1. Pharmacology of Chemotherapy
Cancer Biology
Dr Dean Willis
Department of Pharmacology
University College London
Gower Street, London WC1 6BT

2. 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.

3. Nature Reviews in Cancer
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

4. 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
Host
Parasite
Paul Ehrlich
Nobel Laureate 1908
No effect
Cytotoxic

5. Qualitative Quantitative
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.

6. Characteristics of tumour cells &
sites of therapeutic intervention (present and future)
Blood
vessel
Primary
Tumour
Normal
organ/tissue
Major Modalities for Treatment for cancer
Surgery
Irradiation
Combination of the above (modality therapy)
Chemotherapy

7. 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)

8. Problems associated with Anti-cancer chemotherapy
Growth fraction (percentage of cells actively dividing)
RT is carried into the cell with the virus.
Anti-cancer chemotherapy most effect against cells in cell fraction A. Cells in fraction B can re-enter fraction A.

9. Problems associated with Anti-cancer chemotherapy
Exponential growth of a tumour
Limit of diagnostic procedures.

10. Problems associated with Anti-cancer chemotherapy
Cell cycle: Susceptibility of cancer cells to a given drug is often dependant on cell cycle

11. 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)

12. 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

13. Summary of cytotoxic drug action

14. Action of Alkylating drugs (methlorethamine) Mustine
Other nitrogen mustards
Cycloposphamide
Chlorambucil
Melphalan

15. Action of Alkylating drugs
Resistance
Decreased permeability
Increased production of glutathione
Increase DNA repair
Increased metabolism of drugs
Nitrosoureas carmustine, lomustine
Busulphan
Cisplatin
Administered orally or i.v.
tumours of testes & ovary

16. Anti-metabolites (methotrexate)
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

17. Anti-metabolites (5-Fluorouracil)
Resistance
Decreased levels of thymidine phosphorylase
or affinity for 5FU
Administered parentally
Breast, ovarian, prostate,
pancreatic, hepatic carcinomas

18. Anti-metabolites (Cytosine arabinoside, Cytarabine)
Resistance
Decreased levels of deoxycytidine kinase
Increase in dCTP
Administered oral and i.v.
Chronic granulocytic leukemia

19. Cytotoxic antibiotics Doxorubicin, Dactinomycin, Etoposide (VA)
Resistance
Multidrug resistance
Increased glutathione peroxidase
decreased topoisomerase
Administered i.v.
Acute lymphocytic leukemia
Acute granulocytic leukemia

20. Cytotoxic antibiotics (Dactinomycin, Bleomycin)
Resistance not characterized
Parentally administered
Used in combination with other modalities
Dactinomycin
Minor groove
Bleomycin
Major groove
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

21. Vincristine & vinblastine
Plant alkaloids (vincristine & vinblastine, Taxol)
Vincristine & vinblastine
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
Administered i.v.
Metastatic ovarian and breast cancer

22. Resistance to chemotherapeutic agents

23. 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

24. 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

25. 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
Curative therapy testicular cancer (BEP)
Cisplatin
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