A study of the delivery-targeting concept applied to antineoplastic drugs active on human osteosarcoma. I. Synthesis and biological activity in nude mice carrying human osteosarcoma xenografts of gem-bisphosphonic methotrexate analogues

Article abstract of DOI:10.1016/0223-5234(92)90117-J

With the aim of verifying the concept of osteotic vectorisation, synthesis of three methotrexate (MTX) gem-diphosphonic analogues (compounds A, B and C) was performed. These molecules were tested on BALB/c and NIH III mice previously grafted with subcutaneous implants of OHS, TTX p7 and/or TTX p11 human osteosarcoma cell lines. Antineoplasic activity of compound B and C (active compounds) was compared to the activity for MTX alone and to activity of compound A (inactive compound). Compounds B and C exhibited an increased antineoplasic activity compared to MTX alone and to compound A. At equimolar doses, compound B was found to be 5-6-fold more active than MTX given alone. We have discussed the concept of osteotic vectorisation of compound B, which could be regarded as a prodrug.