Transcript Understanding the cell cycle

Understanding the cell
cycle - chemotherapy
and beyond
Julie Mycroft
Principal Pharmacist
Paediatric Oncology
Royal Marsden NHS Trust
Cancer treatment modalities

Can be used alone
or in combination

Outcome
measured in terms
of survival rates
and response rates
Aims of treatment
Chemotherapy
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To reduce tumour burden

Improvement in
symptoms
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Eradication of
metastases → cure
Hormone Therapy
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Manipulate hormone
environment leading to
regression of tumours
sensitive to hormones
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Adjuvant setting
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Palliation in advanced
disease

Neoadjuvant
History of chemotherapy development
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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
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G1 early growth
phase
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S DNA synthesis
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G2 later growth phase
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M Mitosis
Cell division – mitosis (1)
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Prophase
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Chromatin condenses into
chromosomes. Each
chromosome duplicates and
consists of 2 sister chromatids.
Nucleus breaks down
Metaphase
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Chromosomes align and are
held by microtubules attached
the mitotic spindle and to the
centromere
Cell division – mitosis (2)
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Anaphase
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The centromeres divide. Sister
chromatids separate and move
toward the corresponding poles
Telophase
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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
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The rate of cell division in human tumours
varies considerably from one disease to
another
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Majority of common cancers increase in size
slowly compared to sensitive normal tissues
such as BM and GI epithelium
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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
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The more rapidly growing tumours are more
likely to respond to drug treatment
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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
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The greater the growth faction, the more
likely the treatment will produce cell death
Kinetics of cell killing
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Fractional Cell kill
hypothesis
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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
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Cell Cycle Phase-Specific Agents
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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
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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
Phase Specificity of Cytotoxic Drugs
Phase of cell cyle
Effective agents
G1
Steroids, asparaginase
S phase
Antimetabolites
G2
Bleomycin, etoposide
Mitosis
Vinca alkaloids, taxanes
Phase non-specific
Alkylating agents,
nitrosoureas, antibiotics,
procarbazine, dacarbazine,
platinums
Mechanisms of Action (1)
Alkylating agents and nitrosureas
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Highly reactive molecules
Interfere with replication by covalently linking an
alkyl group (R-CH2+) to nucleic acids and
proteins of the base pairs of the cellular DNA
causes the strands of DNA to cross-link either
within a strand or between strands.
Mechanism of toxicity - impairment of DNA
replication
Examples
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e.g cyclophosphamide, chlorambucil, melphalan,
nitrosoureas eg carmustine
alkylator-like agents - cisplatin, carboplatin,
procarbazine, dacarbazine
Mechanisms of Action (2)
Antitumour Antibiotics
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Disrupt normal replication by binding to DNA
intercalating between the base pairs blocking
the transcription of DNA
Breaks in DNA may also occur
Examples
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Anthracyclines ie Doxorubicin
Epirubin, Mitoxantrone, Actinomycin D
Bleomycin,
Mechanisms of Action (3)
Antimetabolites
 Interfere with normal
synthesis of nucleic acids
 Cell cycle phase specific (S
phase)
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folate antagonist - MTX
pyrimidine antagonists cytarabine, 5-fluorouracil,
capecitabine, gemcitabine
purine antagonists cladribine, mercaptopurine,
thioguanine, fludarabine
adenosine deaminase
inhibitor - pentostatin
Mechanisms of Action (4)
Disrupt the M phase of the cell
cycle
Vinca alkaloids
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Inhibit the assembly of
microtubules by binding to tubulin
resulting in the dissolution of the
mitotic spindle required for
chromosome division
e.g vincristine, vinblastine,
vinorelbine
Taxanes
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Bind to stabilised microtubules
once they have formed, resulting
in arrest of normal mitotic cell
division and subsequently cell
death
e.g paclitaxel, docetaxel
Mechanisms of Action (5)
Camptothecans
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Inhibit type I DNA
topoisomerase.
Act predominantly in
the S phase
e.g topotecan,
irinotecan
Epipodophyllotoxins
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Inhibit type II DNA
topoisomerase and
prevent cells from
entering mitosis
Produce proteinassociated DNA double
strand breaks
e.g etoposide
Mechanisms of Action (6) – Misc.
Asparaginase
Normal Cell
Tumor Cell
Aspartic Acid
+ L-Glutamine
L-Asparagine
Synthetase
L-Asparagine
(cell produced)
L-A´ase
L-Asparagine
Deficiency
Aspartic Acid
+
Ammonia
Cell Proliferation
Cell Death
Combination Chemotherapy (1)
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Early studies used single agents, but remissions
were short and relapse was associated with drug
resistance
Combination chemotherapy is used to try and
improve rate and duration of response by
combining drugs with different mechanisms of
action. This also helps prevent resistance
mechanisms
Despite knowledge of cell kinetics, most
regimens have been decided on empirically
Combination Chemotherapy (2)
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The combination of drugs is chosen based on
some common principles
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Use drugs that are known to be effective as single agents
Use drugs with non-overlapping toxicity
pulsed intermittent therapy should be used to allow the
GIT and the bone marrow to recover
Use the optimal dose and schedule for each individual
agent
If possible use drugs with synergistic killing effects
Use drugs which work at different phases in the cell cycle
Follow schedules that are supported by experience or
observation, not just theory
Short-term toxicity
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Haematopoietic System
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Gastro-intestinal tract
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Bone marrow suppression occurs
when the pool of stem cells has
been damaged by chemotherapy.
The store of mature blood cells in the
bone marrow lasts for around 8 to 10
days following treatment, after which
leucopenia and thrombocytopenia
can develop
Nausea and vomiting are common in
patients treated with intravenous
alkylating agents, doxorubicin and
cisplatin.
Hair loss
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Scalp cooling may be used
Long term toxicity
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Impaired gonadal function
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Pulmonary fibrosis
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Busulfan, Bleomycin
Organ damage
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Procarbazine and alkylating agents
men – decreased spermatogenesis
women – ovarian failure
Liver damage – antimetabolites
Cardiac damage – anthracyclines
Second Cancers
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Alkylating agents, etoposide,
anthracyclines
Drug Resistance
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Cells in a solid tumour are not uniformly
sensitive to a cytotoxic drug
As the tumour grows, greater heterogeneity
develops and cell mutation occurs
Host defence mechanisms and the use of
cytotoxic drugs exert a selection pressure
encouraging the survival of the resistant cells
, which grow and multiply
Cellular Mechanisms of Resistance
Mechanism
Drug
Efficient repair to damaged DNA
alkylating agents
Decreased uptake by cell
MTX, doxorubicin
Increased drug efflux
(p-glycoprotein)
epipodophyllotoxin
vincs, anthracyclines
Decreased intracellular activation
6MP,5-FU
Increased intracellular breakdown
cytarabine
Bypass biochemical pathways
MTX, 6MP, asparaginase
Gene amplification or overproduction of blocked enzyme
MTX, nitrosoureas
Other Mechanisms of Drug Resistance
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Diminished vascularity
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Only a small proportion of cells may be in
cycle, allowing time for repair from cytotoxic
damage before cell division
Hormone Therapy
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Beatson demonstrated that
some inoperable breast
cancers regressed after
removal of the ovaries
(oophorectomy)
Many years later Huggins
showed that metastatic
prostatic cancer regressed
after removal of the testes
(orchidectomy).
In breast cancer, hormone
receptor status is clinically
important in management
Principals of hormone therapy (1)
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Receptor proteins for steroid
hormones are found in both the
cytoplasm and the nucleus
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The interaction between these
hormones and their receptor proteins
promotes cell growth and division.
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The steroid hormone crosses the cell
membrane and forms a complex with a
receptor in the cytoplasm.
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This activated complex passes into the
nucleus where it binds to a protein,
leading to the production of
messenger RNA (mRNA) and then
protein.
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Finally DNA is synthesised and the cell
divides
Principals of hormone therapy (2)
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This interaction provides the rationale for
a number of ways in which hormone
manipulation can modify tumour growth.
It may be possible to:
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lower the plasma concentration of
hormone by removing the source of
production, e.g. the testes or ovaries
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prevent the hormone from binding to
receptor via competitive inhibition or by
reducing synthesis of the receptors
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block binding of the hormone/receptor
complex to DNA in the nucleus
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The precise mode of action of agents
used in hormone therapy is often unclear.
Approaches to hormone therapy (1)
Lowering plasma hormone concentration
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Radiotherapy
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Surgery
Radiotherapy to the ovaries induces the menopause – the ovaries stop
producing eggs and the female sex hormones.
In breast cancer can involve:
the ovaries (oophorectomy)
the adrenals (adrenalectomy)
the breast tissue (mastectomy)
In prostate cancer:
surgical removal of the testes (orchidectomy)
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Medical treatment
Aromatase inhibitors
Analogues of luteinizing hormone–releasing hormone (e.g. goserelin and
leuprorelin)
Approaches to hormone therapy (2)
Blocking the action of circulating hormones
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Anti-oestrogens and anti-androgens
work by blocking the binding of hormones to their receptors.
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Anti-oestrogens (e.g. tamoxifen)
Anti-androgens (e.g. flutamide, megestrol acetate)
Additive hormone therapies
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The action of circulating hormones can also be blocked by
additive hormone therapies, which in breast cancer include
oestrogens, androgens, glucocorticoids and progestogens.
Summary
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A knowledge of the cell cycle is important to
understanding the mechanism of action of cancer
chemotherapy
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Combination chemotherapy is used to try and
improve rate and duration of response by combining
drugs with different mechanisms of action.
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Manipulating the interaction between hormones and
cell growth provides a means for treating hormone
sensitive cancers
Acknowledgements
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The Institute of Cancer Research - interactive
education unit module 4 “An approach to
therapies”
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‘Cancer and it’s Management’ - 3rd Edition
Souhami R and Tobias J (Blackwell Science)