Trimetrexate, methotrexate, and pemetrexed results of comparative in vitro cytotoxicity and modulation by fluphenazine-N-2-chloroethane and leucovorin

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Trimetrexate, methotrexate, and pemetrexed results of comparative in vitro
cytotoxicity and modulation by fluphenazine-N-2-chloroethane and
leucovorin

Sub-category:

Cell-Based Therapy
Category:

Developmental Therapeutics: Immunotherapy
Meeting:

2005 ASCO Annual Meeting

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Abstract No:

2601
Citation:

Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol
23, No. 16S, Part I of II (June 1 Supplement), 2005: 2601
Author(s):

D. R. Ishmael, J. A. Nordquist
Abstract:

Background: Antifolate compounds are useful anticancer agents. They
inhibit the enzyme dihydrofolate reductase and thymidylate synthase .
Trimetrexate and methotrexate are available for treatment of various
malignancies. A new antifol, pemetrexed is approved for treatment of
mesothelioma and non-small cell lung cancer. Premetrexed has greater
inhibition of thymidylate synthase than other antifols and is classified
as a multi-targeted antifol. Fluphenazine-N-2-chloroethane is a potent
irreversible inactivator of calmodulin. It possesses potent
antiproliferative and cytotoxic activity. Methods: The BOT-2 human breast
cancer cell line was used for the in vitro cytotoxicity studies. The cells
were plated into microtiter plates. Drugs were added after 24 hours in 1:4
serial dilutions. The plates were read at 24, 48 and 144 hours. The
endpoint was 100% cell death. MTT was applied at 144 hours. Further
studies were done with combinations of the antifols and agents with
specific targeting. Serial dilutions were made of the antifol and the
adjunct or modulating agent. Results: The results of the cytotoxicity
assays revealed that the antifols; methotrexate and pemetrexed were
inactive against the BOT-2 human breast cancer cell line. Trimetrexate was
active. Leucovorin increased the cytotoxicity of methotrexate and
premetrexed to became active but no effect on the cytotoxicity of
trimetrexate. Fluphenazine-N-2-chloroethane had minimal cytotoxic
activity. It did not effect trimetrexate but modestly increased
cytotoxicity of methotrexate. It had profound effect on premetrexed
increasing cytotoxicity by twelve fold.

Conclusions: Methotrexate and pemetrexed were inactive probably from poor
penetration of the cancer cell. Trimetrexate is more lipid soluble and
does not require carrier mechanisms to enter the cell. Leucovorin
increased activity of methotrexate and pemetrexed but had no effect on
trimetrexate. The calmodulin inhibitor fluphenazine-N-2-chloroethane
increased the cytotoxicity of methotrexate and pemetrexed.


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