In vitro and in vivo toxicity of 5-FdU-alendronate, a novel cytotoxic bone-seeking duplex drug against bone metastasis

Sarah Schott, Sonia Vallet, Robert J. Tower, Seema Noor, Sanjay Tiwari, Christian Schem, Christian Busch

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Background Bone remains one of the most common anatomic sites for cancer metastases, and the limited therapeutic options aggravate cancer-related morbidity and mortality in multiple malignancies. The covalent conjugation of the amino-bisphosphonate alendronate (ale) with the antimetabolite 5-fluoro-2'-desoxyuridine (5-FdU) results in N4-(butyl-(4-hydroxy-4-phosphono)phosphate)-5-fluoro-2'-desoxyuridine (5-FdU-alendronat, 5-FdU-ale), an effective, novel bone-targeting duplex drug directed against skeletal cancer manifestations. Methods In vitro cytotoxicity of ale, 5-FdU or 5-FdU-ale was measured with Alamar Blue and MUH cell viability assays in 14 malignant melanoma, multiple myeloma, bone marrow-derived stromal cell and osteoblast-like cell lines. In vivo toxicity was evaluated using the chicken embryo assay and evaluation of nephrotoxicity and the systemic toxicity in Balb/c nude mice. The effect of 5-FdU-ale on osteoclast was evaluated with Balb/c nude mice in a metastatic breast cancer mouse model. Results A cell line-specific, dose-related cytotoxicity was observed for 5-FdU-ale in all cancer cell lines tested, which was significantly less toxic than 5-FdU alone when compared to the benign osteoblasts or stromal cells. The embryotoxicity of 5-FdU-ale was significantly less than that of the parental drugs alendronate or 5-FdU. 5-FdU-ale showed no signs of unwanted side effects, weight loss or nephrotoxicity in mice. In a bone metastasis mouse model, 5-FdU-ale reduced the number of tumor-associated osteoclasts. Conclusion The coupling of an amino-bisphosphonate with an antimetabolite via an N-alkyl-bonding offers a new strategy for the preparation of amino-bisphosphonates conjugates with a cancer cell-specific, efficacious cytotoxic bone-targeting potential along with a reduced systemic toxicity. The innovative duplex drug 5-FdU-ale therefore warrants further clinical investigation.

Original languageEnglish (US)
Pages (from-to)816-826
Number of pages11
JournalInvestigational New Drugs
Volume33
Issue number4
DOIs
StatePublished - Aug 2015
Externally publishedYes

Keywords

  • Bisphosphonate-antimetabolite
  • Bone metastasis
  • Bone-targeting
  • Chemotherapy
  • Duplex drug

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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