Lecture 22_Cancer I

Question 1

What are your chances of developing some sort of cancer in your lifetime?

Answer 1

1 in 3

Question 2

Incidence vs Prevalence

Answer 2

• Incidence: The risk of contracting the disease (rate of occurrence of new cases).
• Prevalence: How widespread the disease is (proportion of cases in the population at a given time).

Question 3

(T/F) Incidence and mortality from cancer rises with age.

Answer 3

TRUE.

Question 4

Most (60-90%) of cancers are primarily due to…

Answer 4

…environmental factors (nongenetic factors including diet, environmental chemical exposure, cultural and behavioral practices).

Question 5

____ of all cancer deaths in North America are related to the use of tobacco products.

Answer 5

1/3

Question 6

Most mortality rates from cancers have either remained constant or declined during the 20th century except…

Answer 6

…increases in lung cancer incidence.

Question 7

Increases in lung cancer incidence reflect…

Answer 7

…the long latency period of cancer development.

Question 8

Why does the cancer mortality rate for men and women differ from 1940 to 2000?

Answer 8

It wasn’t socially acceptable for women to smoke until after WWII, which explains why the incidence rate of cancer development in women increased at a slower pace.

Question 9

(T/F) Many cancers may not become evident for 10-20 years after exposure to the responsible agent, making it more difficult to ascribe responsibility for the cancer to any particular environmental agent.

Answer 9

TRUE.

Question 10

(T/F) Only natural compounds are carcinogenic.

Answer 10

FALSE. Both natural and synthetic compounds can be carcinogenic.

Question 11

Can cancer fighting drugs can be carcinogenic?

Answer 11

YES.

Question 12

(T/F) Most compounds are not carcinogenic.

Answer 12

TRUE. However, most chemicals have not been tested adequately for their carcinogenicities.

Question 13

Carcinogens come from a wide variety of chemical classes. What does this mean for simplifying carcinogenicity?

Answer 13

There is no simple structure-activity rule that can explain the carcinogenicity of all carcinogens.

Question 14

The final common target of chemical carcinogens is…

Answer 14

…DNA.

Question 15

Two major types of carcinogens:

Answer 15

• Direct acting

- Those requiring metabolic activation

Question 16

Direct acting carcinogens (covalent binding)

Answer 16

• Some compounds (such as alkylating agents used in cancer chemotherapy) are chemically very reactive in their parent form (no metabolism is required for them to be chemically reactive).
• These compounds can bind directly (and somewhat randomly) to sites on DNA, RNA and proteins. It is this ability that is responsible for both their efficacies as cancer killing therapeutics and their abilities to induce the growth of new tumors.

Question 17

Compounds requiring metabolic activation to become carcinogens

Answer 17

The term ultimate carcinogen refers to the compound that ultimately directly interacts with DNA. Most compounds are not carcinogenic when they enter the body, but become so through metabolism (most often several rounds of metabolism).
Eg. the polycyclic aromatic hydrocarbon benzo[a]pyrene is chemically unreactive in its parent form.
The initial step of carcinogen activation is often carried out by a cyt. P450 enzyme but activation may also occur by reductases and peroxidases, eventually yielding a final electrophilic compound that reacts with nucleophilic sites on DNA.
Differences in the metabolic capabilities of different tissues determine their sensitivities to various carcinogens.

Question 18

Significance of epoxide group

Answer 18

Highly reactive, and often makes structures dangerous.

Question 19

Significance of cyt. P450

Answer 19

Various cyt. P450 enzymes are involved in the initial activation of a variety of structurally diverse compounds.

Question 20

Aflatoxin B1

Answer 20

Commonly produced by molds that grow on food. It is a potent hepatic carcinogen. Aflatoxin is subject to epoxide.

Question 21

Metabolic activation of a pro-carcinogen does not guarantee that the reactive electrophile will necessarily react covalently with DNA. Cells have defense mechanisms to deal with these destructive compounds. What are some of these?

Answer 21

• The primary method to protect cells from these reactive metabolites is via conjugation with GSH, sulfate or glucuronides. Carcinogen binding to glutathione protects cell mutation.
• Cells deficient in GSH are at high risk for neoplastic transformation when exposed to carcinogens. Eg. smokers run an increased risk of lung cancer if they are deficient in glutathione S-transferase activity combined with elevated CYP1A1 activity.

Question 22

Covalent interactions of carcinogens with tissue nucleophiles

Answer 22

• In some instances the identity of the ultimate carcinogen has been determined from the chemical characterization of the covalently bound DNA adducts it forms.
• These adducts have been found on all four nitrogen bases in DNA.
• Evidence suggests that different carcinogens may leave different characteristic adduct patterns on nucleotides in ‘hot spots’ of key genes that govern the conversion of normal cells into tumor cells. Different cancers thus may possess unique DNA ‘fingerprints’ which can aid in their identification.

Question 23

Some chemicals may be carcinogenic by nongenotoxic mechanisms. What does this mean what are some examples?

Answer 23

• They act via several different pathways to disrupt normal hormonal regulation of cell growth and by stimulation of oxidative stress that eventually leads to cell DNA damage (they don’t directly bind to DNA).
• Examples: Excessive alcohol consumption can lead to pharyngeal and liver cancer, immunosuppressants (cyclosporine), and endocrine system modifiers (steroids).

Question 24

Significance of endogenous processes.

Answer 24

Endogenous processes such as endogenously produced oxidants (not just exogenous compounds) may also contribute to DNA damage and thus to the development of cancers. The relative importance of endogenous versus exogenous factors is unknown.