dr dean willis department of pharmacology university college london gower street, london wc1 6bt
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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. - PowerPoint PPT PresentationTRANSCRIPT
Dr Dean WillisDepartment of PharmacologyUniversity College LondonGower Street, London WC1 [email protected]
Pharmacology of Chemotherapy
Cancer Biology
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 know the basic mechanisms that develop in tumour cells that leads to drug resistance
To understand the adverse effects of cancer chemotherapy
To understand the scientific rational behind drug combination studies.
Understand the pharmacological rational behind the new anti cancer chemotherapeutics
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.
Learning Tasks & Further Reading
MICROTUBULES AS A TARGET FOR ANTICANCER DRUGS
CLINICAL TRANSLATION OF ANGIOGENESIS INHIBITORS
NF-κB IN CANCER: FROM INNOCENT BYSTANDER TO MAJOR CULPRIT
Nature Reviews in Cancer
Recent reviews relating to chemotherapy
Theory of Chemotherapy. The Man, the film?
Drug
Host Parasite
No effect Cytotoxic
For the case of Chemotherapy bacteria, fungi, protozoa, helminths, viruses and cancer cell are considered parasites.
Theory
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
Paul Ehrlich 1854-1915Nobel Laureate 1908
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)
Bloodvessel
PrimaryTumour
Normalorgan/tissue
Major Modalities for Treatment for cancer
Surgery
Irradiation
Chemotherapy
Combination of the above (modality therapy)
Proliferation Apoptosis
Differentiation
Host systemsIm m unolog ica l/In flam m ation /A ng iogenes is
Invasiveness
MetastasisClassical Anti-cancer drugs
New drugs e.g. im atinib
Retinoids
M etaloprotease inhibitors
M etaloprotease inhibitors
Adhesion m olecules inhibitors
Adhesion m olecules inhibitors
Biological Response M odifiers Angiogenesis inhibitors
Extracellu larM atrix
H yperp las tic
A nap las tic
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)
S
M
G 1
G 2
G 0
A
B
Cnone cycling
cells
Anti-cancer chemotherapy most effect against cells in cell fraction A. Cells in fraction B can re-enter fraction A.
Cell number(tumor size)
Time
1012
109
Problems associated with Anti-cancer chemotherapy
Cell No
Tum
ou
rS
ize
(cm
)
Pe rce n
ta ge o
fc
ell in c ycle (A
)
101210910 3 106
2
10
20
Limit of diagnostic procedures.
Exponential growth of a tumour
Problems associated with Anti-cancer chemotherapy
Cell cycle: Susceptibility of cancer cells to a given drug is often dependant on cell cycle
S
M
G 1
G 2
G 0
D ifferention
A poptos is
A
B
E
D
P ositive factorsG rowth factorsC yclins/cdks
R b gene productp53 gene product
P lant a lkaloidsVinca a lkaloids, taxanes
B leom ycinA lky la ting agents,antim etabolites,m any cytotox ic antib iotics
Log [con]
IrradiationBleomycins
Antimetabolites
Cel
l nu
mb
er
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 agentsCyclophosphamide, Busulfan, Carmustin, Chloramabucil, Ifosfamide, lomustine, Melphan, TreosulfanCisplatin, Carboplatin, Oxaliplatin
•Anti-metabolitesMethotrexate, Fluoruracil, Cytarabine, Cladribine, Fludarabine phosphate, Gemcitabine, Mercaptopurine
•Cytotoxic AntibioticsBleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitomycin
•Plant derivativesEtoposide, Vinblastine, Vincristine
HormoneTamoxifen, Anastrozole, Letrozole
MiscellaneousImatinib, Bortezomib, Bevacizumab, Trastuzumab, Taxol, Cristaspase, Arsenic
Summary of cytotoxic drug action
PU R IN E SYN THES IS PYR IM ID IN E SYN THE SIS
R IB O NU C LEO TIDE S
PR O TEINS
M IR O TU BU LES EN ZYM ES
D N A
R NA( )transfer, m essenger, ribosom al
D EO XY RIBO N U CLEO TID ES
PENTO STATIN (ct2)
6-M ER CAPTO PUR INE(ct2)6-TH IOG U ANIN E (ct2)
M ETH O TREXATE (ct2 )
C YTARABIN E (ct2)
5-FLU O R OU R ACIL (ct2 )
BLEOM YC IN S (ct3)
D OXO R UBIC IN (ct3)ETO PO SID E (ct4)
D ACTIN OM YCIN (ct3)
V IN C A ALKALO ID S (ct4)TAXANES (ct4)
ALKYLATIN G AG EN TS (ct1)M ITO M YC IN (ct3)C ISPLATIN (ct1)
Inh ib its adenosinedeam inase
Inh ib it pu rine syn thesisInh ib it nucleo tidein te rconversion
Inh ib its pu rine synthesisInh ib its D TM P
Inh ib its D N A po lym eraseInh ib its R N A function
Inh ib its D TM P syn thes is
D am ages D N Aand p revent repa ir
C ross-link D N A
Inh ib its topoisom erase II
Inh ib its topoisom erase II
Inh ib its R N A synthesis
Inh ib its R N A synthesis
In terca la tes in D N A
Inh ib it func tion o f m icro tubes
N
NN
N
N
N
NN
N
N
N
NN
N
N
N N
N
N
NH
NHNH
NH
NH
NH 2
NH 2
NH 2
NH 2
NH2
O
OO
O
O
O
OO
O
O
O
OO
O
O
P
PP
P
P
+
CH CH Cl2 2 CH CH Cl2 2
CH CH Cl2 2
CH CH Cl2 2
H C3 H C3
H C3
H C3
CH 2
CH 2
C H 2
C H 2
CH 2
CH 2
C H 2
C H 2
+
+N-7
Deoxyguanosine
Deoxyguanosine
N1 & N3 adenineN3 cytosine
Action of Alkylating drugs (methlorethamine) Mustine
A
A
T
T
C
C
G
G
C
C
G
G
Intra-strand linkage
Cross-linking
Other nitrogen mustardsCycloposphamideChlorambucilMelphalan
Action of Alkylating drugs
CH2
CH2
CH2 CH2
CH2 CH2CH2
CHO
NH
PO
O
Cl
Cl
NH C2
HC
4-Hydroxycyclophosphamide Aldophosphamide
Phosphamide MustardAcrolein
Cyclophosphamide
CH2 CH2
CH2 CH2
NH2
PO
OH
Cl
Cl
N
Nitrosoureas carmustine, lomustineBusulphan
Cisplatin
ResistanceDecreased permeabilityIncreased production of glutathioneIncrease DNA repairIncreased metabolism of drugs
NH2
NH2
Pt2+
Cl_
Cl_
Administered orally or i.v.tumours of testes & ovary
Anti-metabolites (methotrexate)
FF (glu)n
(glu)n
(glu)n
(G lu) (glu)n(glu)nF H 2 F H 4
F H 4
DTMP DUMPThym idyla tesynthase
D ihydro fo la tereduc tase
D ihydro fo la tereduc taseMethotrexate
Methotrexate
O ne-ca rbon U n it
C ellB lood
Polyglutam ates are retained in the cell
DTMP=Deoxythymidylic Acid
DUM P=Deoxyuridylic Acid
Cancer cells have higher rates of g lutamation enzym es levels
ResistanceDecreased transport into cellsDecreased affinity of DHF reductaseIncrease levels of DHF reductase
Administered orally or i.v.Non-Hodgkin’s lymphomaBurkitt’s lymphomaChildhood acute lymphoblastic leukemia
N
N N
N
HO
HO HO
HO
O
O O
O
O
O O
O
O
O O
O
F
F
HN
HN HNCH 3
HN
Inhib ites Thymidilate synthasevia com plexing w ith Tetrahydrofolate
Thym idilate synthaseTetrahydrofolate
P
P P
P
5-F luorouracilF luorouracil-Deoxy Urid ine
+
Thym idinePhosphorylase
D eoxyuridy lic acid D eoxythym idylic acid
Anti-metabolites (5-Fluorouracil)
ResistanceDecreased levels of thymidine phosphorylaseor affinity for 5FU
Administered parentallyBreast, ovarian, prostate,pancreatic, hepatic carcinomas
Anti-metabolites (Cytosine arabinoside, Cytarabine)
P PP P PPN N N N
H O H O H O H OH O H O H O H O
H O
O O O O
O O O OO O O O
H N H N H N H N
Cytosine arabinoside
DeoxycytidineKinase
DCM PKinase
NucleosideDiphosphate
Kinase
AraCM P AraCTPAraCDP
P revents D N A cha in e longation
ResistanceDecreased levels of deoxycytidine kinaseIncrease in dCTP
Administered oral and i.v.Chronic granulocytic leukemia
Cytotoxic antibiotics Doxorubicin, Dactinomycin, Etoposide (VA)
ResistanceMultidrug resistanceIncreased glutathione peroxidasedecreased topoisomerase
D ouble stranded D N A
D ouble stranded D N A break
N on-c leavab le com p lexTrans ien t c leavab lecom plex P ersis tan t c leavab le
com plex
Topo isom erase II
DR
UG
S trand passing, ro ta tionb reak resea ling
Administered i.v.Acute lymphocytic leukemiaAcute granulocytic leukemia
Cytotoxic antibiotics (Dactinomycin, Bleomycin)
A
A
T
T
C
C
G
G
C
C
G
G
Minor groove
Major groove
Dactinomycin
Bleomycin
Resistance not characterizedParentally administeredUsed in combination with other modalities
Resistance due to increase anti-oxidant,and DNA repair mechanismsParentally administeredTreatment 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
Polym erization blocked by vincristine & vinblastine
Polym erization stabilized by Taxol
Tub lindim er
Assem bly
C ontinued d isassem bly
S table m icro tubu le
D rug
D isassem bly
Resistance due to multidrug resistance,altered tublin moleculesAdministered I.v.Childhood leukemia's, Hodgkin'sand non-Hodgkin's lymphoma, testicular,ovarian carcinomas and brain tumours
Vincristine & vinblastine
Resistancealtered tublin molecules
Administered i.v.Metastatic ovarian and breast cancer
Taxol
BindingProtein
TargetProtein
Decreaseuptake
Increaseefflux
DHRF
Nuleus
Topoisomerase II
GSH
SP
Intracellularbinding
Altered targetamount or affinity
Altered targetamount or affinity
Increases metabolism
IncreaseRepair
P-glycoprotein
Resistance to chemotherapeutic agents
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 activityFast drug to be approved by FDA, Approx 80% remission in IFN refractory patientsActivity 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-B is constitutively expressed
I- B
I- B
I- B
I- B
I- B
NF- B
P50
P50
P50 P50
P50
P65
P65
P65 P65
P65
IKK IKK
IKK
Inflammatory genesanti-apoptotic genes
Proteasome
Bortezomib
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
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
EtoposideBleomycin
CisplatinCurative therapy testicular cancer (BEP)
Renal & hepatic FunctionBone Marrow reserveImmune statusPrevious Treatments
Likely natural History of TumorPatients Wishes to undergo treatmentPatients Physical & emotional ToleranceLong term gains & Risks