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Folate receptor specific anti-tumor activity of folate–mitomycin conjugates

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Abstract

Purpose: Folate receptor (FR) targeted drug conjugates were prepared by covalently attaching the vitamin folate, to the potent anticancer drug, mitomycin C (MMC). One such conjugate, called EC72, was synthesized with an intramolecular disulfide bond, and it was found to exhibit efficacious anti-tumor activity against FR-expressing M109 tumors in a manner that yielded no gross or microscopic toxicity, even to FR-positive kidneys. Methods: EC72’s specificity was demonstrated by two methods: (1) blocking EC72’s activity with an excess of co-administered folic acid (FA) in M109 tumor bearing mice and (2) the absence of therapeutic activity in mice bearing FR-negative tumors. The importance of having a cleavable bond in the conjugate was also exemplified, since EC110 (a folate–MMC conjugate constructed with a more resilient amide bond) failed to produce anti-M109 tumor activity. EC72’s therapeutic potential was found to decrease with respect to the increasing size of subcutaneous tumor. However, a combination therapy with paclitaxel reproducibly improved the anti-tumor efficacy relative to either agent alone at well tolerated dose levels and with no apparent increase in toxicity. A more advanced folate–MMC conjugate was also synthesized in an effort to improve activity. Thus, EC118, a molecule constructed with both a reducible disulfide bond and an acid-labile hydrazone bond in the linker region, was tested and found to produce a significantly greater number of tumor regressions of more established M109 tumors than that achieved with EC72. Conclusion: Overall, these data indicate that folate-targeted drug therapy alone, or in combination with paclitaxel, may be a novel and effective clinical approach towards treating FR-positive cancers.

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Notes

  1. 4T1 cells are sensitive to MMC.

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Acknowledgements

The authors wish to thank Dr. Philip S. Low for his valuable comments. This work was supported in part by an NIH FLAIR grant #5R44CA096020-03.

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  1. Endocyte, Inc., 3000 Kent Ave., West Lafayette, IN, 47906, USA

    Joseph A. Reddy, Elaine Westrick, Iontcho Vlahov, Stephen J. Howard, Hari Krishna Santhapuram & Christopher P. Leamon

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  1. Joseph A. Reddy
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Correspondence to Christopher P. Leamon.

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Reddy, J.A., Westrick, E., Vlahov, I. et al. Folate receptor specific anti-tumor activity of folate–mitomycin conjugates. Cancer Chemother Pharmacol 58, 229–236 (2006). https://doi.org/10.1007/s00280-005-0151-z

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  • DOI: https://doi.org/10.1007/s00280-005-0151-z

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