Cancer chemotherapeutics ver 6.0

Stats…
2Siegel et al: CA Cancer J Clin 2014
http://www.neeman-medical.com/sites/default/files/files/Cancer%20in%20India.pdf Accessed on 28.4.16

What Is Cancer?
• Cancer/Neoplasia – a large group of diseases characterized
by the uncontrolled growth and spread of abnormal cells
• Malignant - cancerous
• Benign - noncancerous
3Kasper et al, Harrison's Principles of Internal Medicine, 19th Edition (2015)
DeVita, Hellman, and Rosenberg’s, Cancer Principles & Practice of Oncology 10th Edition

What Is Cancer? – cont.
• Metastasis – malignant tumors that are not enclosed in a
protective capsule have the ability to spread to other
organs
• Mutant cells – disruption of RNA and DNA within normal
cells may produce cells that differ in form, quality and
function from the normal cell

Cancer Progression
5
Benign Tumour
In situ cancer
Invasive cancer
Metastatic
cancer
Mutations in multiple cancer genes are required for the
development and progression of a single cancer
Kasper et al, Harrison's Principles of Internal Medicine, 19th Edition (2015)

What Causes Cancer?
• External Factors – chemicals, radiation, viruses, and
lifestyle
• Internal Factors – hormones, immune conditions, and
inherited mutations
• Theories
• Cellular change/mutation theories
• Carcinogens
• Oncogenes/ protooncogenes

Factors Believed to Contribute to Global Causes of Cancer

Risks For Cancer
• Lifetime risk – the probability that an individual, over the course
of a lifetime, will develop cancer or die from it
• Relative risk – measure of the strength of the relationship
between risk factors and a particular cancer
• Smoking – 30% of all cancer deaths, 87% of lung cancer deaths
• Obesity – 50% higher risk for breast cancer in postmenopausal
women, 40% higher risk in colon cancer for men

Biological Factors
• Some cancers such as breast, stomach, colon, prostate,
uterus, ovaries and lung appear to run in families
• Hodgkin’s disease and certain leukemia's show similar
patterns
• University of Utah research suggests that a gene for breast
cancer exists
• A rare form of eye cancer appears to be transmitted
genetically from mother to child

Reproductive And Hormonal Risks For Cancer
• Pregnancy and oral contraceptives increase a woman’s
chances of breast cancer
• Late menarche, early menopause, early first childbirth,
having many children have been shown to reduce risk of
breast cancer

Occupational And Environmental Factors
• Asbestos
• Nickel
• Chromate
• Benzene
• Arsenic
• Radioactive substances
• Cool tars
• Herbicides/pesticides

Social And Psychological Factors
• Stress has been implicated in increased susceptibility to
several types of cancers
• Sleep disturbances, diet, or a combination of factors may
weaken the body’s immune system

Chemicals In Foods
• Sodium nitrate when ingested forms a potential
carcinogen, nitrosamine
• Sodium nitrate is still used because it is effective in
preventing botulism
• Pesticide and herbicide residues
13

Viral Factors
• Herpes-related viruses may be involved in the development
of leukemia, Hodgkin’s disease, cervical cancer, and
Burkitt’s lymphoma
• Epstein-Barr virus, associated with mononucleosis, may
contribute to cancer
• Human papillomavirus (HPV), virus that causes genital
warts, has been linked to cervical cancer
• Helicobacter pylori causes ulcers which are a major factor
in the development of stomach cancer

Medical Factors
• Some medical treatments actually increase a person’s risk
for cancer
• Diethylstilbestrol (DES) used 1940 to 1960 to control
bleeding during pregnancy, the daughters of mothers that
used DES were found to have an increased risk for cancers
of the reproductive organs
• Estrogen supplementation
• Chemotherapy used to treat one form of cancer may
increase risk for another type of cancer

Cancer’s Seven Warning Signals

Cancer treatment modalities
• Can be used alone or in
combination
• Outcome measured in
terms of survival rates and
response rates

Target Areas for Therapeutic Interventions
18
Invasivity
Motility
Aneuploidy
Angiogenesis
Imune Defense
Evasion
Deregulated
Proliferation
Altered Energy
Metabolism
Immortalization
(Anti-Apoptosis)

19
Paul Ehrlich 1854 - 1915
•Father of Chemotherapy
• Salvarsan for Treatment of Syphilis
• Nobel Prize 1908
• “Magic Bullet Concept”

History of chemotherapy development
20
• 1946 Nitrogen mustard given to
treat lymphomas
• 1947 Antifolates introduced
• 1949 Methotrexate introduced
• 1950s 5-Fluoro-uracil synthesised
• 1952 6-mercaptopurine
described
• 1954 Actinomycin D introduced
• 1960s Combination chemo cured
childhood ALL and HD
• Recent Years Many new agents Focus
changes to optimising timing and
usage and modulating toxicity

The cell cycle

Phases of the cell cycle
• G0 resting phase
• G1 early growth
phase
• S DNA synthesis
• G2 later growth phase
• M Mitosis

Cell division – mitosis (1)
• Prophase
• Chromatin condenses into
chromosomes. Each
chromosome duplicates and
consists of 2 sister chromatids.
Nucleus breaks down
• Metaphase
• Chromosomes align and are
held by microtubules attached
the mitotic spindle and to the
centromere

Cell division – mitosis (2)
• Anaphase
• The centromeres divide. Sister
chromatids separate and move
toward the corresponding poles
• Telophase
• Daughter chromosomes arrive at
the poles and the microtubules
disappear. The condensed
chromatin expands and the
nuclear envelope reappears
• The cytoplasm divides, the cell
membrane pinches inwards and
two daughter cells are produced

The Cell Cycle and Tissue Growth
• The rate of cell division in human tumours varies
considerably from one disease to another
• Majority of common cancers increase in size slowly
compared to sensitive normal tissues such as BM and GI
epithelium
• The relationship between cell cycle and cell death affects
tumour growth

Chemotherapy Effects
• Cytotoxic drugs produce their effects by damaging the
reproductive potential of cells
• The more rapidly growing tumours are more likely to
respond to drug treatment
• this accounts for leukaemias, lymphomas and testicular cancers
being more responsive than colonic / pancreatic cancers

Growth Fraction
• At a given time, the number of cells in a population that
are actively passing through the cell cycle divided by the
total number of cells in the population = growth fraction
• The greater the growth faction, the more likely the
treatment will produce cell death

Kinetics of cell killing
• Fractional Cell kill hypothesis
• A given dose of cytotoxic drug kills
a given proportion of cells, not a
given number
• Smaller tumours require fewer
cycles of chemotherapy than larger
ones
• Pulsed intermittent therapy
• Maximises tumour cell killing whilst
allowing normal tissues damaged
by the drug to recover

Cytotoxic Drug Classification based on cell cycle specificity
• Cell Cycle Phase-Specific Agents
• active in a particular phase of cell cycle
• Depend on the production of some type of unique biochemical
blockade of a particular reaction occurring in a single phase of the cell
cycle
• Cell Cycle Phase-Non-specific Agents
• Cytotoxic effect exerted irrespective of cell cycle state
• equally effective in large tumours in which cell growth is low
• dose dependent
• single dose has same effect as repeated fractions totalling the same
amount

Classification of Chemotherapeutic Agents
• Alkylating agents
• Nitrogen Mustards: Cyclophosphamide,. Chlorambucil,
Melphalan,
• Alkyl Sulfonate: Busulfan
• Nitrosoureas : Carmustine, Lomustine,semustine
• Ethylenimines: Thiotepa
• Triazenes : Dacarbazine
• Antimetabolites
• Folate antagonist: methotrexate and gemcitabine
• Purine analogues: thioguanine, mercaptopurine, pentostatin
• Pyrimidine analogues: fluorouracil, cytarabine

• Plant-derived products
• Vinca alkaloids( vincristine, vinblastine) epipodophyllotoxins (
etoposide) taxanes: (paclitaxel)
• Antibiotics
• doxorubicin , daunorubicin , bleomycin, mitomycin, dactinomycin
• Hormones and related drugs :
• tamoxifen estramustine, flutamide , progestins
• Miscellaneous agent :
• hydroxyurea, cisplatin , mitoxantrone, levamisole, interferon alfa
and aldesleukin.

• Drugs that alters hormonal milieu
• Glucocorticoids: Prednisolon, Prednisone
• Estrogen: Diethylstilbestreol
• Anti-estrogen: Tamoxifen
• Androgen: Testosteron
• Progestin: Medroxy Progesteron Acetate
• Monoclonal Antibodies
• Trantuzumab –anti HER 2
• Rituximab –CD 20
• Imatinib – TKI
• Cetuximab – EGFR
• Bevacizumab-VEGFR

Alkylating Agents
• Contain chem grps that covalently bind cell nucleophiles
• Impt properties of drugs
• Can form carbonium ions
• C w/ 6 electrons highly reactive
• React w/ -NH2, -OH, -SH
• Bifunctional (2 reactive grps)
• Allow cross-linking
33

Alkylating Agents
• Impt targets
• G N7 – strongly nucleophilic
• A N1, A N3, C N3 also targets
• DNA becomes cross-linked w/ agent
• Intra- or inter-strand
•  Decr’d transcr’n, repl’n
•  Chain scission, so strand breaks
•  Inappropriate base pairing (alkylated G w/ T)
• Most impt: S phase repl’n (strands unwound, more
susceptible)  G2 block, apoptosis
34

Nitrogen Mustards
• Loss Cl intramolec cyclization of side chain
Reactive ethylene immonium derivative
36

Cyclophosphamide
• Most common
• Prodrug – liver metab by CYP P450 MFO’s
• Effects lymphocytes
• Also immunosuppressant
• Oral or IV usually
• SE’s: n/v, bone marrow dpression, hemorrhagic cystitis
• Latter due to acrolein toxicity; ameliorated w/ SH-donors
37

Nitrosoureas
• Also activated in vivo
• Alkylate DNA BUT alk’n prot’s toxicity
39

Temozolomide
• Methylates G, A improper G-T base pairing
40

Cisplatin
• Cl- dissoc’s  reactive complex that reacts w/ H2O and
interacts w/ DNA  intrastrand cross-link (G N7 w/
adjacent G O6)  denaturation DNA
• Nephrotoxic
• Severe n/v ameliorated w/ 5-HT3 antagonists (decr gastric
motility)
• Carboplatin – fewer above SE’s, but more myelotoxic

Antimetabolites
• Mimic structures of normal metabolic mol’s
• Inhibit enz’s competitively OR
• Inc’d into macromol’s  inappropriate structures
• Kill cells in S phase
• Three main groups
• Folate antagonists
• Pyr analogs
• Pur analogs
42

Folic Acid Analogs
• Folic acid essential for synth purines, and thymidylate
• Folate: pteridine ring + PABA + glutamate
• In cells, converted to polyglutamates then  tetrahydrofolate
(FH4)
43

• Folate  FH4 cat’d by
dihydrofolate reductase in
2 steps:
• Folate  FH2
• FH2  FH4
• FH4 serves as methyl grp
donor (1-C unit) to
deoxyuridine (dUMP 
dTMP), also regenerating
FH2

Methotrexate
• Higher affinity for enz than does FH2
• Add’l H or ionic bond forms
•  Depletion FH4 in cell  depl’n dTMP  “thymine-less
death”
•  Inhib’n DNA synth
• Uptake through folate transport system
• Resistance through decr’d uptake
• Metabolites (polyglutamate deriv’s) retained for weeks,
months
45

Pyrimidine Analogs
• 5-Fluorouracil – dUMP analog also works through dTMP
synthesis pathway
• Converted  “fraudulent” nucleotide FdUMP 
• Competitive inhibitor for thymidylate synthetase active site, but
can’t be converted to dTMP
• Covalently binds thymidylate synthetase
• Mech action uses all 3routes  decr’d DNA synthesis, also
transcr’n/transl’n inhib’n
50

• Gemcitabine
• Phosph’d  tri-PO4’s
• “Fraudulent nucleotide”
• Also inhib’s ribonucleotide reductase  decr’d nucleotide synth
• Capecitabine is prodrug
• Converted to 5FU in liver, tumor
• Enz impt to conversion overexpressed in cancer cells (?)
51

• Cytosine arabinoside
• Analog of 2’dC
• Phosph’d in vivo  cytosine arabinoside triphosphate
• Inhibits DNA polymerase
• Gemcitabine – araC analog
• Fewer SE’s
53

http://www.pfeist.net/ALL/arac/images/spongo2.gif
42-11
Gemcitabine

Purine Analogs
• 6-Mercaptopurine, 6-Thioguanine
• Converted to “fraudulent nucleotides”
• Inhibit enz’s nec for purine synth
• Fludarabine
• Converted to triphosphate
• Mech action sim to ara-C
• Pentostatin
• Inhibits adenosine deaminase
• Catalyzes adenosine  inosine
• Interferes w/ purinemetab, cell prolif’n
55

Cytotoxic Antibiotics
• Substances of microbial origin that prevent mammalian cell
division
• Anthracyclines
• Doxorubicin
• Intercalates in DNA
• Inhibits repl’n via action at topoisomerase II
• Topoisomerase II catalyzes nick in DNA strands
• Intercalated strand/topoisomerase complex stabilized  permanently
cleaved helix
57

• Epirubicin, mitozantrone structurally related
• SE’s: cardiotoxicity (due to free radical prod’n), bone
marrow suppression
58
Mitozantrone

• Dactinomycin
• Intercalates in DNA minor groove between adjacent GC pairs
• Interferes w/ RNA polymerase movement decr’d transcr’n
• Also may work through topoisomerase II
• Bleomycin
• Glycopeptide
• Chelates Fe, which interacts w/ O2
•  Gen’n superoxide and/or hydroxyl radicals
• Radicals degrade DNA  fragmentation, release of free bases
• Most effective in G2, also active against cells in G0
• Little myelosuppression BUT pulmonary fibrosis
59

Plant Alkaloids
• Work at mitosis
• Effect tubulin, therefore microtubule activity
•  Prevention spindle form’n OR
• Stabilize (“freeze”) polymerized microtubules
•  Arrest of mitosis
• Other effects due to tubulin defects
• Phagocytosis/chemotaxis
• Axonal transport in neurons
61

Taxanes: Paclitaxel, Docetaxel
63

• Etoposide, teniposide
• From mandrake root
• Inhibit mitoch function, nucleoside transport, topoisomerase II
• Campothecins: irinotecan, topotecan
• Irinotecan requires hydrolysis  active form
• Bind, inhibit topoisomerase II
• Repair is difficult
64

Chemotherapy Side Effects
• Chemotherapy targets cells which are dividing rapidly.
• Chemotherapy cannot distinguish between normal cells
and cancer cells
• Healthy Cells which have a high rate of growth and
multiplication include cells of the bone marrow, hair, GI
mucosa and skin.
• Side effects may be drug specific e.g. anthracyclines and
cardiotoxicity, vinca alkaloids and neuropathy/constipation,
bleomycin and pulmonary fibrosis
• Severity of side effects varies between drugs.
• Side effects often occur 7-14 days post treatment.
66http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/chemotherapy/chemotherapy-landing Assessed on
21.05.16

Side Effects: Acute
• Tumour Lysis Syndrome
• A Metabolic Emergency.
• Occurrs due to rapid cell lysis (death) & large amounts of cell
metabolites in blood.
• If untreated can lead to acute renal failure, cardiac arrest and
death
• Neutropenic Sepsis
• Occurs due to Bone Marrow Failure and
• poor immune response to infection.
• Predisposing factors include:
• Neutropenia
• Underlying disease
• Chemotherapy
• Venous access devices
21.05.16

Side Effects: Acute
• Haemorrhage
• Invading tumours e.g gastric MALT
• lymphomas
• Haemorrhagic Cystitis related to high dose Cyclophosphomide
• Anaphylactic Reaction
21.05.16

Side Effects: Bone Marrow
• Neutropenia:
• Increased risk of infection.
• Anaemia:
• Tiredness, lethargy & breathlessness
• Thrombocytopenia:
• Increased risk of bleeding
21.05.16

Side Effects: Gastro-Intestinal
• Nausea & Vomiting
• Diarrhoea & constipation
• Loss of appetite
• Taste Changes
• Mucositis
70
Grade 4 Mucositis
http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/chemotherapy/chemotherapy-landing Assessed on
21.05.16

Side Effects: Body Image and Others
• Body Image
• Hair Loss
• Weight Loss/ Weight Gain
• Long term central venous catheters
• Skin changes (colour, rashes, sensitivity to sunshine/chlorine, dry)
• Others
• Fatigue: Often multi-factorial
• Peripheral neuropathy
• Altered Kidney Function
• Changes in hearing (high dose Cisplatin)
• Cardiac Toxicity (Doxorubicin/ Idarubicin)
• Late Effects: Infertility, secondary malignancy, growth retardation.
21.05.16

Aim Of Combination Chemotherapy
72
INCREASED EFFICACY
Different mechanisms of action Compatible side effects
Different mechanisms of resistance
ACTIVITY SAFETY
http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/chemotherapy/chemotherapy-landing Assessed on
21.05.16

Principles of combination chemotherapy
• Combination chemotherapy accomplishes three important
objectives not possible with single-agent therapy:
• It provides maximum cell kill within the range of toxicity tolerated
by the host for each drug
• It offers a broader range of coverage of resistant cell lines in a
heterogeneous tumor population
• It prevents or slows the development of new drug-resistant cell
lines.
21.05.16

Selection of drugs for combination regimens
• Following principles have been established to guide drug
selection in combination regimens:
• Drugs known to be active as single agents
• Drugs with different mechanisms of action
• Drugs with differing dose-limiting toxicities
• Drugs should be used in their optimal dose and schedule.
• Drugs should be given at consistent intervals. The treatment-free
interval between cycles should be the shortest possible time for
recovery of the most sensitive normal tissue.
• Drugs with different patterns of resistance should be combined to
minimize cross-resistance.
21.05.16

Modes of Chemotherapy
• Primary Chemotherapy
• Used as the sole anti-cancer treatment in a highly sensitive tumor
types, E.g. CHOP for Non-Hodgkins lymphoma
• Adjuvant Chemotherapy
• Treatment is given after surgery to “mop up” microscopic residual
disease. E.g. Adriamycin, cyclophosphamide for breast cancer
• Neoadjuvant Chemotherapy
• Treatment is given before surgery to shrink tumor and increase
chance of successful resection, E.g. Adriamycin, ifosfamide for
osteosarcoma
• Concurrent Chemotherapy
• Treatment is given simultaneous to radiation to increase
sensitivity of cancer cells to radiation. E.g. Cisplatin, 5-
fluourouracil, XRT for head and neck tumors
21.05.16

Deciding which chemotherapy drugs to use
• Factors to consider in choosing which drugs to use include:
• Type of cancer
• Stage of the cancer (how far it has spread)
• Patient’s age
• Patient’s overall health
• Other serious health problems (such as heart, liver, or kidney diseases)
• Types of cancer treatments given in the past
• Considering the side effects
• Avoiding drug interactions
21.05.16

Planning Drug Doses And Schedules
• Doses
• Based on body surface area
• Differ between children and adults
• Adjusted for people
• Who are elderly
• Having poor nutritional status
• Who have already taken or taking other medications
• Who have already received or are currently receiving radiation therapy
• Who have low blood cell counts
• Who have liver or kidney diseases
21.05.16

Planning Drug Doses And Schedules
• Schedule (Cycles)
- A cycle = one dose followed by several days or weeks
without treatment for normal tissues to recover from the
drug’s side effects
The number of cycles = based on the type and stage of
cancer, and side effects
21.05.16

Hematological Considerations For Dose Scheduling
• Lifespan
• Platelet - 7-10 days
• Red blood cell - 120 days
• Neutrophils - 6-12 hours
• Time from Stem Cell to Mature Neutrophil
• ~7-10 days
79

How chemo is given
• In most cases, chemo drugs are put right into the bloodstream
or taken as pills. They then travel throughout the body to kill
cancer cells
• Regional chemo include drugs given into these parts of the
body:
• Intra-arterial – injected into an artery that goes to a certain area of the
body
• Intravesical – put into the bladder
• Intrapleural – put into the chest cavity between the lung and chest wall
• Intraperitoneal – put into the belly (abdomen) around the intestines
and other organs
• Intrathecal – put into the central nervous system (brain and spinal cord)
• Intralesional/intratumoral – injected right into the tumor
• Topical – applied to the skin as a cream or lotion
21.05.16

Deciding On Treatment Intervals
• As short as possible
• Recovery of bone marrow
• Supplies mature cells for 8-10 days
• Onset 9-10th days
• Lowest (nadir) 14-18th days
• Recovery by day 21-28.
• Usual schedule is q21-28 days.
21.05.16

Dose-dense chemotherapy
• A chemotherapy treatment plan in which drugs are given
with less time between treatments than in a standard
chemotherapy treatment plan.
• Gompertzian growth curve:
• Tumor growth follows a mathematically predictable growth
curve, with rapid growth initially, then leveling off to slower
growth
• Cells are most sensitive to chemotherapy when they are rapidly
dividing
• The rationale for dose-dense therapy stems from the
Norton-Simon hypothesis:
• Sequential, consecutive dosing of chemotherapy using single or a
combination of agents increases the dose density over
alternating dosing , improving results
82Citron et al, Breast Care 2008;3:251–255

Norton-Simon hypothesis

CALGB 9741: Trial Specifically Testing Dose Density
Intergroup C9741/CALGB 9741 was a prospective randomized trial that
tested the dose density with chemotherapy doses that could be used in
the outpatient setting
84
DFS and OS were significantly greater with the dose-dense regimens
(risk ratio = 0.74; p = 0.010, and 0.69; p = 0.013, respectively) and
were not affected by the number of positive nodes, tumor size,
menopausal status, or tumor estrogen receptor status
Citron et al, Breast Care 2008;3:251–255

E1199: Paclitaxel vs Docetaxel Weekly vs Q 3 Week

ECOG 1199: DFS

Making The Decision Based on Toxicity ECOG 1199 (Grade 3-4)

Hormonal Therapy
• It involves the manipulation of the endocrine system
through exogenous administration of specific hormones
• Which inhibit the production or activity of such hormones
(hormone antagonists)
• Hormonal therapy is used for several types of cancers
derived from hormonally responsive tissues
• Breast, prostate, endometrium, and adrenal cortex

Inhibitors of hormone synthesis
• Aromatase inhibitors
• Used for the treatment of breast cancer in postmenopausal
women
• When the action of aromatase is blocked, estrogen levels in post-
menopausal women can drop to extremely low levels, causing
growth arrest and/or apoptosis of hormone-responsive cancer
cells
• Letrozole and anastrozole are aromatase inhibitors which have
been shown to be superior to tamoxifen for the first-line
treatment of breast cancer in postmenopausal women
• Exemestane is an irreversible "aromatase inactivator" which is
superior to megestrol acetate for treatment of tamoxifen-
refractory metastatic breast cancer, and does not appear to have
the osteoporosis-promoting side effects of other drugs in this
class

Inhibitors of hormone synthesis
• GnRH analogs
• Analogs of gonadotropin-releasing hormone (GnRH)
• Can be used to induce a chemical castration
• Leuprolide and goserelin are GnRH analogs which are used
primarily for the treatment of hormone-responsive prostate
cancer

Hormone receptor antagonists
• Hormone receptor antagonists bind to the normal receptor
for a given hormone and prevent its activation.
• Selective estrogen receptor modulators (SERMs)
• Used primarily for the treatment and chemoprevention of breast cancer
• Tamoxifen
• Partial agonists
• Raloxifene
• Partial agonist
• Used primarily for chemoprevention of breast cancer in high-risk
individuals, as well as to prevent osteoporosis
• Toremifene and fulvestrant
• Used for treatment of metastatic breast cancer

Hormone receptor antagonists
• Antiandrogens
• Bind and inhibit the androgen receptor
• Blocking the growth- and survival-promoting effects of testosterone on
certain prostate cancers
• Flutamide and bicalutamide
• Used in the treatment of prostate cancer

Hormone supplementation
• Progestogens
• Progestins (progesterone-like drugs)
• Megestrol acetate and medroxyprogesterone acetate
• Used for the treatment of hormone-responsive, advanced breast
cancer, endometrial cancer, and prostate cancer
• Used in the treatment of endometrial hyperplasia, a precursor to
endometrial adenocarcinoma
• Androgens
• Fluoxymesterone is occasionally used for the treatment of advanced
breast cancer

Hormone supplementation
• Estrogens
• Diethylstilbestrol (DES) is occasionally used to treat prostate
cancer through suppression of testosterone production
• Estrace is an estrogen which was also formerly used for anti-
androgen therapy of prostate cancer
• Polyestradiol phosphate is a long-acting derivative of estradiol
that is applied as an intramuscular injection.
• Somatostatin analogs
• Octreotide is an analog of the peptide hormone somatostatin
• Used for
• Zollinger-Ellison syndrome of gastrinoma
• Chronic hypoglycemia of insulinoma
• Treatment of severe diarrhea caused by 5-fluorouracil chemotherapy or
radiation therapy

Targeted Therapies
• Definition
• Allow the cancer treatment to “target” a certain cancer cell by
interfering with the natural functions of tumor growth
• How they work
• They “target” specific parts of a cancer cell or its actions
95
Dietel M et al, Targeted therapies in cancer,

Biology of Targeted Therapy
96
These drugs act on rapidly dividing cells,
which include normal tissues (e.g., hair,
gastrointestinal epithelium, bone marrow)
in addition to cancer cells
Mechanisms of traditional chemotherapy Mechanisms of targeted therapies
Gerber D E, 2008, American Family Physician

Classification of Targeted therapies
• Targeted cancer agents are broadly classified as
• Therapeutic monoclonal antibodies
• Target specific antigens found on the cell surface, such as transmembrane
receptors or extracellular growth factors
• In some cases, monoclonal antibodies are conjugated to radio-isotopes or
toxins to allow specific delivery of these cytotoxic agents to the intended
cancer cell target
• Small molecules
• Penetrate the cell membrane to interact with targets inside a cell
• Usually designed to interfere with the enzymatic activity of the target protein.
97

Monoclonal Antibodies for Cancer Treatment
98

99

10
0Gerber D E, 2008, American Family Physician

Small Molecule Inhibitors for Cancer Treatment
10

Cancer chemotherapeutics ver 6.0

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