ANTICANCER-AGENT-LINKED PHOSPHONATES WITH ANTIOSTEOLYTIC AND ANTINEOPLASTIC PROPERTIES - A PROMISING PERSPECTIVE IN THE TREATMENT OF BONE-RELATED MALIGNANCIES

被引:59
作者
KLENNER, T
WINGEN, F
KEPPLER, BK
KREMPIEN, B
SCHMAHL, D
机构
[1] RHONE POULENC NATTERMANN,W-5000 COLOGNE,GERMANY
[2] UNIV HEIDELBERG,INST INORGAN CHEM,W-6900 HEIDELBERG,GERMANY
[3] UNIV HEIDELBERG,INST PATHOL,W-6900 HEIDELBERG,GERMANY
关键词
Anticancer-agent-linked phosphonates; Bisphosphonates; Bone metastasis; Osteosarcoma; Prophylactic treatment;
D O I
10.1007/BF01612916
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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; S-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]platinum(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. © 1990 Springer-Verlag.
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页码:341 / 350
页数:10
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