Cancer Therapy:

Successes and failures

 Key Issues
• Chemotherapy drug development over the last 40 years
– Combination Chemotherapy
– Adjuvant chemotherapy
– Drug screening programmes
– The platinum drugs

• Hormonal therapy – tamoxifen story

• Targeted therapy – immunotherapy

• Multiple drug resistance (MDR)

• Epidemiology
 Combination
Chemotherapy
• 1965: a most important break-through in cancer therapy
occurred.
– James Holland, Emil Freireich, Emil Frei
• Proposed the idea of combination chemotherapy using
drugs with different mechanisms of action.

• cancer cells might develop resistant to the a single

agent, but unlikely to become resistant to multiple.

• Administered methotrexate vincristine, 6-

mercaptopurine and prednisone: POMP regimen
– Acute lyphocytic leukaemia – children
– ALL now largely curable even at advanced stages
 Combination
Chemotherapy
• Extended to the lymphomas in 1963
– Vincent DeVita George Canellos, NCI, in the
late 1960s.

• Nitrogen mustard, vincristine, procarbazine and

prednisone: MOPP regimen.

• could cure patients with Hodgkin's and non-

Hodgkin's lymphoma.

• Nearly all successful cancer chemotherapy

regimens use the model of multiple drugs given
simultaneously.
 Adjuvant therapy
• Animal studies demonstrated that chemotherapy
was more effective when used to treat tumours of
smaller size.
– Reduce tumour burden by surgery them treat
remainder with chemo.

• Emil Frei used high dose methotrexate to prevented

recurrence of osteosarcoma following surgical
removal of the primary tumour.

• 5-fluorouracil was later shown to improve survival

when used as an adjuvant to in colon cancer.

• adjuvant chemotherapy after complete surgical

resection of breast tumours significantly extended
survival for advanced cancer.
 NCI Drug Screening
Programme
• 1956: Gordon Zubrod,
– led the development of antimalarial agents for the
United States Army took over the Division of
Cancer Treatment of the NCI.
– Guided development of new drugs.
– Two decades that followed, NCCSC established to
test anticancer agents.

• Zubrod interested in natural products of

plant and marine sources, a controversial
programme.

• Led to the discovery of

– Taxanes (in 1964)
– Camptothecins (in 1966).
 The Platinum Drugs
• Platinum-based agents
• Cisplatin discovered at Michigan State University by Barnett
Rosenberg working under an NCI contract.

• A serendipitous discovery: Rosenberg wanted to explore the

effects of an electric field on the growth of bacteria.

• Bacteria ceased to divide in an electric field. T

• The inhibition of bacterial division was pinpointed to an

electrolysis product of the platinum electrode.

• Initiated studies into the effects of platinum compounds on cell

Cisplatin synthesised.

• Pivotal in the cure of advanced testicular cancer. Subsequently,

• Eve Wiltshaw: Institute of Cancer Research UK developed

carboplatin with broad antitumour activity and less
nephrotoxicity.
Some of the players

1. Emil Frei
2. Geoffrey Holland
3. Vincent DeVita
4. Gordon Zubrod
Breast Cancer: Tamoxifen
• Tamoxifen: estrogen receptor
modulator for breast cancer.
– early and advanced breast cancer in
pre - and post-menopausal women
• World's largest selling breast
cancer treatment.

• Used as prophylaxis:
– For women at high risk.
– Reduction of contralateral (in the
opposite breast) breast cancer.
 Tamoxifen

Tamoxifen Estradiol
 Tamoxifen
• Tamoxifen: invented by AstraZeneca
– brand names Nolvadex, Istubal, Valodex.

• Tamoxifen is taken for up to 5yrs or for life in

advanced disease.

• Improved survival rates by 40-50%.

• Usually given in combination with traditional

chemotherapy (methotrexate, 5FU)
 Immunotherapy
• Traditionally cancer treated with:
– Surgery, radiotherapy, chemotherapy
(individually or in combination).

• Chemo and radiotherapy affect healthy

tissue.

• Toxic side effects and development of drug

and radio-resistance

• Immunotherapy may avoid problems of

toxicity and resistance
mAB Trade Tumour Company Date
name
Rituximab Rituxan Non-Hodgkin's Roche/Genentec 1997
lymphoma h
Trastuzumab Herceptin Breast CA Genentech 1998
Gemtizumab Mylotag AML Wyeth/Celltech 2000
Alemtuzumab Campath CLL Genzyme 2001
Ibritumomab Zevalin Non-Hodgkin's Biogen Idec 2002
lymphoma
Tositumomab Bexxar Non-Hodgkin's GSK/Corixar 2003
lymphoma
Cetuximab Erbitux Colorectal Imclone/BMS 2004
Bevacizumab Avastin Colorectal Genentech 2004
 Immunotherapy
• Development of mAB therapy dependent on
a greater understanding of signal
transduction pathways.

• mABs competitively bind to cell surface

receptor and lead to receptor destruction.

• No side effects or toxicity.

• Early days
 Resistance to chemotherapy
• Conventional cancer chemotherapy is limited by tumour
cells which exhibit multidrug resistance (MDR).

• MDR is defined as resistance of tumour cells to the

cytostatic or cytotoxic actions of:
– Multiple
– Structurally dissimilar
– Functionally divergent, drugs commonly used in cancer
chemotherapy.

• MDR can be:

– Intrinsic: The tumour is non-responsive (refractory) at the start
of treatment
– Acquired when the tumour initially responds but then relapses
and becomes refractory to treatment
 What causes MDR?
• Transporter molecules (usually membrane bound) are
mediators of MDR.

• P-glycoprotein (P-gp) is a prototypical MDR protein

• Identified as a 170kDa glycoprotein abundantly expressed

in MDR cells.

• Cloning and purification of MDR gene demonstrated that it

is a unidirectional ATP-dependent drug efflux pump.
– A product of the MDR1 gene
– ATP binding cassette superfamily (small molecule ion
transporters
 Epidemiology
• A success indicating a huge failure:
– Understanding the causes of cancer has been a
major advance

• Studies into the

– Causes
– Risks
– Incidence
– Mortality

• Indicate that the problem of cancer has

hardly been addresses in a satisfactory way
 A Global Concern
• 1990 2000 2010

60 million deaths 80 million deaths

2/3 in developing countries

With 5% of the resources to deal with the
problem

40 million of these deaths are preventable

 A Global Concern
• 9 Million new diagnoses each year

• 5 million deaths each year

• 10% of all deaths in the world each year

• Usually regarded as a problem of developed

countries

• More than half of of all cancers are seen in ¾ of

the world’s population who live in developing
countries
 Epidemiology of Cancer
• Studies on the epidemiology of cancer break
down into two basic areas.

• The biology/molecular genetics of cancer.

• The sociology of cancer.

• Understanding both of these areas in critical for

cancer control.
 Sociology of Cancer
• Where people live.

• Geographic and temporal variability

– Habits
• Smoking ----- Lung cancer.
• Diet ------------ Stomach and colon cancer.
• Food preservatives --------- Stomach and liver cancer.

• Environmental hazards
– Viruses and liver cancer.
Cancer Incidence
CRUK Statistics 2000 Survival
 Summary
• Logical but major advances
– Combination Chemotherapy
– Adjuvant chemotherapy
– Drug screening programmes
– The platinum drugs

• Hormonal therapy – tamoxifen story

• Targeted therapy – immunotherapy

• Multiple drug resistance (MDR)

• Epidemiology