Differential toxicity of carrier-bound methotrexate toward human lymphocytes,marrow and tumor cells |
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Authors: | Barbara CF Chu Stephen B Howell |
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Institution: | T-006 Department of Medicine and Cancer Center, University of California, La Jolla, CA 92093, U.S.A. |
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Abstract: | Methotrexate that was covalently linked to poly-l-lysine (mol. wt 3,000 and 60,000) (MTX-PLL 3K and 60K) was more inhibitory to the growth of five cell lines from human solid tumors (IC50 5?10 × 10?8 M and 1?2.6 × 10?8 M respectively) than to the growth of five lines of human lymphocytes (IC50 5?8 × 10?7 M and 2?5 × 10?7 M). In contrast, both methotrexate that was covalently linked to human serum albumin (MTX-HSA), and the free drug, were equally toxic to the two classes of cells, with IC50 of 3?15 × 10?7 M and 2?7 × 10?8 M, respectively, for the cell types. Uptake studies showed that, whereas MTX and MTX-HSA were transported equally well into WI-L2 lymphocytes, human bone marrow cells, and an astrocytoma tumor line, uptake of MTX-PLL by the astrocytoma cells at 37° was three to four times greater than uptake by WI-L2 lymphocytes or marrow cells. 3H]Deoxyuridine (3H]-Urd) incorporation studies indicated that low concentrations of MTX-PLL 60K (5 × 10?7 M) resulted in inhibition of the target enzyme dihydrofolate reductase (DHFR) in the astrocytoma cells, but no iinhibition of DHFR occurred in WI-L2 lymphocytes or marrow cells until concentrations were reached where the carrier itself became toxic (5 × 10?6 M). Two inhibitors of the lysosomal enzymes, chloroquine and lupuptin, were able to reverse the toxicity of MTX-PLL 60K against the astrocytoma cell line, increasing its IC50 from 2 × 10?8 to 2 × 10?7 M. Both lysosomal inhibitors had no effect on the toxicity of MTX-PLL 60K against the WI-L2 lymphocytes or of MTX or MTX-HSA against either cell type, indicating that the increased toxicity of MTX-PLL 60K against the tumor cells was due, in part, to the ability of the lysosomes of these cells to convert MTX-PLL 60K either to the free drug or to a derivative that was effective in inactivating DHFR. These results suggest that comparable differential toxicity between marrow and tumor cells might also be achieved in vivo if MTX-PLL is infused over long periods at a rate that would maintain a constant serum concentration sufficient to kill tumor cells without affecting bone marrow cells. |
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Keywords: | Author to whom all correspondence should be addressed: Dr Barbara C F Chu Division of Hematology/ Oncology Department of Medicine T-006 School of Medicine University of California La Jolla CA 92093 U S A |
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