Topical treatment with hexadecylphosphocholine (Miltex) efficiently reduces parasite burden in experimental cutaneous leishmaniasis.

Ether-lipids and alkylphosphocholines have been found to have anti-leishmanial activity. Oral treatment with hexadecylphosphocholine (HePC) efficiently reduces parasite burden in murine visceral leishmaniasis. Drugs for the treatment of cutaneous leishmaniasis are most commonly administered parenterally, whereas efficient drugs for topical treatment are not in current use. Here we investigate the efficacy of topical treatment with HePC in mice infected with Leishmania mexicana or L. major, causative agents of cutaneous leishmaniasis in the New and Old World, respectively. BALB/c, CBA/J and C57BL/6 inbred mice do not control infection with L. mexicana because they do not mount an efficient Th1-type anti-parasitic lymphocyte response. In contrast, C57BL/6 mice are resistant to an infection with L. major, developing only transient lesions that heal spontaneously owing to an efficient Th1 response. BALB/c, CBA/J and C57BL/6 mice were infected subcutaneously with L. mexicana amastigotes, causing nodular lesions after 5 months. Topical treatment with HePC (Miltex) was highly effective in reducing parasite burden and healed established lesions. The treatment did not induce a Th1 response in L. mexicana-infected susceptible mice and most of the mice relapsed. In resistant C57BL/6 mice infected subcutaneously with 2 x 10(6) L. major promastigotes at the tail base, nodular lesions developed after 2 weeks. Topical treatment with Miltex reduced the parasite load and the mice healed their lesions much faster than the untreated infected controls. The clinical application of Miltex for treatment of cutaneous leishmaniasis may be highly efficient because humans, similarly to resistant mice, in general do not relapse after healing. Clinical trials should be straightforward considering that Miltex is an approved drug for the treatment of breast cancer metastases.

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

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.

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

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.