Anticancer-agent-linked phosphonates with antiosteolytic and antineoplastic properties: a promising perspective in the treatment of bone-related malignancies?

• Published in: Journal of cancer research and clinical oncology Vol. 116; no. 4; p. 341
• Main Authors: Klenner, T, Wingen, F, Keppler, B K, Krempien, B, Schmähl, D
• Format: Journal Article
• Language: English
• Published: Germany 01.01.1990
• Subjects: Animals; Bone and Bones - drug effects; Bone Neoplasms - drug therapy; Bone Neoplasms - prevention & control; Carcinoma 256, Walker - drug therapy; Diphosphonates - administration & dosage; Diphosphonates - therapeutic use; Drug Evaluation, Preclinical; Organophosphorus Compounds - administration & dosage; Organophosphorus Compounds - therapeutic use; Organoplatinum Compounds - administration & dosage; Organoplatinum Compounds - therapeutic use; Osteosarcoma - drug therapy; Pamidronate; Rats
• ISSN: 0171-5216
• DOI: 10.1007/BF01612916

Bisphosphonates are compounds with a high affinity for bone and other calcified tissues. They inhibit tumor-induced bone destruction and the associated hypercalcemia by hindering the activity of the osteoclasts. Owing to a long biological half-life of bisphosphonates in the bone, a treatment using a prophylactic regimen seems possible. This paper summarizes preclinical studies with the bisphosphonate 3-amino-1-hydroxypropylidene-1,1-diphosphonic acid and two methyl derivatives; 3-N,N-dimethylamino-1-hydroxypropylidene-1,1-diphosphonic acid and 4-N,N-dimetyhlamino-1-hydroxybutylidene-1,1-diphosphonic acid with respect to their bone-protecting activity in therapy as well as in prophylaxis. To find substances that are useful for the treatment of primary tumor, as well as bone metastasis, we synthesized and tested cis-diammine[nitrilotris(methylphosphonato)(2-)-O1,N1]platin um(II) and cis-diammine[( bis-(phosphonatomethyl)amino]acetato(2-)-O1,N1)platinum(II), which contain both an osteotropic and an antineoplastic moiety. Experiments were carried out: (a) in the intratibial transplanted Walker carcinosarcoma 256B of the rat, which mimics osteolytic bone metastasis, and (b) in the transplantable osteosarcoma of the rat, which shows a histology and metastatic pattern similar to that found in man. These investigations indicate that it is possible to effect adjuvant therapy of bone metastases by combination of two compounds with different properties into one structure without losing the therapeutic characteristics of the parent compounds. They thus provide evidence that it may be possible to design compounds well suited for the therapeutic or prophylactic treatment of bone-related malignancies.