We examined the effects of two potential agents on the development of adenomas/adenocarcinomas in these mice. The two classes of agents examined were budes-onide’ and the FTI inhibitor L778,123. The former is a glucocorticoid that presumably interacts with the glucocorticoid receptor, and has been shown to be a profoundly effective agent in the A/J mouse model. L778,123 inhibits the farnesyltransferase enzyme that transfers farnesyl onto proteins and allows their transport to and activation in the cell membrane. FTI inhibitors were initially produced because they should block the farnesylation of the mutant Ras oncogenes (H-ras, N-ras, and K-ras). Although they effectively block H-ras and N-ras farnesylation and activation, they do not block farnesylation of K-ras due apparently to the high affinity of this protein for the farnesyltransferase enzyme. We examined the abilities of these agents to inhibit tumor formation either in a prevention setting in which budes-onide was administered beginning prior to benzo(a)pyrene and throughout the study or in a delayed experiment, which we feel may be closer to that achieved in former or current smokers. http://www.patanol-eyedrops.com/
As shown in Table 2, budesonide or the FTI were administered beginning 12 to 20 weeks after benzo(a)pyrene when small adenoma exist, and were administered for a period of 10 to 18 weeks. Budesonide administration was initiated early, and continually resulted in striking decreases in both tumor multiplicity (65 to 77%) and tumor volume (77 to 98%) in all mice. When budesonide was administered for 18 weeks (weeks 12 to 30) a moderate decrease in tumor multiplicity (36 to 53%) was observed, while the effects on tumor volume were more variable. Tumor volume was decreased 64 to 82% in wild-type or INK 4A-deficient mice, while volume was decreased only 33 to 45% in mice with a p53 mutation or a double-mutant animal. Thus, much of the efficacy of delayed treatment with budesonide was lost if the tumors had a mutation in p53. When FTI was administered for 10 weeks (weeks 20 to 30), a moderate decrease in tumor multiplicity was observed (43 to 47%), while the effects on tumor volume were more variable. Tumor volume was decreased roughly 50% in wild-type or INK 4A-deficient mice, while volume was decreased 84% and 72% in mice with a p53 mutation or a double mutant animal, respectively. Interestingly, the efficacy of delayed administration of FTI were even more striking in tumors with a p53 mutation in contrast to delayed administration of budesonide.
We feel that these models may be more relevant in studying both preventive and therapeutic agents than the standard A/J model. The late intervention, as employed with both budesonide and FTI, appears to be closer to the proposed experiments in humans where individuals, either former or current smokers, with known dysplasia and multiple genetic changes are employed. Furthermore, the model should prove useful for testing chemotherapeutic agents in a model in which tumors contain certain known relevant genetic alterations and grow and progress in situ. This in situ development of tumors has certain advantages over xenograft models, in which transplantable tumors grow subcutaneously and appear to be profoundly susceptible to agents that affect angiogenesis.
Table 2—Effects ofBudesonide or the FTI Inhibitor (L-778,123) on Lung Tumor Multiplicity and Volume in B(a)P-Treated A/J Mice
|Genotype||Treatment||Duration of Treatment, wk||Decrease In Multiplicity, %||Decrease In Volume, %|
|p53+/+ Ink4A+/+||Budesonidef||– 2-40||70||94|
|p53+/+ Ink4A+/-||Budesonide||– 2-40||78||98|
|p53+/- Ink4A+/+||Budesonide||– 2-40||77||94|
|p53+/- Ink4A+/-||Budesonide||– 2-40||66||77|