Transcript Pharmacology of Chemotherapy

Pharmacology of Chemotherapy
David W. Hedley MD
Dept Medical Oncology and Hematology
Division of Applied Molecular Oncology
Chemotherapy
• Cytotoxic agents
- generally given by intravenous injection or
orally
• Most chemotherapy drugs act by damaging
DNA or inhibiting DNA synthesis
• Important exceptions are drugs that target
microtubules
Evolution of Chemotherapy
1940’s – first use of successful use alkylating
agent nitrogen mustard to treat human cancer
1950-1960’s – major alkylating agents and antimetabolites currently in use synthesized.
Effective against wide range of cancer types,
particularly rapidly growing leukemias and
lymphomas.
Scientific principles of cancer chemotherapy
developed.
The Science of Chemotherapy
• Many early concepts derived from radiation
biology:
- clonogenic survival
- fractional cell kill
- need to eliminate all clonogenic cells to
achieve cure
- normal host effects
The Science of
Chemotherapy
L1210 Mouse Lymphoma:
Howard Skipper’s work (1960’s)
• Rapidly growing tumours
• Initially used animal
survival to infer cancer cell
killing in vivo
• Based on relation between
number of cells inoculated
and survival
The Science of
Chemotherapy
• Fractional cell kill of L1210
lymphoma inoculated at
1x106 in vivo
• Single treatment with
chemotherapy drug
• Effect on lifespan with
increasing log cell kill
• Even though you get a lot
of cancer cell, difficult to
achieve cure!
Clinical Implications of Fractional Cell Kill
The Science of Chemotherapy
- Bob Bruce Data Showing Cell Cycle Dependence of Killing by gRadiation, Nitrogen Mustard, and Tritiated Thymidine in Lymphoma
vs. Normal Bone Marrow in vivo (JNCI 1966;37:233-245)
The Science of Chemotherapy
Ian Tannock’s
PhD Project
Using tritiated
thymidine
autoradiography,
showed solid
tumours proliferate
more slowly further
away from blood
vessels.
Cause of drug
resistance
Evolution of Chemotherapy
1970’s - “Golden Age” of medical oncology.
Development of effective combination
chemotherapy regimens.
New classes of drug developed
- anthracyclines, platinum compounds
Cures achieved in some forms of cancer
(lymphomas, leukemias, testis cancer).
Significant responses in some common types of
cancer (breast, stomach, small cell lung cancer)
Effective use of chemotherapy to prevent
recurrence in high risk breast cancer patients.
Evolution of Chemotherapy
1980’s – disillusion sets in.
Development of increasingly complex, toxic (and
expensive) treatment protocols
Some improvement in response rates, but hope
fades for curing common forms of cancer
Intensive search for analogues of existing drugs,
hoping for greater anticancer effect or less
toxicity
Introduction of remaining major types of
chemotherapy (taxanes, topoisomerase I
inhibitors)
Evolution of Chemotherapy
1990’s –still hard going in the clinic, but …..
Post-operative adjuvant chemotherapy established to
reduce mortality in some major causes of cancer
death (breast, colon cancer)
Biochemical basis of drug resistance established
Idea that development of cancers involves
suppression of cell death pathways, and that drug
resistance results from failure of damaged cells to
undergo apoptosis
- e.g. bcl2, p53 stories
Evolution of Chemotherapy
2000’s – rapid development of molecular
targeted agents as alternatives to classical
chemotherapy
Evolution of molecular oncology and rational
cancer therapeutics
- integrating basic science, pharmacology,
pathology, and clinical oncology
Classification of Chemotherapy
(difficult to do; many drugs first identified by
empirical screening for anticancer effect,
rather than rational synthesis)
• DNA damaging agents
- alkylating agents
- platinum compounds
• Antimetabolites
• Topoisomerase inhibitors
• Anti-mitotic agents
Nitrogen Mustard
• First chemotherapy
agent used in man
• Prototype alkylating
agent
• Main toxicity comes
from DNA cross
linkage
DNA Cross Linkage
• Arrests DNA replication
• Can result in DNA
damage and chromosome
breaks
• Also mutagenic!
Chlorambucil
•
•
•
•
Derivative of nitrogen mustard
Much less reactive
Well absorbed by mouth
Remains major drug for treating low grade lymphomas
Cyclophosphamide
• More complex
activation than
nitrogen mustards;
requires cytochrome
p450 in liver
• Can be given orally or
intravenously
• Main side effects are
bone marrow
suppression
Other DNA Damaging Agents
• Platinum compounds
- prototype cisplatin
- main effect interstrand cross
links
- many analogues produced
with broader spectrum
• Nitrosoureas
- transfer chloroethyl group to
guanine at O6 position
Antimetabolite Drugs
• Designed to block DNA synthesis
Based on idea that cancer cells divide more rapidly
than normal cells, so more vulnerable
• Originally considered to be cytostatic rather than
cytotoxic, but now recognized that many produce cell
death by triggering apoptosis
• Unlike most conventional chemotherapy drugs,
development by rational synthesis rather than
empirical screening for anticancer effects
• Most are either nucleoside analogues that interfere
with DNA synthesis, or block methylation of uracil to
thymidylate
Antimetabolite Basics
Nucleoside Analogues
- biochemical pharmacology mirrors the uptake
and metabolism of normal nucleosides
Cytosine arabinoside (cytarabine; Ara-C)
- major chemotherapy drug to treat acute leukemias
Ara-CTP competes with dCTP
-inhibits DNA polymerases
-incorporation into DNA
produces strand breaks;
triggers apoptosis
Ara-C in treatment of
acute leukemia
• High doses to overcome transport resistance
• Because ara-C targets cells in S-phase,
given over 5-7 days to account for slow
cycling populations of leukemia cells
• Major toxicity is suppression of blood
counts
Inhibition of Thymidylate Synthesis
• Pyrimidine base 5Fluorouracil (5FU)
inhibits thymidylate
synthase
• Methotrexate inhibits
dihydrofolate
reductase, reducing
flow of methyl group
carried by reduced
folate
Effects of TS Inhibition
• Decrease in dTTP associated with build up of
dUTP
• Mis-incorporation of dUTP into DNA
• This is removed by DNA repair pathways
• However, DNA repair synthesis also misincorporates dUTP:
“futile repair” cycle results in extensive DNA
damage
• 5-fluorouracil and methotrexate both clinically
important drugs
Natural Products
• Discovered by empirically screening
compounds for anticancer effects in vitro
(similar to antibiotic discovery)
• Mechanisms of action subsequently identified
• Important compounds showing effect in
lymphoma (and other cancers) are:
- topoisomerase inhibitors
- microtubule inhibitors
Topoisomerase II Inhibitors
• Topoisomerase II allows replicated DNA strands to
separate by making breaks, then re-ligating
• Main class of topo II inhibitors are the anthracyclines,
originally from Streptomyces
• Intercalate into DNA and prevent re-ligation step
• Daunorubicin is the classical anthracycline used to
treat acute leukemia
Daunorubicin toxicity
• Bone marrow suppression is most important
early toxicity
• Also causes gastro-intestinal toxicity
- nausea, vomiting, diarrhea
• Hepatobiliary excretion is major route for drug
elimination – toxicity greater in presence of
jaundice
• Cardiac toxicity is most important late effect
- risk increases with accumulated dose
- can result in fatal cardiac failure
Mechanism of Anthracycline Cardiac Toxicity
• As well as intercalating into DNA, daunorubicin avidly binds
mitochondrial inner membrane of cardiac muscle
• Daunorubicin chelates iron, which catalyzes formation of the free
radical semiquinone
• Redox cycling transfers high energy electron to oxygen, generating
oxygen free radicals
• Produce lipid peroxidation damage to mitochondrial membranes
Microtubule Inhibitors
• Vinca alkaloids (from periwinkle plant)
- destabilize microtubules
- vincristine commonly used to treat acute lymphoblastic
leukemias
• Taxanes (from Pacific yew tree bark)
- stabilize microtubules
- taxotere most active in current use
• Main effect of these drugs is to cause metaphase arrest
and chromosomal damage
- probably have additional effects due to microtubule
disruption in interphase cells
Effects of Vincristine on T-cell Leukemia Cell Line
Chemical Structure of Taxol
Many natural products are very complex organic
molecules. Complexity can make them useful starting
points for drug development
Why Don’t We Cure Cancer With
Chemotherapy?
• Toxic side effects limit dose
• Cancer cells show drug resistance
- innate drug resistance, or acquired
resistance during treatment
Toxic Effects of Chemotherapy
• Generic side effects are damage to rapidly
dividing normal cells
- bone marrow, gut mucosa, hair follicles
• Nausea due to triggering CNS vomiting centres
• Drug-specific side effects:
- myocardium (anthracylines)
- kidney (platinum)
- nervous system (microtubule agents)
• Toxicity increases with dose of drug used
Combination Chemotherapy
• Drugs selected for combinations based on:
- differences in side effects; allows each to be used
at full dose
- different mechanisms of action; cancer less likely
to be cross-resistant
• Prototype curative combination is MOPP (nitrogen
mustard, vincristine (Oncovin), procarbazine and
prednisone (glucocorticoid steroid) - 1970
• Typically given as outpatient every 3-4 weeks, to
allow recovery of normal tissue side effects
How Far Can You Push Chemotherapy?
• Generally, the more you give the greater the
anticancer effect
• Bone marrow suppression is main lethal side effect
of chemotherapy
• Bone marrow transplantation (either patient’s or
normal donor) bypasses this dose-limiting toxicity,
allows more chemo. Can be curative in some
situations, including acute leukemia
• Although higher response rates, other side effects
may prevent curative doses from being achieved
Drug Resistance
• Main factor determining if a cancer will be
cured with chemotherapy
• Complex and multifactorial, but main
causes of drug resistance are probably now
understood
Development of Drug Resistance
in a Leukemia Patient
• Antique chart (from my
residency days!) of newly
diagnosed AML patient treated
with ara-C plus daunorubicin,
followed by ara-C plus 6thioguanine maintenance
chemotherapy
•
represents circulating
leukemic blasts
• Shows initial clearance of
leukemia with treatment, and
reappearance of normal
granulocytes and platelets
Development of Drug Resistance
in a Leukemia Patient
• Blood counts
remaining fairly
normal during
maintenance
chemotherapy
Development of Drug Resistance
in a Leukemia Patient
• Eventually leukemic
blasts reappear in
circulation
• Initially respond to
intensified chemotherapy
• Then rapid accumulation
of drug resistant
population
• High dose Ara-C can overcome transport resistance because
transporter is non-saturable
• Activity of deoxycytidine kinase can be increased by inhibiting
endogenous deoxycytidine using ribonucleotide reductase inhibitors
- but these can also enhance normal tissue toxicity
Overcoming Drug Resistance
• Some cellular mechanisms of multidrug
resistance (P-glycoprotein-mediated drug efflux,
glutathione conjugation) can be reversed
pharmacologically
• Able to enhance anticancer effects in model
systems
• Results in clinical trials disappointing
- probably because of multifactorial nature of
drug resistance
P-glycoprotein
• First multidrug resistance mechanism to be
characterized (Vic Ling, OCI, 1975)
• P-glycoprotein is transmembrane ATP-dependent
efflux pump
• Actively transports many types of chemotherapy
from cells (anthracyclines, vinca alkaloids,
taxanes)
• Overexpression in cancers causes drug
resistance
• P-glycoprotein inhibitors tested in clinical trials
P-glycoprotein in Acute Leukemia
• P-glycoprotein overexpressed in some AML
patients
• Higher levels associated with drug resistance and
worse prognosis
• But clinical trials of P-glycoprotein inhibitors fail
to show significant improvement in
chemotherapy response
- other resistance mechanisms also operating
- high Pgp levels might be linked to aggressive
biology, rather than directly to drug resistance
Targeting Cell Survival Pathways
• Recent evidence that failure of DNA damaged
cells to undergo apoptosis is major cause of
multidrug resistance
• Suppression of apoptosis often occurs due to
oncogenic mutations – i.e. common feature of
cancers
• Potential to reverse this mechanism by
molecular therapies – e.g. p53 gene therapy or
small molecule inhibitors of PI3-kinase
pathway
Where is Chemotherapy Going?
• Incremental improvements in patient outcome
continue, using newer drugs and combinations
• Unlikely that this will result in major
improvements in cure rates for common forms of
cancer
• Over past 2-3 years drug development programs
refocused on molecular targeted therapeutics
• Potential for major advances based on new
biology
• Molecular oncology revolution will need close
interactions between clinical oncology,
pathology, pharmacology, and basic science