Antitumour activity of miltefosine alone and after combination with platinum complexes on MXT mouse mammary carcinoma models

Abstract

Summary.Miltefosine, an alkylphosphocholine structurally related to alkyllysophospholipids showed highly selective antitumour activity against the hormone-sensitive variant of the s.c. transplantable MXT mouse mammary adenocarcinoma, the ovary-dependent MXT (M3.2), whereas it was inactive against the hormone-insensitive MXT (M3.2) OVEX variant. A dose of 32 mg/kg miltefosine p.o. daily for 5 weeks was well tolerated. Histopathological evaluation gave no signs of gastroenteral toxicity. After therapy the microarchitecture of the MXT (M3.2) tumours changed from that of a moderately differentiated adenocarcinoma to that of an anaplastic mammary carcinoma. A dose of 16 mg/kg miltefosine p.o. daily, though in effective per se, enhanced the antitumour activity of suboptimal i.p. doses of cisplatin and the hormone-like platinum analogue [meso-l,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]dichloroplatinum(II). Furthermore, it was shown, that miltefosine exhibited no (anti)hormonaI properties. However, the mechanism of action of miltefosine remains unclear.

Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy

“…Nevertheless, despite not achieving the primary objectives related to significant increases in progression-free survival rates, some optimism still remained for this agent in advanced soft tissue sarcoma patients (Bailey, et al, 2006), as well as to warrant further evaluation of perifosine in combination with rituximab or other active agents in patients with relapsed/refractory Waldenstrom's macroglobulinemia (Ghobrial, et al, 2010), and with currently available therapies in renal cancer (Cho, et al, 2012). Furthermore, a number of studies have reported the potentiation of antitumor activity following combination of perifosine with distinct anticancer drugs in cancer cells derived from several types of leukemia (Nyakern, et al, 2006;Papa, et al, 2008;Tazzari, et al, 2008), multiple myeloma Hideshima, et al, 2006), osteosarcoma (Yao, et al, 2013), medulloblastoma (Kumar, et al, 2009), lung cancer (Elrod, et al, 2007), colon cancer (M. B. Chen, et al, 2012, and glioma (Momota, et al, 2005), as well as following combination of miltefosine with different anticancer compounds or treatments in distinct cancer cell types (Haberkorn, et al, 1992;Papagiannaros, et al, 2006;Spruss, et al, 1993;Thakur, et al, 2013). Thus, phase II clinical trials were conducted with…”

Milteforan, a promising veterinary commercial product against feline sporotrichosis

“…For this objective, drug repurposing is an excellent alternative to finding new treatments since these drugs already approved to be used in humans and animals, initially developed to treat other diseases, can help treat infections caused by different pathogens (59,60). Such is the case of commercial MFS, which was initially used as an antineoplastic drug (27,28) that is now the only available oral treatment for leishmaniasis in dogs and humans (29)(30)(31)(32), and was recently proven to be effective for the treatment of infections caused by Candida species (39,40). As previously demonstrated (45,46,48), MFS also has in vitro fungicidal activity against Sporothrix species by inhibiting the growth of both fungal morphologies.…”

“…For this objective, drug repurposing is an excellent alternative to finding new treatments since these drugs already approved to be used in humans and animals, initially developed to treat other diseases, can help treat infections caused by different pathogens (59,60). Such is the case of commercial MFS, which was initially used as an antineoplastic drug (27,28) that is now the only . CC-BY-NC-ND 4.0 International license perpetuity.…”

“…However, in the last few years, many S. brasiliensis clinical strains have been reported to show resistance to both azoles and AMB (24)(25)(26), which complicates sporotrichosis treatment. Miltefosine (MFS), also known as hexadecyl phosphocholine, is a synthetic glycerol-free phospholipid analog initially used as an antineoplastic drug (27,28). Nowadays, MFS is the only available oral drug used in the treatment of visceral and cutaneous leishmaniasis in dogs and humans due to its significant antiparasitic activity, in vitro and in vivo, against Leishmania species (29-32).…”

“…Miltefosine (MFS), also known as hexadecyl phosphocholine, is a synthetic glycerol-free phospholipid analog initially used as an antineoplastic drug (27, 28). Nowadays, MFS is the only available oral drug used in the treatment of visceral and cutaneous leishmaniasis in dogs and humans due to its significant antiparasitic activity, in vitro and in vivo , against Leishmania species (29–32).…”