In vivo and in vitro investigations on biological effects of aromatic bis-(2-chloroethyl)amino-bisphosphonic acids, new agents proposed for chemotherapy of bone tumors: cytostatic activity in rat osteosarcoma; toxicity and genotoxicity in liver and bone marrow; mutagenicity in S. Typhimurium

Pool, B.L.; Berger, Martin R.; Schlehofer, Jörg R.; Wingen, F.

doi:10.1007/bf00195363

Cited by 8 publications

(4 citation statements)

References 24 publications

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“…13 3-[Bis-(2-chloroethyl)-amino]-4-methylphenylhydroxymethane-1,1-bisphosphonic acid (BCMP), a derivative of BAD, had a lower cytostatic activity than BAD alone against rat osteosarcoma, and as a result it was not further investigated. 14 Keppler et al prepared a bisphosphonate cisplatin-analogue in which a phosphonate is complexed with diaminoplatinum (cis-diammine[nitrilotris(methylphosphonato)(2)-O 1 ,N 1 ]platinum(II), AMDP). 15 The therapeutic efficacy of this complex was better than pamidronate but not superior to conventional cisplatin in a transplantable osteosarcoma model of the rat, even at a 28-fold higher dose.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Although it showed a higher anticancer activity than monotherapy with either melphalan or pamidronate in N -methyl- N -nitrosourea induced mammary carcinomas in Sprague–Dawley rats, a combination therapy of pamidronate and melphalan showed the best therapeutic efficacy in this tumor model . 3-[Bis-(2-chloroethyl)-amino]-4-methylphenyl-hydroxymethane-1,1-bisphosphonic acid (BCMP), a derivative of BAD, had a lower cytostatic activity than BAD alone against rat osteosarcoma, and as a result it was not further investigated …”

Section: Introductionmentioning

confidence: 99%

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Development of Novel Bisphosphonate Prodrugs of Doxorubicin for Targeting Bone Metastases That Are Cleaved pH Dependently or by Cathepsin B: Synthesis, Cleavage Properties, and Binding Properties to Hydroxyapatite As Well As Bone Matrix

Hochdörffer¹,

Ajaj²,

Schäfer-Obodozie³

et al. 2012

J. Med. Chem.

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Bone metastases are a frequent cause of morbidity in cancer patients. The present palliative therapeutic options are chemotherapy, hormone therapy, and the administration of bisphosphonates. The affinity between bisphosphonates and the apatite structure of bone metastases is strong. Thus, we designed two low-molecular-weight and water-soluble prodrugs which incorporate a bisphosphonate group as a bone targeting ligand, doxorubicin as the anticancer agent, and either an acid-sensitive bond (1) or a cathepsin B cleavable bond (3) for ensuring an effective release of doxorubicin at the site of action. Cleavage studies of both prodrugs showed a fast release of doxorubicin but sufficient stability over several hours in human plasma. Effective binding of prodrug 1 and 3 was demonstrated with hydroxyapatite and with native bone. In orientating toxicity studies in nude mice, the MTD of 1 was 3-fold higher compared to conventional doxorubicin, whereas 3 showed essentially the same MTD as doxorubicin.

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Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of Novel Bisphosphonate Prodrugs of Doxorubicin for Targeting Bone Metastases That Are Cleaved pH Dependently or by Cathepsin B: Synthesis, Cleavage Properties, and Binding Properties to Hydroxyapatite As Well As Bone Matrix

Hochdörffer¹,

Ajaj²,

Schäfer-Obodozie³

et al. 2012

J. Med. Chem.

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“…Therefore, the negative findings in our model system using SV40 transformed cells may be important not only for the lacking potential carcinogenic effects, rather the results may indicate also a lacking potential of the resistance phenomena by the mechanism of DNA amplification. In contrast BAD had been shown to be active in the assay for amplification [37]. Therefore the activities reported there and the findings on the genotoxicity of melphalan reported by others [38], indicate that when BAD is detectably genotoxic, it is probably due to its melphalan-acting moiety and not to the APD part of the molecule.…”

Section: Discussionmentioning

confidence: 58%

Anticancer activity of bisphosphonic acids in methylnitrosourea-induced mammary carcinoma of the rat — benefit of combining bisphosphonates with cytostatic agents

et al. 1988

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This study primarily describes the cytostatic activity of a bisphosphonate and of an alkylating agent linked bisphosphonate toward mammary carcinomas in vivo. Bisphosphonates had been shown to be therapeutically active in bone metastases. There is no animal tumor model available in which both primary mammary carcinomas and bone metastases can be studied simultaneously. Therefore, the Walker carcinosarcoma model, which was used as a model for bone metastasis in earlier studies, was combined with the M-methyl-N-nitrosourea (MNU) induced mammary carcinoma as a model for the primary tumor. Four-, or six-week treatment of MNU-induced mammary carcinomas in Sprague-Dawley rats with the new aromatic bisphosphonate 4[4-[bis(2-chloroethyl)-amino]-phenyl]-1-hydroxybutane-1, 1-bisphosphonate (BAD) showed higher antitumor activity than treatment with melphalan or with 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APD) alone. BAD is the APD moiety covalently bound to a molecule derived from melphalan. A combination therapy with 11.75 mg/kg/day APD and 0.6 mg/kg/day melphalan showed the best therapeutic efficacy in this tumor model. In comparison to monotherapy with BAD, APD, or melphalan, a significantly higher rate of complete remissions was achieved. APD, itself, was not genotoxic in 3 employed short term assays. Since bisphosphonates had been shown to be therapeutically active in bone metastases, the antitumor potency of these compounds against experimental primary mammary carcinomas, coupled with the non-genotoxicity of APD and the inhibition of osteolytic bone metastases, might be an important advancement for adjuvant chemotherapy of human mammary carcinomas.

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“…68 Some researchers have examined the effects of bisphosphonates on osteosarcoma cell lines. 28,49,[69][70][71][72][73][74] Some indication exists that the amino-bisphosphonate pamidronate may be more effective than clodronate in inhibiting cell growth in these cell lines. 69 Research also has shown that marked synergy exists when bisphosphonates are combined with chemotherapy drugs such as taxanes, doxorubicin, dexamethasone, and cyclooxygenase 2 inhibitors.…”

Section: Inhibition Of Tumor Cell Proliferation and Induction Of Apopmentioning

confidence: 99%

Bisphosphonates and Cancer

Milner¹,

Farese²,

Henry³

et al. 2004

J Vet Int Med

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Bisphosphonates form a family of drugs characterized pharmacologically by their ability to inhibit bone resorption and pharmacokinetically by similar intestinal absorption, skeletal distribution, and renal elimination. Two groups of bisphosphonates exist chemically, non-amino-bisphosphates and amino-bisphosphonates. The amino-bisphosphonates have greater antiresorptive capabilities and represent a newer generation of bisphosphonates. The primary mechanism of action of bisphosphonates is inhibition of osteoclastic activity. Non-amino-bisphosphonates are incorporated into the energy pathways of the osteoclast, resulting in disrupted cellular energy metabolism leading to apoptosis. Amino-bisphosphonates exert their effect on osteoclasts via their inhibition of the mevalonate pathways, resulting in disruption of intracellular signaling and induction of apoptosis. Bisphosphonates also inhibit cancer cell proliferation, induce apoptosis in in vitro cultures, inhibit angiogenesis, inhibit matrix metalloproteinase, have effects on cytokine and growth factors, and are immunomodulatory. Clinical applications in oncology could include therapy for hypercalcemia of malignancy, inhibition of bone metastasis, and therapy for bone pain. Although bisphosphonates are regarded as metabolically inert in the body, adverse effects do occur and include esophagitis, gastritis, suppression of bone repair, and allergic reactions. Little is published on the effects of bisphosphonates in dogs with cancer. Further research into the role of bisphosphonates in veterinary oncology is needed to identify clinical efficacy and safety of these potentially beneficial drugs.Key words: Adverse effects; Alendronate; Etidronate; Hypercalcemia of malignancy; Multiple myeloma; Osteosarcoma; Pamidronate; Zoledronate. Bisphosphonates form a family of drugs characterized pharmacologically by their ability to inhibit bone resorption, and pharmacokinetically by similar absorption, distribution and elimination.1 The ability to inhibit bone resorption makes them useful drugs in the control of bone metabolism. The development of bisphosphonates was prompted by studies that showed that inorganic pyrophosphate binds strongly with calcium phosphate, thereby inhibiting crystal formation and dissolution in vitro.2,3 However, no in vivo effect occurred because of the hydrolysis of pyrophosphate before it reached the bone.2,3 Bisphosphonates were developed in an effort to circumvent this hydrolysis and are characterized by the presence of a geminal carbon (Fig 1). Bisphosphonates have been used for some time in human medicine as therapeutic agents for osteoporosis, bone pain associated with metastatic disease, Paget's disease of bone, and hypercalcemia of malignancy and in diagnostic nuclear medicine and targeted radiotherapy.1,4-6 Numerous reports exist on the experimental use of bisphosphates in dogs, primarily as a model of human bone disease. The reported use of bisphosphonates in veterinary oncology is limited to a single peer-reviewed publication, 28 although a ...

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In vivo and in vitro investigations on biological effects of aromatic bis-(2-chloroethyl)amino-bisphosphonic acids, new agents proposed for chemotherapy of bone tumors: cytostatic activity in rat osteosarcoma; toxicity and genotoxicity in liver and bone marrow; mutagenicity in S. Typhimurium

Cited by 8 publications

References 24 publications

Development of Novel Bisphosphonate Prodrugs of Doxorubicin for Targeting Bone Metastases That Are Cleaved pH Dependently or by Cathepsin B: Synthesis, Cleavage Properties, and Binding Properties to Hydroxyapatite As Well As Bone Matrix

Development of Novel Bisphosphonate Prodrugs of Doxorubicin for Targeting Bone Metastases That Are Cleaved pH Dependently or by Cathepsin B: Synthesis, Cleavage Properties, and Binding Properties to Hydroxyapatite As Well As Bone Matrix

Anticancer activity of bisphosphonic acids in methylnitrosourea-induced mammary carcinoma of the rat — benefit of combining bisphosphonates with cytostatic agents

Bisphosphonates and Cancer

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