Levels of rectal mucosal polyamines and prostaglandin E2 predict ability of DFMO and sulindac to prevent colorectal adenoma.
OBJECTIVE
Combination of polyamine and prostaglandin E2 (PGE2)-synthesis inhibitors reduced the risk of colorectal adenoma (CRA) by 70% in patients who received polypectomies. We studied effects of the combination of difluoromethylornithine (DFMO) and sulindac on biomarkers and investigated factors that modify their efficacy.


METHODS
We analyzed rectal mucosal levels of polyamines (spermidine, spermine, and putrescine) and PGE2, treatment regimens, and risk of CRA in 267 participants of a phase IIb/III chemoprevention trial of DFMO/sulindac.


RESULTS
In the group that received DFMO/sulindac, spermidine-to-spermine ratio (Spd:Spm) in rectal mucosa decreased between baseline and 12- and 36-month follow-up examinations (0.30, 0.23, and 0.24, respectively; P < .001 for both comparisons to baseline). Putrescine levels decreased between baseline and 12 months (0.46 vs 0.15 nmol/mg protein; P < .001) but rebounded between 12 and 36 months (0.15 vs 0.36 nmol/mg protein; P = .001). PGE2 levels did not change, although aspirin use was significantly associated with lower baseline levels of PGE2. No significant associations were observed between changes in biomarker levels and efficacy. However, drug efficacy was greatest in subjects with low Spd:Spm and high PGE2 at baseline; none of these subjects, versus 39% of those given placebo, developed CRA (P < .001). Efficacy was lowest in subjects with high Spd:Spm and low PGE2 at baseline; 28% developed CRA, compared with 36% of patients given placebo (P = .563).


CONCLUSIONS
A combination of DFMO and sulindac significantly suppressed production of rectal mucosal polyamines but not PGE2. No relationship was found between changes in biomarker levels and response. However, baseline biomarker levels modified the effect of DFMO/sulindac for CRA prevention.
Thompson
Patricia A
PA
Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724-5024, USA. pthompson@azcc.arizona.edu
Wertheim
Betsy C
BC
Zell
Jason A
JA
Chen
Wen-Pin
WP
McLaren
Christine E
CE
LaFleur
Bonnie J
BJ
Meyskens
Frank L
FL
Gerner
Eugene W
EW
D000236:Adenoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000601:surgery; D000368:Aged; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D001706:Biopsy; D003113:Colonoscopy; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000601:surgery; D015232:Dinoprostone / Q000378:metabolism*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000518:Eflornithine / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D016013:Likelihood Functions; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016609:Neoplasms, Second Primary / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011073:Polyamines / Q000378:metabolism*; D011700:Putrescine / Q000378:metabolism; D012007:Rectum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism; D013467:Sulindac / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
D016588:Anticarcinogenic Agents; D054316:Biomarkers, Pharmacological; D004791:Enzyme Inhibitors; D011073:Polyamines; D013467:Sulindac; D013096:Spermine; D015232:Dinoprostone; D013095:Spermidine; D011700:Putrescine; D000518:Eflornithine