Cigarette smoking and the risk of invasive epithelial ovarian cancer in a prospective cohort study.

Few cohort studies have examined the association between cigarette smoking and ovarian cancer risk, either overall, or by histological subtype. In relation to the latter, it has been suggested that mucinous ovarian tumours may be aetiologically unrelated to the other types of epithelial tumours and that their respective associations with cigarette smoking may differ. We examined the association between smoking and ovarian cancer risk using data from participants in a randomised controlled trial of screening for breast cancer involving 89,835 women aged 40-59 years at recruitment. Cox proportional hazards models were used to estimate rate ratios (RR) and 95% confidence intervals (CI). During an average of 16.5 years of follow-up, we observed 454 incident cases of ovarian cancer (184 serous, 67 endometrioid, 32 mucinous, 171 other or unknown). We found that women who had smoked for several decades had an approximately two-fold increased risk of epithelial ovarian cancer. Relative to never-smokers, women who had smoked for 40 years or more were at the highest risk (RR=2.50, 95% CI=1.37-4.56). The association with non-mucinous tumours was similar to that observed overall. For mucinous tumours, a two-fold increased risk was observed with smoking of shorter duration, although the number of mucinous tumours in our data-set was small. Long-term cigarette smoking may be associated with an increased risk of epithelial ovarian tumours.

Synthesis and dopamine transporter affinity of the four stereoisomers of (+/-)-2-(methoxycarbonyl)-7-methyl-3-phenyl-7-azabicyclo[2.2.1]heptane.

All four stereoisomers of (+/-)-2-(methoxycarbonyl)-7-methyl-3-phenyl-7-azabicyclo[2.2. 1]heptane were synthesized and evaluated as cocaine binding site ligands at the dopamine transporter. The in vitro binding affinities (Ki) of the 7-azabicyclo[2.2.1]heptane derivatives were measured in rat caudate-putamen tissue and found to be 100-3000-fold less potent (Ki = 5-96 microM) than cocaine and 2beta-(methoxycarbonyl)-3beta-phenyltropane (2, WIN 35,065-2). Surprisingly, the 3alpha-phenyl isomers (6c, 6d) were more potent than the 3beta-phenyl isomers (6a, 6b). Molecular modeling studies revealed that the rigid 7-azabicyclo[2.2.1]heptane derivatives possess molecular topologies which are significantly different than the molecular topologies of the 2beta-(methoxycarbonyl)-3-phenyltropanes.

Synthesis, structure, dopamine transporter affinity, and dopamine uptake inhibition of 6-alkyl-3-benzyl-2-[(methoxycarbonyl)methyl]tropane derivatives.

A series of 6-alkyl-3 beta-benzyl-2-[(methoxycarbonyl)methyl]tropane analogues were synthesized and evaluated as cocaine binding site ligands at the dopamine transporter (DAT). The in vitro affinity (Ki) for the DAT of the 6-alkyl-3 beta-benzyl-2-[(methoxycarbonyl) methyl]tropane analogues was determined by inhibition of [3H]WIN 35,428 in rat caudate putamen tissue. The inhibition of dopamine uptake (IC50) was also measured for selected compounds which demonstrated moderate affinity for the dopamine transporter. The unsubstituted enantiopure analogues (-)-19a (Ki = 33 nM) and surprisingly (+)-20a (Ki = 60 nM) were found to be almost equipotent with the high-affinity binding components of cocaine and WIN 35,065-2 and exhibited slightly more potent dopamine uptake inhibition than both cocaine and WIN 35,065-2. In general, substitution at the 6-position of racemic 19a and 20a with alkyl groups was found to result in decreased activity relative to increased chain length of the substituent. The 3 beta-benzyl-2 beta-[(methoxycarbonyl)methyl]-6 beta-methyltropane (21b; Ki = 57 nM) was the only 6-alkyl derivative to exhibit moderately potent activity. The 6 beta-isomer 21b was 4-fold more potent than the 6 alpha-isomer 19b (Ki = 211 nM) and was nearly equipotent with (-)-19a and (+)-20a as well as with cocaine and WIN 35,065-2. The results of this study further demonstrate the steric constraints associated with the C(6)-C(7) methylene bridge of the tropane ring system for molecular recognition of cocaine analogues at the cocaine binding site(s) on the DAT.

A prospective cohort study of cigarette smoking and the risk of endometrial cancer.

Case-control studies have shown inverse associations between cigarette smoking and endometrial cancer risk. However, two small prospective cohort studies have not clearly supported an association. Moreover, quantitative measures of smoking have been examined infrequently. Our aim was to study the association between smoking and endometrial cancer risk in a large prospective cohort. We used proportional hazards models to estimate hazard ratios relating cigarette smoking to endometrial cancer risk among 70 591 women aged 40-59 years at recruitment into a randomised controlled trial of mammography screening for breast cancer. During an average of 10.6 years of follow-up (751 833 person-years), a total of 403 women were diagnosed with incident endometrial cancer. We found that a reduced endometrial cancer risk was evident only among women who currently smoked 20 cigarettes per day or more (hazard ratio=0.62, 95% CI=0.42-0.92, P for trend=0.03). There was some suggestion of an inverse association with smoking duration, but this was less clear. The association did not vary with menopausal status, relative body weight, or the use of hormone replacement therapy, but it appeared to be stronger among parous than nulliparous women. The underlying biological mechanisms of this association remain unclear.

Obesity and colorectal cancer risk in women.

BACKGROUND: Several large studies of obesity and colorectal cancer risk have found no association among women but a reasonably consistent positive association among men. In women, a positive association that is stronger among, or limited to, those who are premenopausal has been suggested by studies that stratified analyses by age, although no previous study has examined the association by menopausal status. METHODS: We used proportional hazards analyses to estimate hazard ratios relating obesity to colorectal cancer risk among 89,835 women aged 40-59 years at recruitment into the Canadian National Breast Screening Study, a multicentre randomised controlled trial of mammography screening for breast cancer. During an average 10.6 years of follow up (936,433 person years), a total of 527 women were diagnosed with incident colorectal cancer (363 colon and 164 rectal). RESULTS: We found that obesity (body mass index > or = 30 kg/m(2)) was associated with an approximately twofold increased risk of colorectal cancer among women who were premenopausal at baseline (hazard ratio 1.88, 95% confidence interval 1.24-2.86). There was no association among postmenopausal women (p for interaction=0.01), and there was only a weak positive association in the entire cohort. CONCLUSIONS: Our data suggest that obesity is associated with a twofold increased risk of colorectal cancer in premenopausal women but is not associated with altered risk in postmenopausal women. Effect modification by menopausal status may better explain the inconsistent or weak findings in previous studies than the presumed lack of an association among women.