INTRADERMAL ADMINISTRATION OF LIPOPOLYSACCHARIDE IN TREATMENT OF HUMAN CANCER

Lipopolysaccharide (LPS) has been recognized as a potent antitumor age nt in animal tumor models; however, its use in human cancer therapy ha s been limited to only one trial, in which LPS from Salmonella was giv en intravenously. It was not very successful because of poor tumor res ponse and was also toxic. We originally developed LPS prepared from Pa ntoea agglomerans (LPSp), and this was a well-purified, small-molecula r-mass (5 kDa) agent. We chose intradermal rather than intravenous adm inistration in the hope that the former would release LPS slowly into the bloodstream, and thus be less toxic while preserving antitumor act ivity. In our animal tumor models, intradermal administration was inde ed less toxic and more beneficial for tumor regression than intravenou s administration. We made a pilot study with intradermal administratio n of LPSp on the treatment of ten advanced cancer patients. Five of th em had evaluable tumor, which had failed earlier to respond to convent ional chemotherapy. Cyclophosphamide was also administered in this tri al, in anticipation of its synergistic effect with LPSp. In this study LPSp was injected intradermally into each patient twice a week, start ing with an initial dose of 0.4 ng/kg, and raising it to 600 or 1800 n g/kg. A 400-mg/m(2) dose of cyclophosphamide was given intravenously e very 2 weeks. After completion of the dose escalation, the treatment w as continued for at least 4 months, and it was found that 1800 ng/kg L PSp was well tolerated. A significant level of cytokines was observed in the sera for at least 8 h. These results indicate higher tolerable doses and remarkably more continuous induction of the cytokines than w ere reported in a previous study by others using intravenous administr ation. Three of the five evaluable tumors showed a significant respons e to our combined therapy. Intradermally administered, LPS was less to xic and elicited a tumor response ill combination with cyclophosphamid e; it can thus can be applied to cancer treatment even in humans.