Premium
Systemic, sustained delivery of chemopreventive agent is effective against dibenzo[a,l]pyrene‐induced DNA adducts
Author(s) -
Russell Gilandra Keshawn,
Vadhanam Manicka V,
Kausar Hina,
Gupta Ramesh C
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.562.4
Subject(s) - bioavailability , carcinogen , chemistry , adduct , pyrene , benzo(a)pyrene , anticarcinogen , pharmacology , lung cancer , carcinogenesis , medicine , endocrinology , biochemistry , organic chemistry , gene
Only a handful of chemopreventive agents have been found effective against lung tumorigenesis presumably due to limited bioavailability. In this study we determined relative potential of a chemopreventive agent given by a novel sustained delivery system versus the diet in diminishing carcinogen‐induced DNA adducts. Using 32 P‐postlabeling we first determined that when dibenzo[ a,l ]pyrene (DBP) (0.5 mg/kg, b.w.) was given i.p. in five equal doses on alternate days, it induced nearly three times more lung DNA adducts in female A/J mice than when it was given as a single dose. Next, mice were given oltipraz either via the diet (400 ppm) or by subcutaneous silastic implants (two, 2‐cm implants containing 5 mg), or sham treatment, and then challenged with DBP (5 x 100 μg/kg, i.p.). Analysis of the lung DNA five days after the last DBP treatment showed > over 47% reduced DNA adducts by oltipraz implants compared with control (106 ± 36 versus 201 ± 118 adducts/10 10 N); adduct levels remained unaffected by the dietary oltipraz. Measurement of residual oltipraz in the implants showed that a total of < 3 mg of oltipraz was delivered by implants compared with 29 mg by diet over 18 days. Our data suggest that systemic sustained delivery by implants may circumvent bioavailability problem associated with dietary route for some compounds, and lower the effective dose. (CA‐118114, ES‐011564, and KY Lung Cancer Res. Program).