Chemotherapy in experimental brain tumor, part 2: pretreatment with leukotriene C4 prolongs survival.
Previous work in our laboratory has shown a correspondence between the chemosensitivity of C6 rat glioma and that of human glioblastoma (GBM) to a panel of chemotherapeutic agents in vitro, as determined by the MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide] colorimetric assay. In the present study, an in vivo model of intracerebral C6 glioma in Sprague-Dawley rats was used to determine if a correlation exists between in vitro chemosensitivity and in vivo survival of the animals, and post-mortem histopathological changes in the tumor. Cisplatin (CDDP) and methotrexate (MTX), agents previously shown to demonstrate high and low in vitro cytotoxicity, respectively, against C6, were administered by intra-carotid infusion over the course of two days. In a separate series of animals, LTC4 was administered prior to infusion of CDDP or MTX; LTC4 was used in view of its known, selective, vasogenic effect on the permeability of brain tumor capillaries. It was found that survival of animals treated with CDDP alone was increased, although this did not reach statistical significance; histopathologically, CDDP-treated animals showed significant tumor necrosis. However, in CDDP-treated animals, pre-treatment with LTC4 increased survival to a statistically significant degree. When administered alone, LTC4 (not followed by CDDP) had no effect on either survival or histology. The survival-enhancing effect of CDDP, when combined with LTC4, was probably not due to any cytotoxic effect of LTC4; this is based on our finding that, on the in vitro MTT colorimetric assay, LTC4 showed low cytotoxicity for C6 glioma cells. By contrast with CDDP, MTX -- with or without pretreatment with LTC4 -- affected neither survival nor tumor histology. With respect to the question of correspondence between the MTT colorimetric in vitro assay and in vivo effect, MTX showed a clear correlation: low cytotoxicity in vitro and poor in vivo response. In the case of CDDP, the correspondence was not clear-cut: there was a high level of in vitro chemosensitivity of the C6 cell line to CDDP as well as post-mortem tumor necrosis, but in vivo testing showed no significant prolongation of survival. However, pre-treatment with LTC4 did significantly extend survival in animals treated with CDDP.
Black
P
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Department of Neurosurgery, Allegheny University of the Health Sciences, Philadelphia, Pennsylvania 19102-1192, USA.
Hand
C M
CM
Vender
J R
JR
Finkelstein
S D
SD
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D003124:Colorimetry; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D017997:Leukotriene C4 / Q000627:therapeutic use* / Q000633:toxicity; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D011292:Premedication; D051381:Rats; D017207:Rats, Sprague-Dawley; D016019:Survival Analysis; D013778:Tetrazolium Salts / Q000032:analysis; D013844:Thiazoles / Q000032:analysis
D013778:Tetrazolium Salts; D013844:Thiazoles; D017997:Leukotriene C4; C022616:thiazolyl blue; D002945:Cisplatin; D008727:Methotrexate