Drug treatments for metastasis of the Lewis lung carcinoma: lack of correlation between inhibition of lung metastasis and survival.
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 10(5) 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.
Merriman
R L
RL
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285.
Shackelford
K A
KA
Tanzer
L R
LR
Campbell
J B
JB
Bemis
K G
KG
Matsumoto
K
K
D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002277:Carcinoma / Q000401:mortality / Q000517:prevention & control* / Q000556:secondary; D055598:Chemical Phenomena; D002621:Chemistry; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000401:mortality / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D009012:Mopidamol / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology*; D009362:Neoplasm Metastasis / Q000401:mortality / Q000517:prevention & control*; D011437:Propylamines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D047069:Pyrazolones; D011897:Random Allocation; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D005343:Fibrinolytic Agents; D007093:Imidazoles; D009281:Naphthalenes; D011437:Propylamines; D011720:Pyrazoles; D047069:Pyrazolones; D013764:Tetrahydronaphthalenes; C060380:LY 150310; C060383:LY 135305; C060381:LY 189332; D009012:Mopidamol; C018845:nafazatrom