A comparison of the relative chemosensitivity of human gliomas to tamoxifen and n-desmethyltamoxifenin vitro

Abstract

Tamoxifen has been shown to inhibit the proliferation of human gliomas in vitro. This inhibition is independent of tamoxifen's known anti-estrogenic properties. Tamoxifen is an inhibitor of protein kinase C (PKC), a calcium- and phospholipid-dependent serine kinase which plays a critical role in the proliferation of certain cell lines. Gliomas overexpress PCK, and their growth rate is coupled to the level of this key enzyme. As such, the effect of tamoxifen may be mediated by its inhibitory effect on PKC. To further investigate this possibility, we compared the chemosensitivity of cultured glioma lines to both tamoxifen and N-desmethyltamoxifen (DMT). DMT is the major metabolite of tamoxifen in humans and is a ten-fold more potent inhibitor of PKC. Seven lines were tested using the standard MTT assay, which quantitates metabolically active cells colorimetrically using a tetrazolium dye. Four of the seven lines were also tested using a tritiated thymidine uptake assay. In the MTT assay, all seven lines showed significantly greater sensitivity to DMT, while three of the four lines tested in the thymidine uptake assay were more sensitive to DMT. Correlation between the two assays was good. The dose of tamoxifen required to produce a 50% inhibition of optical absorbance or thymidine uptake (ID50) was typically five- to ten-fold greater than the ID50 for DMT, approximating the relative strength of the two compounds as PKC inhibitors. In addition to providing some support for the ypothesis that triphenylethylenes inhibit gliomas via PKC inhibition, these findings have clinical significance.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis and Biological Evaluation of Boron-Containing Polyamines as Potential Agents for Neutron Capture Therapy of Brain Tumors

“…The F98 glioma cell line was derived from an undifferentiated brain tumor induced by administering N -ethyl- N -nitrosourea to a pregnant inbred CD Fisher 344 rat and has been propagated in vitro and in vivo since 1971. Its morphology and in vitro characteristics have been described in detail, , and it has been used by us to evaluate a variety of boron compounds as potential delivery agents for BNCT. ,, The assay that was employed to detect the toxicity and/or growth inhibitory effects has been widely used and is based on the incorporation of sulforhodamine B (SRB) by biosynthetically active (i.e., S phase) surviving cells following exposure to the test compound.…”

“…Its morphology and in vitro characteristics have been described in detail, 70,71 and it has been used by us to evaluate a variety of boron compounds as potential delivery agents for BNCT. 59,72,73 The assay that was employed to detect the toxicity and/or growth inhibitory effects has been widely used 74 and is based on the incorporation of sulforhodamine B (SRB) by biosynthetically active (i.e., S phase) surviving cells following exposure to the test compound.…”

Boron-Containing Polyamines as DNA Targeting Agents for Neutron Capture Therapy of Brain Tumors: Synthesis and Biological Evaluation

“…The F98 glioma cell line was derived from an undifferentiated brain tumor induced by administering N -ethyl- N -nitrosourea to a pregnant inbred CD Fisher 344 rat and has been propagated in vitro and in vivo since 1971. Its morphology and in vitro characteristics have been described in detail, , and it has been used by us to evaluate a variety of boron compounds as potential delivery agents for BNCT. ,, The assay that was employed to detect the toxicity and/or growth inhibitory effects has been widely used and is based on the incorporation of tritiated thymidine ([ 3 H]TdR) by biosynthetically active (i.e. S phase) surviving cells following an exposure to the test compound.…”

“…N 1 ,N (8,11), 456 (27,32), 457 (63,67), 458 (100, 100), 459 (99, 99), 460 (52,34), 561 (10,9). Anal.…”

Tumor Decelerating and Chemo-Potentiating Action of Methyl Jasmonate on a T Cell Lymphoma In Vivo: Role of Altered Regulation of Metabolism, Cell Survival, Drug Resistance, and Intratumoral Blood Flow

“…Absorbance at 540 nm was measured by the ELISA plate reader (Labsystems Finland). ID 50 values were calculated by following a method described by Vertosick et al (19).…”