Hexadecylphosphocholine differs from conventional cytostatic agents

Abstract

Alkylphosphocholines, and especially their main representative hexadecylphosphocholine (HPC), show high anticancer activity in methylnitrosourea (MNU)-induced autochthonous rat mammary carcinoma. The regression of MNU-induced rat mammary carcinoma during HPC treatment can be evaluated by computed tomography and sonography. This allows a noninvasive monitoring of therapy in vivo (tumor size, morphology, and blood supply). Both diagnostic modalities can show a rapid concentric decrease in tumor volume as well as the appearance of cystic, scarry, and necrotic areas in the tumor tissue as a result of HPC treatment. In addition, prior to, during and after therapy tumor perfusion can be assessed by color Doppler sonography in vivo. A more than 4-fold difference in HPC efficacy was observed when the colony growth of explanted MNU-induced mammary carcinoma cells was measured in the methylcellulose colony assay (IC50 = 180 mumol HPC/l) and the Hamburger Salmon colony assay (IC50 = 740 mumol HPC/l). In the latter assay, growth of concomitantly seeded untransformed cells, especially of fibroblasts, is much lower than in the methyl-cellulose colony assay. We therefore assume that the antitumor efficacy of HPC against MNU-induced mammary carcinoma is enhanced by neighboring cells such as fibroblasts. Cell culture experiments with the three MNU-induced rat mammary carcinoma cell clones 1-C-2, 1-C-30, and 1-C-32 revealed IC50 values in the range of 50-70 mumol HPC/l. The volume of 1-C-2 cells increased up to 4-fold after 72 h of permanent exposure to 100 mumol HPC/l, a concentration that completely inhibited proliferation of tumor cell numbers without being cytotoxic. Nucleotide triphosphate levels dropped significantly after 24 h and were slowly restored in spite of continued exposure. After 72 h, they nearly reached those levels observed in plateau-phase cells. This suggests that HPC-induced growth inhibition has similarities with physiologically occurring growth arrest. Finally, replication of RNA viruses and DNA viruses was suppressed 30-fold and 7-fold, respectively, at low concentrations of HPC (12 mumol/l), which caused no or negligible growth inhibition in the virus-harboring cells, thus demonstrating specific antiviral activity of HPC. From these observations we conclude that HPC differs in many important aspects from conventional cytostatic agents and is certainly worth following-up in further investigations.

Intracellular mediators of erucylphosphocholine-induced apoptosis

“…Alkylphosphocholines (APC) have been proposed as promising membrane targeted antineoplastic drugs, exerting cytotoxic effects in cell culture as well as in animal models (Berger et al, 1993;Clive et al, 1999;Konstantinov and Berger, 1999;Smorenburg et al, 2000;Ruiter et al, 2001). Similar to alkyllysophospholipids, (ALP), APC primarily interfere with cellular membranes without direct interaction with the DNA (Berggren et al, 1993;Bergmann et al, 1994;Berkovic et al, 1995;Zheng et al, 1990;Lucas et al, 2001).…”

“…These lipophilic drugs lack bone marrow toxicity and even exert growth stimulatory effects on hematopoietic progenitor cells inducing leukocytosis and thrombocytosis after systemic application (Vehmeyer et al, 1992;Ergezinger et al, 1999;Berkovic et al, 2001). Hexadecylphosphocholine (HePC) represents the first APC used in clinical trials (Miltex R ), (Berger et al, 1993;Clive et al, 1999;Konstantinov and Berger, 1999;Smorenburg et al, 2000). However, because of its gastrointestinal toxicity and its hemolytic side effects, the application of HePC is limited to topical treatment Verweij et al, 1992).…”

Recent Developments in the Chemotherapy of Chagas Disease

“…stimulated interest in this class of compounds previously shown to have antiviral and anticancer activities [79]. Miltefosine is used as a topical agent and has been tested by the oral route in phase I and II clinical trials, which have provided valuable information on human tolerance for the drug [80], The mode of action of this drug is unknown although it presumably interferes with cellular signal transduction [81].…”

Novel chemotherapeutic agents for the treatment of glioblastoma multiforme

“…Two classes of synthetic phospholipid analogues, the alkyllysophospholipids (ALP) as well as the closely related alkylphosphocholines (APC) have been identified that exert potent antineoplastic effects in cell culture and animal models, including brain tumours [229][230][231]. In contrast to most of the antineoplastic drugs in clinical use, these agents primarily interfere with cellular membranes without direct interaction with the DNA.…”