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.
|
Authors | Joseph A Reddy, Elaine Westrick, Iontcho Vlahov, Stephen J Howard, Hari Krishna Santhapuram, Christopher P Leamon |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 58
Issue 2
Pg. 229-36
(Aug 2006)
ISSN: 0344-5704 [Print] Germany |
PMID | 16331500
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
|
Chemical References |
- Antineoplastic Agents, Phytogenic
- Carrier Proteins
- Folate Receptors, GPI-Anchored
- Receptors, Cell Surface
- Mitomycin
- Folic Acid
|
Topics |
- Animals
- Antineoplastic Agents, Phytogenic
(administration & dosage, chemistry, pharmacology)
- Carrier Proteins
(physiology)
- Folate Receptors, GPI-Anchored
- Folic Acid
(administration & dosage, chemistry, pharmacology)
- Mice
- Mitomycin
(administration & dosage, chemistry, pharmacology)
- Receptors, Cell Surface
(physiology)
|