Pharmacology 2060A/B Lecture 17: Module 17

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Cancer Chemotherapy
Cancer– refers to the uncontrolled proliferation of cells. Cancer cells are often referred to as neoplastic, meaning
they have abnormal and uncontrollable cell growth
Characteristics of Cancer Cells
1) Persistent uncontrollable cell proliferation
2) Invasive– cancer cells invade adjacent tissue, facilitating cancer growth in different areas of the body
3) Metastatic– the ability of cancer cells to travel to different sites in the body and invade to form new tumours
4) Immortal– Cancer cells do not die, they continually divide
5) Angiogenesis– Cancer cells develop their own blood vessels to supply nutrients. This is a critical step to allow
them to proliferate
Treatment Modalities for Cancer
1. Surgery- the tumor is removed
2. Radiation– high energy radiation is used to shrink tumours and kill cancer cells. Radiation therapy
damages DNA of both cancerous and non-cancerous cells
3. Chemotherapy- Drugs are used to treat cancer. As cancerous cells are dividing rapidly, chemotherapeutic
drugs target rapidly dividing cells
The Cell Cycle
As the treatment of cancer involves targeting cell proliferation, an understanding of the cell cycle is essential for
understanding the mechanism of drug action
Obstacles to Successful Chemotherapy
Toxicity to Normal Cells
Neoplastic cells (cancer cells) are very similar to normal cells. Therefore it is difficult to specifically target
only cancer cells during chemotherapy
The most cellular toxicity occurs to cells with a high growth fraction. The growth fraction is the ratio of
proliferating cells to cells in the resting (G0) state. Examples of cells with a high growth fraction include:
bone marrow, GI epithelium, hair follicles and the germinal epithelium of the testes, that gives rise to
sperm
Aside from killing cancer cells, chemotherapeutic drugs kill normal cells
Cure of Cancer Requires 100% Cell Kill
In order to cure cancer, we must kill virtually all cancerous cells in the body. This is difficult as there are
not good tests to determine whether cancerous cells are present in the body in low numbers
The kinetics of cell death with chemotherapy are first-order. This means that a constant percentage of
cancerous cells are killed at a given dose of drug
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Difficult Early Detection
Cancer is almost always significantly progressed by the time it is diagnosed
In the figure the red line shows the progression of the tumour growth. Notice how the
tumour is not detected until there are 109 tumour cells
The dark blue line shows what happens when treatment is started late and the treatment regimen is not
effective
The light blue line shows a better prognosis when treatment is initiated earlier and the treatment regimen is
more effective
The green line shows how decreasing the tumour burden with surgery followed by chemotherapy can be
effective if possible
Various cancers have screening programs established in Canada. Some of the screening guidelines (from
the Canadian Cancer Society) include:
Breast Cancer– Clinical Breast Examination every 2 years for women over 40. High risk patients should be
screened more often and screening may start earlier than age 40
Cervical Cancer – The most important risk factor for cervical cancer is Human Papillomavirus (HPV) infection.
HPV is spread primarily by genital skin-to-skin contact and it is estimated that over 75% of women AND men will
have at least one HPV infection in their lifetime. Sexually active women should have a Pap test every 1-3 years
Colorectal Cancer
Men and women over 50 who are not at high risk should have a fecal occult blood test every two years
Colonoscopy may also be performed every 5 years in high risk patients
Prostate Cancer– Men over 50 should have the Digital Rectal Exam and/or the Prostate Specific Antigen blood test
Skin Cancer– Self-checks should be performed regularly. In particular, look for changes to birthmarks and/or
moles, any new skin growths, and sores that don’t heal properly
Testicular Cancer– Males over the age of 15 should regularly perform the Testicular Self Examination
Solid Tumours Respond Poorly To Chemotherapy
Solid tumours have a large fraction of cells in the resting (G0) state. As most chemotherapeutic drugs target
proliferating cells, solid tumours don’t respond as well
Drug Resistance
Cells can develop resistance to drugs used during chemotherapy
Mechanisms of resistance can include:
oDecreased drug uptake
oIncreased drug efflux
oDecreased drug activation (in the case of prodrugs)
oReduced target sensitivity
oIncreased cellular (primarily DNA) repair
oDecreased apoptosis (programmed cell death)
P-glycoprotein is an efflux drug pump that pumps drugs out of cells (Module 2). By not allowing cellular
accumulation of chemotherapeutic drugs, P-glycoprotein can cause multiple drug resistance
Resistant cells are not killed by chemotherapeutic agents and therefore this phenomenon can cause
therapeutic failure
Strategies to Achieve Maximum Benefit from Chemotherapy
Intermittent Chemotherapy
The intent of this strategy is to kill cancer cells by administering chemotherapeutic drugs intermittently. This allows
time for normal cells to recover
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