This randomized phase II trial is studying how well sulindac works in preventing melanoma in healthy participants who are at increased risk of melanoma. Sulindac may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether sulindac is more effective than a placebo in preventing melanoma in individuals with many moles and abnormal moles.

PRIMARY OBJECTIVE:

I. To determine sulindac and metabolite levels in healthy participants with atypical nevi and benign nevus at increased risk for melanoma treated with sulindac versus placebo.

SECONDARY OBJECTIVES:

I. To assess the effects of sulindac on apoptosis in atypical nevi of these participants.

II. To assess the effects of sulindac on VEGF expression in atypical nevi of these participants.

III. To assess sulindac and metabolite levels in plasma and its association with drug levels in the target tissue.

OUTLINE: This is a multicenter study. Participants are randomized to 1 of 2 treatment arms.

ARM I: Participants receive oral sulindac twice daily.

ARM II: Participants receive oral placebo twice daily.

In both arms, treatment continues for 8 weeks in the absence of unacceptable toxicity.

Blood and tissue samples are collected at baseline and/or after completion of study therapy and analyzed for sulindac and metabolite levels via high performance liquid chromatography tandem mass spectrometry; the detection of apoptotic cells via TUNEL assay; and VEGF expression via immunohistochemistry assays.

After completion of study therapy, participants are followed for 2 weeks.

Criteria:

• Healthy participants at risk for developing melanoma and meeting the following criteria: must have >= 4 large (>= 5 mm and < 15 mm) atypical nevi and have 1 benign nevus amenable to biopsies
• No histologically confirmed melanoma on the baseline biopsy
• No more than 1 prior cutaneous melanoma
• One prior stage I, IIA, or IIB melanoma allowed provided patients have been off treatment > 3 months
• Modified dermoscopy score < 4.8
• Karnofsky performance status 80-100%
• ANC >= 1,500/mm^3
• No family history of melanoma involving >= 2 first degree relatives
• Platelets count >= 100,000/mm^3
• Total bilirubin =< 2.0 mg/dL
• AST/ALT =< 2.0 times upper limit of normal
• Creatinine =< 1.5 mg/dL
• Not pregnant or nursing
• Fertile patients must use effective contraception
• More than 6 months since prior and no concurrent tanning bed use or other methods to promote sun-tanning
• Willing to minimize sunlight exposure by applying sunscreen/sunblock or wearing clothing to shield skin during outdoor activity during study participation
• Willing or able to limit alcohol consumption to less than 3 servings a week during the study period
• No frequent, chronic or moderate/severe gastrointestinal (GI) complaints
• Upper GI problems requiring prescription or nonprescription medical remedies for symptoms of heartburn, dyspepsia, nausea, or abdominal pain > once a week on average
• History of peptic ulcer, occult or gross intestinal bleeding
• No prior allergic reaction to aspirin (unless subsequent dosing with other NSAIDs has been well tolerated)
• No history of allergic reaction to lidocaine or xylocaine
• No history of allergic reaction (e.g., urticaria, asthma, or rhinitis) or gastric intolerance attributed to compounds of similar chemical or biological composition to sulindac
• No invasive cancer or cancer treatment within the past 5 years, except nonmelanoma skin cancer
• No immunosuppression by medication or disease, including any of the following: AIDS, oral prednisone, immunosuppressant/immunomodulator (i.e., cyclosporine, chemotherapeutic agent, or biologic therapy)
• No uncontrolled intercurrent illness
• No ongoing or active infection
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• No psychiatric illness/social situations that would limit compliance with study requirements
• At least 30 days since prior participation and no concurrent enrollment or planning to enroll in another clinical trial
• No NSAIDs for more than 5 days per month within the past 3 months and no concurrent non-study NSAIDs, except low dose aspirin (81 mg/day)
• Willing or able to refrain from herbal medicines, above-standard vitamins, or minerals during study
• Standard daily multivitamin/mineral supplement (i.e., therapeutic doses of calcium and vitamin D for osteoporosis) allowed
• No concurrent lithium, phenytoin, or sulfonamides
• WBC >= 3,000/mm^3
• No history of bleeding or clotting disorder
• At least 3 months since prior and no concurrent coumadin or other systemic anticoagulant other than aspirin