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Pharmacology of Chemotherapy
Cancer Biology
Dr Dean Willis
Department of Pharmacology
University College London
Gower Street, London WC1 6BT
[email protected]
Learning Objectives
To know the basic phenotypic and biochemical differences between
normal and cancer cells
To understand the basic principal of cancer chemotherapy and its limitations
To know the four main groups of anti-cancer cytotoxic drugs
To understand the adverse effects of cancer chemotherapy
To know the basic mechanisms that develop in tumour cells that leads to drug
resistance
Understand the pharmacological rational behind the new anti cancer
chemotherapeutics
To understand the scientific rational behind drug combination studies.
Learning Tasks & Further Reading
Revise mammalian DNA replication and the biosynthesis of nucleotides.
Read Pharmacology, Rang, Dale & Ritter. Anti-cancer Drugs
Chemotherapy of Neoplastic Diseases. Section IX. Goodman & Gilman’s.
The Pharmacological Basis of Therapeutics. 10th Edition.
Nature Reviews in Cancer
Recent reviews relating to chemotherapy
CLINICAL TRANSLATION OF ANGIOGENESIS INHIBITORS
MICROTUBULES AS A TARGET FOR ANTICANCER DRUGS
NF-κB IN CANCER: FROM INNOCENT BYSTANDER TO MAJOR CULPRIT
Theory of Chemotherapy. The Man, the film?
For the case of Chemotherapy bacteria, fungi, protozoa, helminths, viruses and cancer
cell are considered parasites.
Find Qualitative (preferable) or Quantitative Biochemical difference between Host and
Parasite which when exploited by a selective drug results in a cytotoxic effect to the
parasite but not host
Theory
Drug
Paul Ehrlich 1854-1915
Nobel Laureate 1908
Host
Parasite
No effect
Cytotoxic
CHEMOTHERAPY: The basis of anti-cancer chemotherapy and the problem
Qualitative
Quantitative
The goal is to selectively kill malignant cells and spare normal host cells. Selective toxicity
is not possible to the degree seen with antibacterial or even anti-viral chemotherapy, as
malignant cells are derived from the host and the differences between normal and
malignant cells are much more subtle. Therefore, successful treatment is dependent on
killing malignant tumor cells with doses and strategies that allow recovery of normal
proliferating cells.
Characteristics of tumour cells &
sites of therapeutic intervention (present and future)
Blood
vessel
Primary
Tumour
Normal
organ/tissue
Extracellular
Matrix
Invasiveness
Proliferation
Metastasis
Adhesion molecules inhibitors
Metaloprotease inhibitors
Apoptosis
Hyperplastic
Adhesion molecules inhibitors
Metaloprotease inhibitors
Classical Anti-cancer drugs
New drugs e.g. imatinib
Differentiation
Anaplastic
Retinoids
Host systems
Immunological/Inflammation/Angiogenesis
Biological Response Modifiers
Angiogenesis inhibitors
Major Modalities for Treatment for cancer
Surgery
Irradiation
Chemotherapy
Combination of the above (modality therapy)
Problems associated with Anti-cancer chemotherapy
Because cells are derived from self, most therapies rely on quantitative
(usually proliferation/growth) rather than qualitative. Therefor host cells are
invariably effected.
Therapeutic Index= LD50/ED50
For anti-cancer drugs this tends to be low therefore Tox problems
• Bone Marrow (G-CSF shorten period of Leukopenia)
• Healing
• Alopecia
• Damage to gastrointestinal epithelium (nutritional state)
• Depression of growth (children)
• Sterility
• Teratogenicity
• Severe nausea (treat with 5-HT3-receptor antagonist)
Problems associated with Anti-cancer chemotherapy
Growth fraction (percentage of cells actively dividing)
1012
109
Cell number
(tumor size)
Time
G2
M
S
C
none cycling
cells
A
G1
G0
B
Anti-cancer chemotherapy most effect
against cells in cell fraction A. Cells in
fraction B can re-enter fraction A.
Problems associated with Anti-cancer chemotherapy
Percentage of
cell in cycle (A)
Tumour
Size (cm)
20
10
2
103
106
Cell No
109
1012
Exponential growth of a tumour
Limit of diagnostic procedures.
Problems associated with Anti-cancer chemotherapy
Cell cycle: Susceptibility of cancer cells to a given
drug is often dependant on cell cycle
Bleomycin
Alkylating agents,
antimetabolites,
many cytotoxic antibiotics
Plant alkaloids
Vinca alkaloids, taxanes
G2
B
M
A
S
Positive factors
Growth factors
Cyclins/cdks
E
D
Rb gene product
p53 gene product
Cell number
Apoptosis
Antimetabolites
Bleomycins Irradiation
Log [con]
G1
G0
Differention
Problems associated with Anti-cancer chemotherapy
Minimal immune response
• Because the tumour is self the immune response as difficulty recognizing the
tumour
• The drug receives no help (or little help) from the immune system
• Many anti-cancer drugs are toxic to immune cells (Bone marrow)
• Cancer cells can hide
Tumour cell heterogeneity & cell phenotype instability
Drug Resistance
•Specfic drug
•Drug of same chemical class
•Multi-drug resistance:- P170 (mdr1 gene)
Summary anti-cancer chemotherapy's
Cytotoxic drugs
•Alkylating agents
Cyclophosphamide, Busulfan, Carmustin, Chloramabucil, Ifosfamide, lomustine, Melphan, Treosulfan
Cisplatin, Carboplatin, Oxaliplatin
•Anti-metabolites
Methotrexate, Fluoruracil, Cytarabine, Cladribine, Fludarabine phosphate, Gemcitabine, Mercaptopurine
•Cytotoxic Antibiotics
Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitomycin
•Plant derivatives
Etoposide, Vinblastine, Vincristine
Hormone
Tamoxifen, Anastrozole, Letrozole
Miscellaneous
Imatinib, Bortezomib, Bevacizumab, Trastuzumab, Taxol, Cristaspase, Arsenic
Summary of cytotoxic drug action
PURINE SYNTHESIS
PYRIMIDINE SYNTHESIS
5-FLUOROURACIL (ct2)
Inhibits DTMP synthesis
PENTOSTATIN (ct2)
Inhibits adenosine
deaminase
RIBONUCLEOTIDES
BLEOMYCINS (ct3)
6-MERCAPTOPURINE(ct2)
6-THIOGUANINE (ct2)
DEOXYRIBONUCLEOTIDES
ALKYLATING AGENTS (ct1)
MITOMYCIN (ct3)
CISPLATIN (ct1)
Inhibit purine synthesis
Inhibit nucleotide
interconversion
Damages DNA
and prevent repair
Cross-link DNA
DNA
DOXORUBICIN (ct3)
ETOPOSIDE (ct4)
Inhibits topoisomerase II
Inhibits RNA synthesis
METHOTREXATE (ct2)
Inhibits purine synthesis
Inhibits DTMP
RNA
(transfer, messenger, ribosomal)
DACTINOMYCIN (ct3)
Intercalates in DNA
Inhibits topoisomerase II
Inhibits RNA synthesis
CYTARABINE (ct2)
Inhibits DNA polymerase
Inhibits RNA function
PROTEINS
VINCA ALKALOIDS (ct4)
TAXANES (ct4)
Inhibit function of microtubes
MIROTUBULES
ENZYMES
Action of Alkylating drugs (methlorethamine) Mustine
Deoxyguanosine
CH2CH2Cl
H3C
CH2CH2Cl
N
+
CH2CH2Cl
In tra -s t ra n d lin k a g e
C
C
G
A
G
C
C
G
A
+
CH2
O
N
O
NH
N
NH2
CH2
CH2CH2Cl
O
N
O
P
NH
N
T
CH2
H3C
H3C
NH2
N
O
N
P
O
N
N
O
CH2
CH2
O
N
O
Other nitrogen mustards
N-7
CH2
+
NH2
O
N
P
O
N
O
NH
N
O
N
P
CH2
NH
N
N
N1 & N3 adenine
N3 cytosine
O
CH2
Cycloposphamide
Chlorambucil
Melphalan
N
P
T
C ro s s -lin k in g
G
N
H3C
O
Deoxyguanosine
NH
N
NH2
NH2
Action of Alkylating drugs
NH
CH2
H2C
P
O
CH2
O
CH2
CH2
Cl
CH2
CH2
Cl
Resistance
Decreased permeability
Increased production of glutathione
Increase DNA repair
Increased metabolism of drugs
N
Cyclophosphamide
4-Hydroxycyclophosphamide
Aldophosphamide
Acrolein
Nitrosoureas carmustine, lomustine
Busulphan
CH2
HC
Cisplatin
NH2
Administered orally or i.v.
tumours of testes & ovary
2+
Pt
Cl_
NH2
NH2
O
CHO
Cl_
Phosphamide Mustard
P
OH
CH2
CH2
Cl
CH2
CH2
Cl
N
Anti-metabolites (methotrexate)
Cell
Blood
Methotrexate (glu)n
Methotrexate(glu)n
F(Glu)
F(glu)n
Dihydrofolate
reductase
Dihydrofolate
reductase
FH4
FH4(glu)n
FH2 (glu)n
DTMP
One-carbon Unit
Thymidylate
synthase
DUMP
Polyglutamates are retained in the cell
Cancer cells have higher rates of glutamation enzymes levels
DTMP=Deoxythymidylic Acid
DUMP=Deoxyuridylic Acid
Resistance
Decreased transport into cells
Decreased affinity of DHF reductase
Increase levels of DHF reductase
Administered orally or i.v.
Non-Hodgkin’s lymphoma
Burkitt’s lymphoma
Childhood acute lymphoblastic leukemia
Anti-metabolites (5-Fluorouracil)
O
O
P
F
HN
O
F
HN
P
+
N
O
Thymidine
Phosphorylase
O
O
N
HO
5-Fluorouracil
HO
Fluorouracil-Deoxy Uridine
Inhibites Thymidilate synthase
via complexing with Tetrahydrofolate
O
O
P
O
O
CH3
HN
HN
N
P
O
O
Thymidilate synthase
Tetrahydrofolate
HO
Deoxyuridylic acid
Resistance
Decreased levels of thymidine phosphorylase
or affinity for 5FU
N
HO
Deoxythymidylic acid
Administered parentally
Breast, ovarian, prostate,
pancreatic, hepatic carcinomas
Anti-metabolites (Cytosine arabinoside, Cytarabine)
O
Deoxycytidine
Kinase
HN
HO
O
O
N
HO HO
Cytosine arabinoside
P
O
HN
O
O
DCMP
Kinase
N
P P
O
HN
O
O
HO HO
N
HO HO
AraCDP
AraCMP
Nucleoside
Diphosphate
Kinase HN
P
P
P
O
O
N
HO HO
AraCTP
Prevents DNA chain elongation
Resistance
Decreased levels of deoxycytidine kinase
Increase in dCTP
O
Administered oral and i.v.
Chronic granulocytic leukemia
Cytotoxic antibiotics Doxorubicin, Dactinomycin, Etoposide (VA)
Topoisomerase II
Transient cleavable
complex
Double stranded DNA
DRUG
Strand passing, rotation
break resealing
Non-cleavable complex
Persistant cleavable
complex
Double stranded DNA break
Resistance
Multidrug resistance
Increased glutathione peroxidase
decreased topoisomerase
Administered i.v.
Acute lymphocytic leukemia
Acute granulocytic leukemia
Cytotoxic antibiotics (Dactinomycin, Bleomycin)
Dactinomycin
Minor groove
C
C
G
A
G
Resistance not characterized
Parentally administered
Used in combination with other modalities
T
Bleomycin
Major groove
G
C
C
G
A
T
Resistance due to increase anti-oxidant,
and DNA repair mechanisms
Parentally administered
Treatment of testicular and ovarian cancer
Note cytotoxic antibiotics do share some modes of action
DNA binding and topoisomerase II inhibition
Plant alkaloids (vincristine & vinblastine, Taxol)
Steady state
Disassembly
Vincristine & vinblastine
Assembly
Tublin
dimer
Polymerization blocked by vincristine & vinblastine
Drug
Resistance due to multidrug resistance,
altered tublin molecules
Administered I.v.
Childhood leukemia's, Hodgkin's
and non-Hodgkin's lymphoma, testicular,
ovarian carcinomas and brain tumours
Taxol
Resistance
altered tublin molecules
Continued disassembly
Administered i.v.
Metastatic ovarian and breast cancer
Polymerization stabilized by Taxol
Stable microtubule
Resistance to chemotherapeutic agents
Decrease
uptake
Increase
efflux
P-glycoprotein
Binding
Protein
Intracellular
binding
GSH
Target
Protein
Altered target
amount or affinity
DHRF
Increases metabolism
S
P
Altered target
amount or affinity
Topoisomerase II
Increase
Repair
Nuleus
New anti-cancer drugs: Imatinib
Treatment Chronic myelogenous leukaemia
CML caused by reciprocal translocation between chromosomes 9 and 22
Philadelphia chromosome BCR-ABL gene which encodes a protein with high
tyrosine kinase activity
Fast drug to be approved by FDA, Approx 80% remission in IFNg refractory patients
Activity against c-kit & PDGF receptor
New anti-cancer drugs: Bortezomib
Treat multiple myeloma ( current drugs 5 year survival is approx 29%)
In MM (and other tumors ) NF-kB is constitutively expressed
IKKg
IKK IKK
I-kB
I-kB
I-kB
P50
P50
P65
Proteasome
P65
P50
P65
Bortezomib
I-kB
P50
I-kB
P50
P65
P65
NF-kB
Inflammatory genes
anti-apoptotic genes
Combination therapy
Knowledge of the pharmacokinetics of each cytotoxic agent is less
important than knowing the maximal dose and the duration of that drug
can be administrated before adverse side effects become unacceptable
Bleomycin
Etoposide
Cisplatin
Curative therapy testicular cancer (BEP)
Individual drugs must be active against the tumour
Drugs must have different modes of action
• Minimize drug resistance
• Hit cancer cells in different parts of cell cycle
Drugs must have limited overlapping toxicity
Individuals should be optimally scheduled
Renal & hepatic Function
Bone Marrow reserve
Immune status
Previous Treatments
Likely natural History of Tumor
Patients Wishes to undergo treatment
Patients Physical & emotional Tolerance
Long term gains & Risks