylating agents are also mutagenic and

Alkylating agents
- largest class of anticancer agents- commonly
used drugs 5 subgroups 1) nitrogen mustards2)
alkyl sulfonates3) nitrosoureas4) aziridines5)
platinum compounds
Mechanism of action- Alkylating agents form
highly reactive electrophilic species (i.e.
electron deficient) which covalently bind alkyl
groups (eg. -CH2Cl) onto nucleophilic sites (i.e.
excess of electrons) of cellular macromolecules
(e.g. bases of DNA protein)
Alkylating agents
The nitrogen mustards are cytotoxic chemotherapy
agents similar to mustard gas. Although their
common use is medicinal, in principle these
compounds may also be used for chemical warfare
purposes. The prototype nitrogen mustard drug is
mustine which is no longer commonly in use but
was the first drug to be used as an anticancer
chemotherapeutic. It is a schedule 1 substance in
the Chemical Weapons Convention. Other nitrogen
mustards include cyclofosfamide, ifosfamide,
chlorambucil, carmustine, lomustine and melphalan.
bis(2-chloroethyl) ethylamine
Cyclofosfamide requires conversion into active
substances in vivo
cytochrome P450
Aldehyde oxidase
carboxyfosfamide (nontoxic)
acrolein (cytotoxic)
phosphoramide mustard (the active principle)
Akrolein zpusobuje hemoragickou cystitidu,
prevence hydratace, MESNA (merkaptoetansulfonan
sodný, donor SH-skupin prevede akrolein na
  • Used in a wide variety of neoplastic diseases
    (combination therapy).
  • Burkitt's lymphoma
  • Bladder cancer
  • Bone cancer
  • Cervical cancer
  • Endometrial cancer
  • Lung cancer
  • Prostate cancer
  • Testicular cancer
  • Cancer of the adrenal cortex

  • Adverse effects (cytotoxicity, mutagenicity,
  • Nausea and vomiting
  • Diarrhea
  • Depression of blood cell counts
  • Loss of appetite
  • Alopecia (hair loss)
  • Irritation of the bladder (hemorrhagic cystitis,
    prevention MESNA inactivates acrolein)
  • Cough
  • Fever and/or chills
  • Lower back or side pain
  • Skin and mouth ulcers
  • Amenorrhea (cessation of menstrual periods)
    testicular atrophy, and sterility
  • Secondary cancers

  • Similar to cyclofosfamide
  • Broader spectrum of anticancer activity than

  • Low-dose oral Cy is used as immunosuppresant drug
    to treat lupus erythematodes, autoimunne
    hemolytic anemias, nephrotic sy. etc.

Platinum drugs Cisplatin
  • 1965 Rosenberg et al. observed inhibition of
    bacterial deviding in a solution near a Platinum
  • Malignancies for which cisplatin is used
  • Testicular cancer
  • Ovarian cancer
  • Bladder cancer
  • Head and neck cancer
  • Esophagus cancer
  • Small cell and non-small cell lung cancer
  • Non-Hodgkin's lymphoma
  • Adverse effects
  • Kidney damage
  • Decreased blood levels of magnesium, potassium,
    and calcium
  • Nausea and vomiting (one of the strongest
  • Taste changes, including a metallic taste to
  • Neurotoxicity - Sensation of 'pins and needles'
    in hands and/or feet
  • Decreased red blood cell counts

Platinum drugs Carboplatin
  • Eliminated renally. Use
  • Germ cell tumors
  • Ovarian cancer
  • Head and neck cancer
  • Small cell and non-small cell lung cancer
  • Bladder cancer
  • Relapsed and refractory (resistant to ordinary
    treatment) acute leukemia
  • Endometrial cancer.
  • Adverse Effects
  • Myelotoxicity (Decreased white blood cell count
    with increased risk of infection, Decreased
    platelet count with increased risk of bleeding)
  • Altered kidney function (at high doses)

Platinum drugs Oxaliplatin
  • Oxaliplatin is primarily used in the treatment
    of metastatic or recurrent colorectal cancer.
  • Adverse Effects
  • Neuropathy
  • Tiredness, weakness
  • Diarrhea
  • Nausea and vomiting
  • Abdominal pain
  • Fever
  • Loss of appetite

Alkylating agents nitrosoureas
  • BCNU (karmustin)
  • CCNU (lomustin)
  • Fotemustin
  • Lipophilic, enter CNS, Brain tumors
  • Hodgkin's disease
  • Non-Hodgkin's lymphoma
  • Multiple myeloma
  • AE late hematotoxicity

  • Anthracyclines (anthracycline antibiotics) rank
    among the most effective anticancer drugs ever
  • The first anthracyclines doxorubicin (DOX) and
    daunorubicin (DNR) were isolated from the
    pigment-producing Streptomyces peucetius early in
    the 1960s and were named
  • Mehanism of action
  • Intercalation in its role as an intercalating
    agent the drug wedges between the bases of DNA
    and blocks DNA synthesis and transcription.
  • Enzyme inhibition the drug inhibits the activity
    of an enzyme, topoisomerase type II.
  • Formation of iron-mediated free oxygen radicals
    that damage the DNA and cell membranes (effect,
    adverse effects)

Intercalating Agents Mechanism of action
Intercalating drugs have planar regions that
stack between paired bases in DNA forming tight
drug-DNA interaction The intercalated drug
molecules affect the structure of the DNA,
preventing polymerases and other DNA binding
proteins from functioning properly. The result is
prevention of DNA synthesis, inhibition of
transcription and induction of mutations.
  • Doxorubicin (Adriamycin)
  • Daunorubicin
  • Epirubicin
  • Idarubicin
  • Structure tetracyclic aglycone with
    quinone-hydroxyquinone groups sugar moiety
  • Poor oral absorption therefore given by IV

  • Doxorubicin is useful in a wide range of cancers
    and only a few cancer types are unresponsive to
    the drug. These unresponsive types include colon
    cancer, melanoma, chronic leukemias and renal
  • Doxorubicin is commonly used to treat Hodgkin's
    disease, breast cancer, lung cancer, soft tissue
    sarcoma, Kahler's disease (multiple myeloma) and
    recurring instances of ovarian cancer. Commonly
    used doxorubicin-containing regimens are ABVD
    (Adriamycin, Bleomycin, Vinblastine,
    Dacarbazine), CHOP (Cyclophosphamide, Adriamycin,
    Vincristine, Prednisone) and FAC (5-Fluorouracil,
    Adriamycin, Cyclophosphamide).
  • Epirubicin similar to doxorubicin
  • Daunorubicin shows much narrover spectrum of
    activity acute lymphoblastic or myeloblastic
  • Multidrug resistance to all anthrycyclines

  • Adverse effects
  • Acute nausea, vomiting, and heart arrhythmias,
    decrease in white blood cells and alopecia.
  • Chronic cardiomyopathy and congestive heart
    failure usually refractory to common medications.
    This cardiotoxicity is related to a patient's
    cumulative lifetime dose. Second-generation
    analogs like epirubicin or idarubicin exhibit
    improvements in their therapeutic index, but the
    risk of inducing cardiomyopathy is not abated.
  • Dexrazoxane is a cardioprotectant agent that is
    sometimes used to reduce the risk of
  • Liposomal formulations of daunorubicin and
    doxorubicin have been approved that appear to be
    somewhat less toxic to cardiac tissue.

Plant-derived inhibitors of mitosis
  • Inhibitors of mitosis (spindle poisons or mitosis
    poisons) include several different chemotherapy
  • Unlike the previous drugs discussed, they do not
    work to alter DNA structure or function. Rather,
    they interfere with the mechanics of cell
  • They function in a cell-cycle dependent manner,
    halting division during early mitosis.
  • Vinca alkaloids destroy mitotic spindles.
  • Taxanes inhibit the microtubule function through
    stabilizing of GDP-bound tubulin in the

Vinca alkaloids
The Vinca alkaloids are a subset of drugs that
are derived from the periwinkle plant,
Catharanthus roseus (also Vinca rosea, Lochnera
rosea, and Ammocallis rosea). It is also
commonly called the Madagascar periwinkle or the
rose periwinkle. While it has been historically
used to treat numerous diseases, it has most
recently been employed for its anti-cancer
properties. The plant grows in warm regions of
the world and especially in the
Southern United States.
  • The mechanism involves binding to the
    tubulin monomers and keeping the
    microtubules (spindle fibers) from forming.
  • There are four major vinca alkaloids
    in clinical use
  • VinblastineVincristineVindesineVinorelbine

Vinca alkaloids Vincristine
  • Drug Usage
  • Vincristine is administered intravenously and is
    used to treat many different types of cancer. It
    is frequently used in combination with other
    drugs (Acute leukemia, Rhabdoyosarcoma,
    Neuroblastoma, Hodgkin's disease and other
    lymphomas, Lymphorecticular neoplasms,Childhood
  • Side effects
  • Hair loss, Nausea/stomach pain/vomiting, Lowered
    blood cell count, Nervous system problems such as
    neuropathy or sensory impairment

Vinca alkaloids Vinblastine
  • Drug Usage
  • Breast cancer
  • Testicular cancer
  • Lymphomas

Paclitaxel (Taxol)
  • The drug is used for a variety of cancers,
    including ovarian, breast, small-cell and
    large-cell lung cancers, and Karposi's sarcoma -
    one of most active of all anticancer drugs.
  • In combination with cisplatin in ovarian and lung
  • AE myelusuppression, alopecia, neuropatthy,
    mouth sores, allergic reaction, nausea, vomiting,
    or diarrhea

Paclitaxel is derived from slowly growing Taxus
brevifolia (It takes about 2g of paclitaxel
the bark from about 3-10 trees to treat one
patient). Over-harvesting for production of this
drug has resulted in the Pacific Yew becoming a
rare species, despite the fact the drug can be
produced semi-synthetically from cultivated yews.
The pharmaceutical industry is also still
exploiting closely-related wild yew species in
India and China for the same purposes, which
threatens some of those species as well.
Nowadays, 10-Deacetylbaccatin can be extracted in
relatively large amounts from various yew-related
species and is easily converted by several steps
of organic synthesis into paclitaxel. Cell
cultures can also be used to provide the starting
10-deactylbaccatin material.
  • A semi-synthetic derivative of compound
    extracted from the renewable and readily
    available European yew tree.
  • Used mainly for the treatment of breast, ovarian,
    and non-small cell lung cancer.

Plant-derived topoisomerase inhibitors
  • Topoisomerase I inhibitors irinotecan and
    topotecan derived from kampthotecin
  • Topoisomerase II inhibitors etoposide and
    teniposide derivatives of podophylotoxin
  • Both type I and type II topoisomerases change the
    supercoiling of DNA. Topoisomerases unwind or
    religate DNA during replication.

Camptothecin derivatives
More than 30 years ago it was found that extracts
from a Chinese tree, Camptotheca Acuminata, had
potent anticancer activity against a mouse
leukemia. The active substance, designated
Camptothecin, was tried clinically, but was too
Camptothecin derivatives
  • Topotecan is indicated for small cell lung cancer
    after failure of first-line chemotherapy and
    metastatic carcinoma of the ovary following
    failure of initial or subsequent chemotherapy.
  • AE granulocythopenia, thrombocytopenia, diarrhea
  • Irinotecan is indicated for colorectal cancers
    and is usually taken with other drugs in
  • Prodrug of the active compound SN-38
  • AE granulocythopenia, thrombocytopenia, diarrhea

Topoisomerase II inhibitors
  • Synthetic Podophyllotoxin derivatives etoposide,
  • Podophyllotoxin is a non-alkaloid toxin present
    in the rhizome of American Mayapple Podophyllum
    peltatum (mandrake)

Etoposide Teniposide
  • Use of etoposide chemotherapy for malignancies
    such as lung cancer, testicular cancer, lymphoma,
    non-lymphocytic leukemia, and glioblastoma
    multiforme. It is often given in combination
    with other drugs.
  • Use of teniposide childhood acute lymphocytic
  • Adverse effects trombocythopenia, neutropenia

Hormonal Treatment
  • Strictly speaking, this is not chemotherapy.
  • Cancer arising from certain tissues, including
    the mammary and prostate glands, may be inhibited
    or stimulated by appropriate changes in hormone
  • Some forms of breast, ovarian and prostate cancer
    are subject to hormonal treatments.
  • The idea behind the majority of hormone-based
    cancer treatments is to starve the cancer cells
    of the hormonal signals that would otherwise
    stimulate them to divide.
  • The drugs used in these treatments work by
    blocking the activity of the hormone in the
    target cell.

Hormonal Treatment
  • Some newer treatments are designed to prevent the
    production of the hormone, cutting off the signal
    at the start.
  • The hormonal treatments are often combined with
    surgery and/or radiation and/or chemotherapy. In
    these situations, the hormonal treatments are
    referred to as an 'adjuvant' treatment.

Hormonal Treatment
  • Selective Estrogen Receptor Modulators (SERMs)
    These agents work by interfering with the
    activity of the estrogen receptor.
  • Aromatase Inhibitors These drugs work by
    blocking the production of estrogen by the enzyme
    that makes it from its precursor.
  • Receptor Down-regulators This class of drugs
    work by lowering the levels of the receptor for
  • Selective Androgen Receptor Modulators (SARMs)
    These agents work by interfering with the
    activity of the androgen receptor.
  • Additional Hormone Treatments

Breast Cancer - Selective Estrogen Receptor
Modulators (SERMs)
  • One of estrogen's normal activities is to cause
    the proliferation of cells in the breast and
    uterus each month new cell linings must be
    created for the milk glands and the endometrium.
  • In some breast cancer patients this normal
    expression of estrogen contributes to the growth
    and divison of the cancer cells.
  • The drugs work by causing changes in the shape of
    estrogen receptors, preventing the action of the
  • The blockage of estrogen in the target cells
    causes changes in gene expression and alters the
    behavior of the cells, preventing cell division.

Breast Cancer - Selective Estrogen Receptor
Modulators (SERMs)
  • In 1992, tamoxifen became the first SERM to be
    used for the treatment of breast cancer. While it
    does decrease estrogenic effects in the breast,
    it unfortunately has a pro-estrogenic activity in
    the uterus, causing a rise in uterine cancer for
    tamoxifen-treated breast cancer patients.
  • Recently, next generation SERMs such as
    raloxifene have been investigated for their
    potential as breast cancer treatments. This drug
    appears to have anti-estrogenic effects in both
    breast and uterine tissues.

Breast Cancer - Selective Estrogen Receptor
Modulators (SERMs)
  • Tamoxifen is used to treat breast cancer in both
    pre- and postmenopausal women with advanced or
    metastatic breast cancer.
  • It is also given to reduce the risk of invasive
    breast cancer in women who have been treated for
    ductal carcinoma in situ.
  • Patients being treated with tamoxifen are also at
    increased risk for blood clots in the legs (deep
    venous thrombosis) and lungs, and also for
    strokes. These events are serious but rare.
  • Tamoxifen may also increase the risk of
    endometrial cancer in patients receiving
    treatment that have not undergone a hysterectomy.

Breast Cancer - Selective Estrogen Receptor
Modulators (SERMs)
  • Raloxifene is currently prescribed to prevent
  • One known benefit of raloxifene treatment is that
    it exerts pro-estrogen effects in the bone and
    heart. As a consequence lowered cholesterol and
    stronger bones appear to be common benefits of
    taking this drug.
  • Moreover, in studies raloxifene has not been
    shown to increase risk of endometrial cancer or
    vaginal disharge/bleeding.

Selective Estrogen Receptor Modulators (SERMs)
  • Uterus - tamoxifen may increase endometrial
    carcinoma risk, but raloxifene does not. Data on
    toremifene and clomifene is insufficient.
  • Breast - all SERMs decrease breast cancer risk,
    and tamoxifen is mainly used for its ability to
    inhibit growth in estrogen receptor-positive
    breast cancer.
  • Deep venous thrombosis - the risk may be elevated
    in all SERMs.
  • Cholesterol and triglycerides - levels respond
    favorably to SERMs.
  • Bone turnover and postmenopausal osteoporosis
    respond favorably to SERMs.
  • Hot flashes are increased by all SERMs.

Aromatase inhibitors
  • After menopause, women produce a consistent low
    level of estrogen that is derived from androgen
    precursors. These precursors are converted to
    estrogen through the actions of the enzyme
  • By blocking the action of this enzyme, aromatase
    inhibitors prevent the formation of estrogen.
  • There are two types of aromatase inhibitors that
    have been approved as treatment for
    postmenopausal women with estrogen-receptor
    positive metastatic breast cancer
  • steroidal inhibitors such as exemestane and
  • non-steriodal inhibitors (anastrozole and

Aromatase inhibitors
  • Aminoglutethimide
  • Inhibitor of adrenal steroid synthesis (blocks
    conversion of cholesterol to pregnenolone)
  • Inhibits also extra-adrenal estradiol and estrone
  • Inhibitor of aromatase enzyme (catalyzes
    conversion of androstenedione to estrone)

Prostate Cancer - Specific Androgen Receptor
Modulators (SARM's)
  • Among other activities, testosterone and
    dihydroxytestosterone bind to specific receptors
    in the cells of the prostate.
  • A normal function of this binding is to regulate
    the growth of the prostate cells.
  • In cancer cells, this regulation is compromised.
  • The androgens bind to the receptors in cancer
    cells and contribute to their growth and
  • Anti-androgen molecules via the preferential
    binding to the androgen receptors, prevent the
    androgens from binding and therefore reduces
    their pro-growth activities.
  • Flutamide
  • Bicalutamide

Gonadotropin-releasing hormone agonists (GnRH)
  • A gonadotropin-releasing hormone agonists are
    synthetic peptides modeled after the hypothalamic
    neurohormone GnRH that interacts with its
    receptor to elicit the release of the pituitary
    hormones FSH and LH.
  • Agonists do not quickly dissociate from the GnRH
    receptor. As a result initially there is an
    increase in FSH and LH secretion (so-called flare
    effect), however after about ten days a profound
    hypogonadal effect is achieved through receptor
    downregulation (a negative feedback effect)
  • It stops the production of sex hormones
    (testosterone and oestrogen).

Gonadotropin-releasing hormone agonists (GnRH)
  • Goserelin is an injectable gonadotropin releasing
    hormone super-agonist (GnRH agonist) available as
    a 1-month depot and a long-acting 3-month depot.
  • Goserelin is used to treat hormone-sensitive
    cancers of the prostate and breast (in
    pre-/perimenopausal women) and some benign
    gynaecological disorders (endometriosis, uterine
    fibroids and endometrial thinning). In addition,
    goserelin is used in assisted reproduction.
  • Other GnRH
  • leuprolide
  • buserelin
  • nafarelin

  • Glucocorticoids (prednisone, prednisolone,
    methylprednisolone, dexamethasone) are used in
    hematological malignancies
  • G induce apoptosis of lymphocytes
  • G reduce th activity of RNA polymerase
  • Use acute leukemias, lymphoma and other
    hematological cancers

  • The activation or supplementation of enzymes that
    normally function to limit cell growth can also
    decrease tumor cell division.
  • Asparaginase is an enzyme that breaks down
    (disassembles) the amino acid asparagine which is
    needed for cell maintenance and growth.
  • In many cases of leukemia, unlike normal cells,
    the leukemia cells are unable to make their own
    asparagine and must rely on outside sources of
    asparagine for survival.
  • By depleting free asparagine in the body, which
    is necessary for cancer cell survival
    asparaginase treatment results in a depletion of
    cancerous cells while normal cells are more
    likely to be preserved.

New promising approaches to cancer treatment and
  • Specific Inhibitors
  • Biological response modifiers
  • Antibodies
  • Anticancer vaccines
  • Cancer prevention using vaccines
  • (e.g. Vaccine against Human papilomavirus)

Supplemental information
  • This additional information is not required in
    the rigorous examination.

Specific Inhibitors
  • A small number of these drugs have already been
    approved, and quite a number are currently in
    clinical trials.
  • Drugs targeting cancer-specific processes,
    instead of processes common to all cells.
  • Because these drugs are not directly toxic, and
    because they only affect cancer cells, they offer
    the hope of being highly specific with few side
  • Blocking a single pathway in a cancer cell may be
    enough to slow it down, but it often does not
    inhibit the cancer enough to kill it.
  • Therefore, many specific cancer drugs are
    currently being used together with traditional

Specific Inhibitors
  • Types of Specific Inhibitors
  • Antisense Oligonucleotides
  • Ribozymes
  • Drugs that Affect Molecular Receptors
  • Angiogenesis Inhibitors
  • Histone Deacytlase Inhibitors
  • Kinase Inhibitors
  • Enzyme Activators
  • Proteasomes

Antisense Oligonucleotides
  • If a protein is helping a cancer cell to grow,
    then the appropriate antisense oligonucleotide
    could be used to prevent that protein from ever
    being made.
  • Single stranded string of nucleic acid bases with
    a sequence complementary to the sequence of a
    given mRNA (the antisense sequence) enters the
    cell, binds to that specific mRNA and inactivate
  • The bound mRNA is not suitable for translation
    and is degraded.

  • Ribozymes, RNA molecules with catalytic activity,
    are involved in a variety of cellular processes,
    but their most interesting property from the
    standpoint of cancer therapy is their ability
    to cleave messenger RNA (mRNA) molecules.
  • When an mRNA is cleaved, it can no longer be
    translated to produce protein.
  • By targeting the mRNAs encoding proteins with
    pathological roles in cancer, ribozymes can slow
    or inhibit cancerous growth.

Specific Receptor Antagonists
  • An example is the HER-2/neu oncogene product,
    that functions as a growth factor receptor.
  • Particular signalling pathways are often affected
    in a given type of cancer.
  • Drugs designed to inhibit these specific
    signalling pathways promise to inhibit cancer
    growth without harming normal cells.
  • Approved Treatments
  • Bexarotene (Targretin)
  • Denileukin diftitox (ONTAK)

Angiogenesis Inhibitors
  • Tumors produce factors that stimulate the
    formation of blood vessels to provide them with
    the food and oxygen they need (neoangiogenesis).
  • Approaches to the inhibition of angiogenesis
  • Matrix Metalloproteinases Inhibitors Growing
    blood vessel cells secrete enzymes called matrix
    metalloproteinases that are able to digest the
    extracellular matrix and allow blood vessels to
    invade the area and supply the tumor with
    nutrients. Inhibition of this process is the
    target of several drugs.
  • Endothelial Cell Inhibitors inhibit angiogenesis
    by acting to prevent the growth or activities of
    the endothelial cells that form the blood
  • Inhibitors of Angiogenesis Activation The drugs
    in this class of angiogenesis inhibitors work by
    blocking the cascade of events that cause blood
    vessels to form.

Kinases and Cancer
  • One key feature of cancer cells is their ability
    to reproduce in the absence of external signals
    such as growth factors. In the normal process,
    growth factors that are excreted by other cells
    bind to receptors on the cell surface,
    stimulating the cell to divide.
  • Cancerous cells turn on the pathway in the
    absence of the growth factor. This may occur
    because of a mutation in a kinase or phosphatase
    gene. In one example, chronic myeloid leukemia, a
    particular chromosomal transloction (termed the
    Philadelphia chromosome) has been identified that
    creates a novel kinase that is 'on' all the time.
  • Several new cancer treatments are designed to
    inhibit aberrantly activated kinases within
    cancer cells in an effort to prevent cell
    division. Two of the most promising new drugs are
    Gleevec (Glivec) and Iressa.

Proteasomes and Cancer
  • Proteasomes control the half-life of many
    short-lived regulatory proteins, such as those
    involved in the cell cycle. Therefore, proteasome
    malfunction can lead to abnormal regulation of
    the cell cycle and uncontrolled cell
  • In a normal cell, proteasomes break down proteins
    that inhibit the cell cycle, such as
    cyclin-dependent kinase inhibitors (CKI).
  • Inhibition of proteasome function causes cell
    cycle arrest and cell death. Tumor cells are more
    susceptible to these effects than normal cells,
    in part because they divide more rapidly and in
    part because many of their normal regulatory
    pathways are disrupted.
  • The first proteasome inhibitor specifically
    interacts with a key threonine (an amino acid)
    within the digestive site (catalytic site) of the
    proteasome, the resulting inhibition seems to be
    sufficient to prevent the degradation of
    ubiquitinated proteins.

Antibodies in Cancer Treatment
  • Unfortunately many cancer cells tend to go
    unnoticed by the immune system because they
    originate from normal body cells. Despite the
    fact that they behave like foreign organisms
    within our bodies, cancer cells often do not
    elicit a significant immune response.
  • Antibodies can be used to inhibit the growth of
    cancer cells in several different ways
  • Antibodies that stimulate cell killing function
    by targeting proteins on the surface of cancer
    cells. The antibodies themselves mark the cell
    for destruction by cells of the immune system.
    This process is termed antibody dependent
    cellular cytotoxicity.
  • Blockage of receptors These antibodies may
    function as a blockade to the receipt of required
    growth signals.
  • Immunotoxins This approach utilizes antibodies
    to target toxic molecules to the cancer cells.
    These toxic molecules can be proteins that
    inhibit cellular activities or radioactive
    compounds that cause DNA damage and the induction
    of apoptosis.

Antibodies in Cancer Treatment
Carter P Improving the efficacy of
antibody-based cancer therapies. Nat Rev Cancer
Specific Antibody Treatments
  • There are several cytotoxic antibody treatments
    that are currently in testing or are being used
    to treat particular types of cancer. Some
    antibodies that are currently approved for cancer
    treatment include
  • tositumomab
  • alemtuzumab
  • trastuzumab (Herceptin)
  • gemtuzumab
  • rituximab
  • Ibritumomab
  • And many others

Specific Antibody Treatments
  • Many tumors overproduce proteins necessary for
    cell growth and division. An example is the
    overexpression of the HER2 receptor protein,
    which is found in excessive quantities in some
    breast and ovarian cancer cases.
  • Herceptin is a monoclonal antibody specifically
    engineered to bind to the HER2 protein. It is not
    known exactly how Herceptin functions to stop the
    growth of sensitive tumors, but there is evidence
    that it may have more than one mechanism of
    action. It is thought that Herceptin may
    prevent tumor growth by inhibiting the binding of
    extracellular growth signals to receptors on the
    cell surface.

Biological response modifiers
  • Biological response modifiers are compounds that
    are used to treat cancer by altering or
    augmenting naturally occurring processes within
    the body.
  • Immunotherapy makes use of BRMs to enhance the
    activity of the immune system to increase the
    body's natural defense mechanisms against cancer.
  • The role of cytokines in the body's defenses
    makes them appealing targets for treating some
    cancers. Cytokines are normally found in very
    small amounts. When used as cancer treatments the
    concentrations used are greatly increased.
  • The cytokines most frequently used to treat
    cancer are interleukin-2 and alpha interferon.
    These compounds do have side effects when used at
    the high doses necessary for cancer treatment and
    their effectiveness varies depending on the
    cancer type.

Cancer vaccines
  • The purpose of cancer vaccines is to stimulate
    the body's defenses against cancer by increasing
    the response of the immune system.
  • Tumor vaccines usually contain proteins found on
    or produced by cancer cells. By administering
    forms of these proteins and other agents that
    affect the immune system, the vaccine treatment
    aims to involve the patient's own defenses in the
    fight to eliminate cancer cells.
  • Immunotherapy is a new field in cancer treatment
    and prevention, and many strategies are being
    exmined in clinical trials.
  • It is likely that tumor vaccines and other
    approaches designed to increase the activity of
    the immune