Does and Aspirin a day keep GI cancer away orIf you take a Cox 2 what does it do?

2

I’m not sure what these do but take them for several years and let me know how you do

3

Baseline ASA is derived from the bark of the willow tree- and

is a irreversible inhibitor of cyclo-oxygenase 1&2

Most of the other NSAIDS are reversible inhibitors although some have very long binding e.g. indomethacin.

4

Some more baseline Cyclo-oxygenases are one of 3 key enzymes in

arachidonic acid metabolism

Cyclo oxygenase converts ADA into prostaglandins, thromboxanes, prostacyclin and malondialdehyde.

Cox 1- Prostaglandin H synthetase 1-Responsible for mucosal integrity

Cox 2-Prostaglandin H synthetase 2-an inducible enzyme associated with inflammatory response and possible

tumor induction. Also may play a part in neo angiogenesis.

5

Getting tired of baseline yet? Cox 1 converts ADA to prostaglandin G2, an

endo peroxidase which is then reduced to an alcohol. During the early peroxidase reaction free radicals are produced. Free radicals are implicated in mutagenesis.

A large number of NSAIDS suppress chemical carcinogenesis in rodents eg Cancer Invest 20(4) 490-98,2002

6

So if they do suppress carcinogenesis what is the mechanism?

May reduce free radicals which are tumor promoting.

May suppress prostaglandin production which may act in other ways to promote tumor development or metastases such as modulating an inflammatory response caused by Cox 2. Prostaglandins are known to be involved in several steps of cell transformation, tumor growth and metastases. In this way might suppress polyp formation or subsequent steps from a polyp to cancer

Angiogenesis inhibitors

7

Suppress Prostaglandin production

Some NSAIDS decrease growth of tumor cells in vitro at the G1-S phase-ornithine decarboxylase is one of the enzymes inhibited.

8

Mechanisms

Several studies show that mRNA expression and Cox 2 protein are increased in colorectal, gastric and esophageal tissue around cancer and in the cancers themselves.(Am J Med 2001;110-665-695)

Cox 2 is up regulated between 2 and 50 fold in CRC

Cox 1 mRNA and protein has been variably associated with an increase.

By inhibiting Cox 1 and or 2 production at source carcinogenesis may be inhibited.

9

So does it work?

In one study a group used a selective Cox 2 inhibitor vs Sulindac to suppress chemically induced polyps in mice.

The number of polyps/mouse in Cox 2 treated-161; Sulindac-312, control-424.

Interestingly Cox 2 was not highly expressed in the intestinal epithelium but in the interstitial cells(Cell 87:803-809, 1996) Inflammatory response and neoangiogenesis?

10

Ok s’more- but this time from mice to men Some human tissue 14 CRC and 6 adenomas from surgical

resections

low to normal messenger RNA in normal mucosa for Cox 2

Cox 2 increased in 12/14 CRC

Cox 1 was equivalent in normal mucosa and in cancers and adenomas

Gastroenterol 1994;107;1183-88

11

So any relationship between tumors and Cox 60 cases of CRC - immunohistochemistry for Cox 2

Cox2 predominantly seen in tumor cells but seen in some stromal and endothelial cells and in normal mucosa adjacent to the cancer but not distant from the cancer

They divided the group between low and high Cox2 -(low Cox2- 79% of tumors)

Pts with low Cox 2 better survival- Cox 2 therefore might be involved in the transformation of cells that lead to mets.

12

Anti Angiogenesis, another twist Cox 2 inhibitor suppresses gastric cancer in vivo

(mouse model) but not the growth of cancer cells in vitro

Gastrointestinal cancers produce several substances including growth factors (VGEF) which have an effect on angiogenesis

Two tumor cell lines were used in mice one over expressed Cox 2, the other did not

Mice were treated with Indomethacin and a Cox 2 inhibitor

13

Twist and shout Both decreased tumors in a dose dependent

fashion regardless of the expression of Cox 2 in the tumors

Both decreased angiogenesis

VEGF and BFGF were suppressed (Lab Invest 1999;79-1469-77)

However, others have found that angiogenesis in xenografts could be suppressed by Cox 1 suppression but not by Cox 2 in Cox 2 negative expressing tumors.

14

Summary of mechanism Antiangiogenesis

Cox 2 inhibition displayed by tumor but not by normal tissue- Low cox 2 expressing tumors may have a better survival so Cox 2 inhibition may increase survival.

Prostaglandin inhibition

Suppression of the genesis of tumors by reducing free radical expression.

15

Typical Colon Cancer Patient A high risk colon cancer patient is: A tall

nulliparous hard drinking male couch potato,who is short for his weight, who had an early menarche, was never on the birth control pill, may or may not have eaten fibre, but little calcium, may or may not have used antioxidants, never taken ASA or a Cox 2 inhib (perhaps), and probably has a high animal fat intake, and may or may not have used tobacco.

16

Definitions Case Control- draw people from an observed

population and compare to those “matched” from the general population

Cohort study-Follow a group of people over a number of years and note any disease processes that develop and match with the characteristics of that group against the group that did not develop the disease(s) in question

17

Case Controls A large Australian population based c-c

study compared ASA use in 715 incident cases of CRC with 727 controls-

if one used ASA RR of CRC 0.53-Kune- Cancer Res 1988 48; 4399-4004

18

CC 12174 cases and 34934 controls in a GP Research

database-overall risk of 9 cancers- those that received at least 7scripts for NSAIDS 3-36 mo before cancer

RR- Esophagus 0.64; Stomach 0.51, colon 0.76; rectum 0.75, Pancreatic 1.49, Prostate 1.33

This was in patients largely over 65 who could get these meds free so they did not think they took much over the counter

BMJ 320: 1642-6, 2000

19

ASA - what does it keep away North West US-1326 incident cases- a

decrease in the risk if one used ASA-0.6

Summary--8/10 epidemiologic case control studies show some reduction of either colorectal polyps or cancer in aspirin users

20

Cohort Studies 13,987 elderly (median age 73) residents of

a Leisure home.

Those who used ASA 1/day-RR colon cancer 1.3- rectal cancer 1 (JNCI 1991,1182)

Gender difference men RR 1.5, women 1.0

21

Cohort cont’d 662,424 adults surveyed for a variety of lifestyle and

med issues from 1982-1988

Grps non users; ASA < 1/mo; 1-15/mo; >16/mo.

111CRC deaths from CRC recorded

RR of >16/mo 0.6 and for rectal 0.8, 1-15 0.72 and <1 .83-.85

(NEJM 1991 325:1593)

22

Yep cohort again 12668 people 25-74- ASA use over 30 days

previous to survey

1257new incident cases in 12.4 yrs F-up

RR CRC 0.9

men<65- 0.4 (Epidemiology 1994;5;138)

23

Cocohort-Ann Int Med 1994;121:1241-6 47900 male respondents mailed questionnaires

1986,1988,1990

ASA Users (2+times per week)-other drugs recorded including acetaminophen and other NSAIDS-33806 non users and 14094 users

251 diagnosed as CRC-#of cases per persons yr

-Non user-184/185310;

user 85/75637

24

Givannucci Ann Int Med cont’d RR among users 0.7 95%Ci 0.53-0.92- both

colon and rectum and both proximal and distal colon- and an inverse association between ASA use and metastatic cancer

Excluding men who had endoscopy for occult or overt bleeding men who took ASA were at a decreased risk for adenoma.

Stronger association with current users.

25

Women and Giovannucci- NEJM1995;333:609-14

Nurses health study (2+ tabs/wk)

Initial study 12 yrs of follow up and a slight but NS lower risk of CRC.

Subsequent study looking at women who took ASA for >10yrs RR 0.7

*If took ASA for >20yrs RR 0.56

True for both colon and rectal cases

26

ASA-Sturmer et al Ann Intern Med 128:713-720 ,1998

RCT-22071 male Physicians 40-84

12 years of Follow up

ASA 325 EOD for 5 years and b carotene 4 groups ASA and BC, ASA and placebo, BC and p; and p

CRC in 341 pts - RR of ASA 1.03

This study was a study to examine the effect of ASA on cardiovascular health and was terminated early due to the beneficial effects found. Patients did not have their GI tracts checked routinely and hence patients may have been looked at more closely in ASA group. Thus may have detected more but now 12 yrs of follow up.

27

Intervention studies In colorectal cancer it is generally accepted that

sporadic cancers especially left sided ones develop from an adenomatous polyp to a premalignant lesion with successive genetic changes as described by Volgelstein

Several observational studies suggested the regression of rectal polyps in FAP syndrome with polyps returning after Sulindac (NSAID) stopped

28

Polyps can they be prevented? Three of the earlier studies also looked at polyps- In

the northern US cohort study polyps were 0.4 RR in ASA users ( 212 polyp found)

In case control of subjects participating in randomized trial of FOB

147 polyps--176 controls without adenomas FOB+ and 153 case of no adenomas FOB -

ASA use for 3 mos RR 0.6

BMJ 307:285, 1993

29

polyps Post hoc evaluation of pts enrolled in RCT

of B carotene,Vit C and VitE for polyp prevention-793 pts asked re ongoing use of ASA at 6 mos and 1 yr

593- no use; 98 inconsistent; 102 consistent

Consistent RR 0.52, intermittent-0.92- so despite no difference in CRC may have been in difference in polyp formation.

JNCI 1993;85 912-16

30

Polyps in FAP-NEJM 2002:346:1054-9 FAP patients-41- randomized to two doses

of sulindac (cox 1&2 inhibitor) vs placebo

4 year treatment with 76% compliance in sulindac group

No diff in the mean number 0.69 or size 0.17 of poyps

Sulindac did not slow the growth of polyps

Mucosal prostaglandin was lowered.

31

Fap and cox 2-Steinbach NEJM 2000;342926):1946-52 77 patients with FAP- after 6 mo those on

celecoxib 400 mg BID had a mean reduction of 28% in polyps (p=0.003) and a 30.7% reduction in polyp size.

Reductions in group receiving 100 mg of Cox 2 BID NS

32

Any concern about safety profile of Cox 2?

The pooled results of 4 randomized trials have suggested an increased risk of cardiovascular events (Mukherjee et al. Risk of cardiovascular events associated with selective Cox-2 inhibitors. JAMA 2001;286:954-9.

Interestingly a 7000 person adjuvant trial using rofecoxib is about to begin.

33

So In randomized studies appoximately1.5% of patients

hospitalized for bleeding complications secondary to non specific NSAIDS

Do not know if specific Cox 2 inhibitors are better although they might be for a subgroup of CRC which over express Cox2- Can Cox 2 prevent mets- Unknown

Can ASA or other NSAIDS prevent polyps and then subsequent cancers- unknown

34

So- So Are there cardiovascular side effects to cox 2

inhibitors?

What about the bleeding risks of NSAIDS

What about the dose of these drugs- it may be necessary to be higher than we think based on Cox 2 data

35

Final conclusions. Mechanistically it is plausible that NSAIDS and Cox 2

inhibitors might inhibit the formation of cancers in the GI tract and there certainly is a wealth of observational studies to support that- but no proof in any randomized trial except for polyps in FAP

If you have a headache take an ASA but don’t take it to prevent CRC

Do not know anything about dose of ASA

Perhaps if you take it- take it for at least 20-30 years and you will probably live that long.

36

I’m not sure what these do but take them for several years and let me know how you do