Carcinogenesis (Hankinson)

Question 1

Wk5

What % of human cancers result from effects of environmental factors?

Answer 1

80-90% according to epidemiological evidence.

Question 2

Wk5

What led to increases in lung cancer and decreases in stomach cancer? What does this show about causes of cancer?

Answer 2

Smoking caused increase and advent of refrigeration (and therefore less bacteria etc) caused decrease. Genetic causes are NOT principal cause but rather environmental factors

Question 3

Wk5

4 types of carcinogenic chemicals

Answer 3

(1) promoters (2) initiators (3) complete carcinogens (4) cocarcinogens

Question 4

Wk5

Where do carcinogens come from?

Answer 4

Large quantity comes from plants or other things in nature like mold (aflatoxin B1). Many known carcinogens are initiators (see slide 15)

Question 5

Wk5

What is a procarcinogen?

Answer 5

It is inactive until metabolized to intermediate (Phase 1 often CYP p450) where it becomes active. These nonreactive compounds are more dangerous because they have longer half-lifes than compounds that are very reactive before metabolism. Ex: Benzo(a) pyrene - after metabolism becomes active and binds to DNA

Question 6

Wk5

What is TPA and how does it work?

Answer 6

Natural carcinogen from a plant that mimics DAG but has a much longer half life.

Leads to over activation of PKC

Is mitogenic, stimulates transcription of some genes, disrupts gap junctions, stim production of ROS, induce chromosomal aberrations, proinflammatory

Question 7

What combinations of initiators and promoters yeild tumors?

Answer 7

Initiator then promotor both needed to cause tumors:

Initiator first, then promoter applied frequently (if promoter applied too infrequently no tumors)

Initiator first, then promotor applied way later (initiators show memory)

Question 8

Why would evolution select for phase 1 metabolites that are reactive intermediates and carcinogenic?

Answer 8

There is usually no problem with carcinogenic phase I metabolites until around 50 yo. Up until a few years ago people didn’t live that long and died of other things first anyway.

Moreover, since the onset of cancer resulting from active metabolites doesn’t occur until beyond reproductive age there is no evolutionary pressure for change (although technically he’s wrong here bc men can DEFINITELY still have progeny through their 50s)

Question 9

Are both initiators and promoters genotoxic (mutate DNA)?

Answer 9

No. Initiators are genotoxic (metabolic intermediates mutate DNA). Promoters are non-genotoxic (just stimulate replication of initiated cells)

Question 10

How/why exactly is benzo(a)pyrene a carcinogen?

Answer 10

Benzo(a)pyrene is metabolized by CYP1A1 to benzo(a)-7,8-diol-9,10-epoxide (BPDE) and THAT is carcinogenic

BPDE is carcinogenic because: poor substrate for phase II enzymes (glutathione); long half life; highly mutagenic; reisistant to DNA repair (binds guanine to make it pair with adenine instead but doesn’t distort DNA, so doesn’t get repaired)

Also binds Ah receptor and turns on tx of CYP1A1 (not main carcinogenic action though)

Specifically can mutate G –> T in p53 so lack of DNA repair

Complete carcinogen

Note: Benxo(a)pyrene found in cigarette smoke, smog, burned food, called “ultimate carcinogen”

Note: Glutathione does Phase II metabolism for benzo(a)pyrene (and BPDE)

Question 11

Some initiating agents are direct acting and are actually used for cancer chemotherapy. What is the problem with this?

Answer 11

These cause other cancers later on

Question 12

Dioxin

Answer 12

Promoter

Binds Ah receptor and stimulates gene transcription of growth promoters (main promoting function)

Also tx of CYP1A1 (remember CYP1A1 metabolizes benzo(a)pyrene to its toxic/carginogenic intermediate!)

Has long half life, like many promoters

Question 13

What is most important in tumor promotion? (At least this is the emerging consensus)

Answer 13

Inflammation

Question 14

Complete carginogen

Answer 14

Can act as an initiator and a promoter

Ex: Benzo(a)pyrene at high concentrations (BaP-diol-epoxide is the initiator but BaP itself binds Ah receptor to turn on growth promoting genes that make it a promoter too)

Question 15

What specific mutation do both Aflatoxin B1 and Benzo(a)pyrene cause?

Answer 15

G –> T in the p53 gene

Is G –> T because guanine adducted with BPDE can base pair with A rather than C

And also because methylated (5-methylguanine) CpG sites are good binding sites for carcinogen

Question 16

Aflatoxin B1

Answer 16

Carcinogen produced by Aspergillus flavus and found in grain contaminated with mold.

Hepatocarcinogen

Mutates G –> T in p53 so lack of DNA repair

Question 17

Polymorphisms that affect susceptibility to cigarette-related lung cancer in Japanese people

Answer 17

1) Single nucleotide substitution in CYP1A1 increases risk
2) Glutathione S-transferase M1 reduces risk

Combo of mutated CYP1A1 and NO glutathione S-transferase M1 makes you very susceptible to cigarette-related lung cancer