Combinatorial chemoprevention: efficacy of lovostatin and exisulind on the formation and progression of aberrant crypt foci.
BACKGROUND
There are several advantages to combinatorial chemoprevention strategies over monotherapeutic approaches. Both the HMG-CoA reductase inhibitor (HRI) lovastatin (LOV) and the selective apoptotic antineoplastic drug (SAAND) exisulind (EXS) have shown remarkable chemopreventive effects in previous studies, in cell lines and limited studies in rodents. Here, experiments were designed to assess the potential use of these two compounds in combinatorial chemoprevention therapy, using two bio-assays in which inhibition of the carcinogen-induced preneoplastic lesions, aberrant crypt foci (ACF), was used to quantitate efficacy.


METHODS
ACF were induced by the carcinogen azoxymethane (AOM) in F344 rats by two sequential weekly i.p. injections at a dose of 15 mg/kg. F344 rats were fed seven experimental diets containing LOV @ 50 parts per million (ppm), EXS @ 100, 250 and 1000 ppm and combination diets containing EXS at 100, 250 and 1000 ppm, each combined with LOV @ 50 ppm. Quantification of ACF number and type (singlet, doublet, triplet and four or more) was performed on whole mounts of rat colons stained with 1.0% methylene blue.


RESULTS
During the initiation protocol, administration of LOV @ 50 ppm alone and the combination of LOV @ 50 ppm with EXS @ 1000 ppm significantly decreased the mean number of ACF when compared to the positive control by 49% and 47%, respectively; however EXS @ 250 ppm displayed tumor promoting effects by significantly increasing the mean number of ACF by 64%. The post-initiation protocol administration of EXS @ 100, 250 and 1000 ppm and the combinations of LOV @ 50 ppm with EXS @ 100 and 250 ppm significantly increased the mean number of ACF when compared to the positive control by 44%, 48%, 55%, 49% and 40%, respectively.


CONCLUSIONS
LOV shows greater promise than EXS in fulfilling the role as a supplemental chemopreventive agent in combinatorial chemopreventive strategies for cancers such as colon cancer. EXS did not augment this activity, failing to enhance chemopreventive therapy in this animal model.
Division of Basic Research and Department of Pathology, University of South Carolina School of Medicine, South Carolina Cancer Center, Columbia, SC 29203, USA.
Kenneth P
KP
Kim
Clark
C
Whitehead
Gary
G
Piazza
Michael J
MJ
Wargovich
D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D008148:Lovastatin / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D011230:Precancerous Conditions / Q000517:prevention & control*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D013467:Sulindac / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use*
D016588:Anticarcinogenic Agents; D013467:Sulindac; D008148:Lovastatin; C025463:sulindac sulfone