This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Merriman, R. L. Articles by Matsumoto, K. Search for Related Content PubMed PubMed Citation Articles by Merriman, R. L. Articles by Matsumoto, K.

Drug Treatments for Metastasis of the Lewis Lung Carcinoma: Lack of Correlation between Inhibition of Lung Metastasis and Survival

Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285

The abilities of the Eli Lilly compounds LY150310, LY189332, and LY135305 to inhibit spontaneous metastasis and to increase animal survival were evaluated. These compounds represent widely varied structures and were evaluated because they have been found to inhibit thromboxane synthetase, cyclooxygenase, and thrombin activation, respectively. These biochemical processes have been proposed in the literature as targets for antimetastatic drugs. The purpose of this investigation was twofold: (a) to compare the antimetastatic activities of the Eli Lilly compounds to those of the reference antimetastatic compounds nafazatrom and RA233, and (b) to examine the correlation between inhibition of spontaneous lung metastasis and survival. Spontaneous metastasis of the Lewis lung carcinoma was used to evaluate the antimetastatic activity of the compounds. In this model 5 x 10⁵ tumor cells were implanted into the gastrocnemius muscle, the primary tumor was resected on Day 14, and metastatic lung lesions were counted on Day 25. Compounds were administered every 12 h on Days 5 through 19. Nafazatrom, LY150310, LY189332, and LY135305 were found to inhibit spontaneous lung metastasis in a dose-dependent manner. The ED₅₀ values for the respective inhibitions with these compounds were 50, 0.5, 2, and 0.35 mg/kg/day; the respective therapeutic indexes (LD₅₀/ED₅₀) were 7, 180, 255, and 511. To evaluate the effect of nafazatrom, LY150310, LY189332, and LY135305 on animal survival, the compounds were given at maximally antimetastatic doses of 200, 60, 20, and 6 mg/kg/day, respectively. Two dosing schedules were used: (a) on Days 5 through 19 and (b) on Day 5 until death. Neither the median survival times nor the numbers of long-term survivors were significantly changed with any of the compounds at any dosing schedule. RA233, given to a maximally tolerated dose of 200 mg/kg/day on Day 5 until death, did not inhibit lung metastasis and did not increase median survival time. Postmortem examination of animals dosed with nafazatrom, LY150310, LY189332, and LY135305 showed complete inhibition in lung lesions and the appearance of lesions in the liver, kidney, spleen, and brain. The results of this investigation show that the effect a compound has on the number of metastatic lesions in a target organ may not be predictive of its effect on survival. To successfully translate laboratory data into the clinic, survival should be considered as a predictor of a compound's potential clinical utility.

¹ To whom requests for reprints should be addressed, at Department MC7R1, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285.

Received 12/28/87. Revised 12/28/88. Revised 5/ 2/89. Accepted 5/18/89.

This article has been cited by other articles:

				B. L. Neubauer, A. M. McNulty, M. Chedid, K. Chen, R. L. Goode, M. A. Johnson, C. D. Jones, V. Krishnan, R. Lynch, H. E. Osborne, et al. The Selective Estrogen Receptor Modulator Trioxifene (LY133314) Inhibits Metastasis and Extends Survival in the PAIII Rat Prostatic Carcinoma Model Cancer Res., September 15, 2003; 63(18): 6056 - 6062. [Abstract] [Full Text] [PDF]