Anticancer drugs

1
Anticancer drugs
4th year, General MedicinePractical Ing. J.
Chládek, Ph.D.
2
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)

3
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

4
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.

5
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.

6
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
  death.
• Tumor suppressors. Genes whose protein products
  can directly or indirectly prevent cell division
  or lead to cell death.

7
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
  individuals.

8
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.
9
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
  replication.
• Bcl-2 a membrane associated protein that
  functions to prevent apoptosis.

10
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
  problems
• 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
  factor
• BRCA involved in DNA repair.

11
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).

12
Characteristics of Cancer Cells

• 1) Excessive autonomous cell growth
• tumor cells produce growth factors that stimulate
  their own proliferation (i.e. autocrine
  stimulation)
• 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
  inhibition)
• (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
  barriers
• 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

13
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).

14
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.

15
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
16
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
17
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.

18
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
  defenses.

19
Classical types of cancer treatment

• Often in combination, either simultaneously or
  sequentially
• 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.

20
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
  drugs.
• 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.

21
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).

22
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.

23
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

24
Mechanisms of resistance
? deletion of enzyme to activate drug
? increased detoxication of drug
? reduced uptake of drugs
active metabolite
inactivated cytotoxic drug
C
? increased efflux (multidrug resistance)
defective cellular target
T
rapid repair of drug-induced lesion
T
increased concentration of target molecules
T- cellular target T - gene amplification
25
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
  cardiotoxicity
• amifostine reduces hematotoxicity, ototoxicity
  and neurotoxicity of alkylating agents

26
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.

27
General rules of chemotherapy

• 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

28
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
  function.
• 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
  replication.
• Other Chemotherapy Agents These agents inhibit
  cell division by mechanisms that are not covered
  in the categories listed above.

29
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
Vincristine,
Vinblastine
Paclitaxel, Docetaxel
Cyclophosphamide
Bleomycin
Actinomycin D
M
G
0
resting
G
Hydrocortisone
G
2
1
S
Actinomycin D
Purine antagonists
5-Fluorouracil
Methotrexate
Cytosine arabinoside
Cyclophosphamide
Methotrexate
5-Fluorouracil
6-Mercaptopurine
Cytosine arabinoside
6-Thioguanine
Daunomycin
30
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,
  cisplatin

31
Antimetabolites

• 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
  survive.
• Antimetabolites used in the treatment of cancer
  interfere with the production or function of the
  nucleic acids, RNA and DNA

32
Antimetabolites

• Folate Antagonists
• Purine Antagonists
• Pyrimidine Antagonists

33
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
  MTX-poly-glutamate)
• Polyglutamates are retained in cells.

34
Methotrexate discovery

• 1945 folic acid identified as an essential
  growth factor for Lactobacillus casei, later
  synthetized
• 1948 Sidney Farber (Children's Hospital Boston)
  used FA as a supportive therapy of
  children with leukemia their symptoms
  deteriorated.
• 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
  aminopterine.
• Methotrexate designed as an DHFR inhibitor.
• Marketed in 1953.

35
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.

36
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
37
Methotrexate

• 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
  years)
• Low-dose MTX once a week (7.5-25 mg p.o., i.m.,
  s.c.) immunosuppressive therapy of psoriasis,
  rheumatoid arthritis, Crohn disease

38
Resistance to Methotrexate

• There are three known ways in which a cell may
  acquire
• immunity to the effects of this folate
  antagonist
• 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
  binding

39
Purine Antagonists

• 6- merkaptopurine

• 6- thioguanine

• fludarabine

40
Purine Antagonists
41
Mechanizm of action of 6-mercaptopurine
6-mercaptopurine
Guanine
Hypoxanthine
hypoxanthine-guanine phosphoribosyltransferase
(HPRT)
Adenosine monophosphate
Guanosine monophosphate
Inosine monophosphate
Purine synthesis de novo
42
Metabolism of 6-mercaptopurine
6-thioxantine 6-thiouric acid
Metabolic inactivation Metabolic activation
Xanthine oxidase
Non-enzymatic
6-thioinosine monophosphate
6-thioguanosine -monophosphate
TPMT
TPMT
Incorporated in DNA as a false nucleotide
methyl-TIMP
methyl-MP
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)
43
6-mercaptopurine

• 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.)

44
Fludarabine

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

45
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
  enzymes.
• The pyrimidine antagonist may also be
  incorporated into a growing DNA
  chain and lead to termination of the process.

46
Pyrimidine Antagonists

• 5-fluorouracil

Thymine
Uracil
Cytosine arabinoside (Ara-C)
Gemcitabine
Capecitabine
47
5-fluorouracil

• 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

48
5-fluorouracil

• 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.

49
5-fluorouracil

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

50
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.

51
Cytarabine

• Malignancies for which cytarabine is used
  include
• 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

52
Capecitabine

• 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
  processing.
• Malignancies for which capecitabine is used
  include
• Metastatic colorectal cancer
• Metastatic and/or resistant breast cancer
• Capecitabine is administered as an oral tablet.

53
Gemcitabine

• 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
  include
• Non-small cell lung cancer (in combination with
  cisplatin)
• Pancreatic cancer (advanced or metastatic)
• Gemcitabine is administered as an intravenous
  infusion.

54
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
  separate.
• As this is necessary in DNA replication, the
  cells can no longer divide.
• Cell-cycle nonspecific effect
• Alkylating agents are also mutagenic and
  carcinogenic

T
A
G
C
C
G
G
A
T
G
C
55
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)
56
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.
cyclofosfamide
ifosfamide
bis(2-chloroethyl) ethylamine
57
Cyclofosfamide requires conversion into active
substances in vivo
cytochrome P450
4-hydroxycyclofosfamide
aldofosfamide
Aldehyde oxidase
Non-enzymatic
carboxyfosfamide (nontoxic)
acrolein (cytotoxic)
phosphoramide mustard (the active principle)
CH2
CH
CHO
Akrolein zpusobuje hemoragickou cystitidu,
prevence hydratace, MESNA (merkaptoetansulfonan
sodný, donor SH-skupin prevede akrolein na
thioétery)
58
Cyclofosfamide

• 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

59
Cyclofosfamide

• Adverse effects (cytotoxicity, mutagenicity,
  immunosuppression)
• 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

60
Ifosfamide

• Similar to cyclofosfamide
• Broader spectrum of anticancer activity than
  cyclofosfamide

61
Cyclofosfamide

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

62
Platinum drugs Cisplatin

• 1965 Rosenberg et al. observed inhibition of
  bacterial deviding in a solution near a Platinum
  electrode
• Malignancies for which cisplatin is used
  include
• 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
  emetogens)
• Taste changes, including a metallic taste to
  foods
• Neurotoxicity - Sensation of 'pins and needles'
  in hands and/or feet
• Decreased red blood cell counts

63
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)

64
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

65
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

66
Anthracyclines

• Anthracyclines (anthracycline antibiotics) rank
  among the most effective anticancer drugs ever
  developed
• 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)

67
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.
68
Anthracyclines

• Doxorubicin (Adriamycin)
• Daunorubicin
• Epirubicin
• Idarubicin

• Structure tetracyclic aglycone with
  quinone-hydroxyquinone groups sugar moiety
  daunosamine
• Poor oral absorption therefore given by IV

69
Anthracyclines

• 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
  cancer.
• 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
  leukemias
• Multidrug resistance to all anthrycyclines

70
Anthracyclines

• 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
  cardiotoxicity.
• Liposomal formulations of daunorubicin and
  doxorubicin have been approved that appear to be
  somewhat less toxic to cardiac tissue.

71
Plant-derived inhibitors of mitosis

• Inhibitors of mitosis (spindle poisons or mitosis
  poisons) include several different chemotherapy
  drugs.
• Unlike the previous drugs discussed, they do not
  work to alter DNA structure or function. Rather,
  they interfere with the mechanics of cell
  division.
• 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
  microtubule.

72
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

Vincristine
73
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
  leukemias
• Side effects
• Hair loss, Nausea/stomach pain/vomiting, Lowered
  blood cell count, Nervous system problems such as
  neuropathy or sensory impairment

74
Vinca alkaloids Vinblastine

• Drug Usage
• Breast cancer
• Testicular cancer
• Lymphomas

75
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
  carcinomas.
• 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.
76
Docetaxel

• 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.

Docetaxel
Paclitaxel
77
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.

78
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
toxic.
79
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
  chemotherapy.
• Prodrug of the active compound SN-38
• AE granulocythopenia, thrombocytopenia, diarrhea

80
Topoisomerase II inhibitors

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

81
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
  leukemia.
• Adverse effects trombocythopenia, neutropenia

82
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
  balance.
• 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.

83
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.

84
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
  estrogen.
• Selective Androgen Receptor Modulators (SARMs)
  These agents work by interfering with the
  activity of the androgen receptor.
• Additional Hormone Treatments

85
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
  hormone.
• The blockage of estrogen in the target cells
  causes changes in gene expression and alters the
  behavior of the cells, preventing cell division.

86
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.

87
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.

88
Breast Cancer - Selective Estrogen Receptor
Modulators (SERMs)

• Raloxifene is currently prescribed to prevent
  osteoporosis.
• 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.

89
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.

90
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
  aromatase.
• 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
  letrozole).

91
Aromatase inhibitors

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

92
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
  division.
• 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

93
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).

94
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

95
Glucocorticoids

• 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

96
Enzymes

• 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.

97
New promising approaches to cancer treatment and
prevention

• Specific Inhibitors
• Biological response modifiers
• Antibodies
• Anticancer vaccines
• Cancer prevention using vaccines
• (e.g. Vaccine against Human papilomavirus)

98
Supplemental information

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

99
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
  effects.
• 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
  chemotherapy.

100
Specific Inhibitors

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

101
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
  it.
• The bound mRNA is not suitable for translation
  and is degraded.

102
Ribozymes

• 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.

103
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)

104
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
  vessels.
• 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.

105
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.

106
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
  proliferation.
• 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.

107
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.

108
Antibodies in Cancer Treatment
Carter P Improving the efficacy of
antibody-based cancer therapies. Nat Rev Cancer
20011118-129
109
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

110
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.

111
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.

112
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