Species of Clostridium bacteria are notable for their ability to lyse tumor cells growing in hypoxic environments. We show that an attenuated strain of Clostridium novyi (C. novyi-NT) induces a microscopically precise, tumor-localized response in a rat orthotopic brain tumor model after intratumoral injection. It is well known, however, that experimental models often do not reliably predict the responses of human patients to therapeutic agents. We therefore used naturally occurring canine tumors as a translational bridge to human trials. Canine tumors are more like those of humans because they occur in animals with heterogeneous genetic backgrounds, are of host origin, and are due to spontaneous rather than engineered mutations. We found that intratumoral injection of C. novyi-NT spores was well tolerated in companion dogs bearing spontaneous solid tumors, with the most common toxicities being the expected symptoms associated with bacterial infections. Objective responses were observed in 6 of 16 dogs (37.5%), with three complete and three partial responses. On the basis of these encouraging results, we treated a human patient who had an advanced leiomyosarcoma with an intratumoral injection of C. novyi-NT spores. This treatment reduced the tumor within and surrounding the bone. Together, these results show that C. novyi-NT can precisely eradicate neoplastic tissues and suggest that further clinical trials of this agent in selected patients are warranted.

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Swine were infected with Mycobacterium bovis to develop a model for pulmonary and disseminated tuberculosis in humans. Pigs were inoculated with various doses of M. bovis by intravenous (i.v.), intratracheal (int), or tonsillar routes. Animals were euthanized between 17 and 60 days after inoculation, and tissues were collected for culture and histopathologic examination. Lesions of disseminated tuberculosis were found in pigs given 10(4) or 10(8) cfu of M. bovis i.v. or int; localized pulmonary disease was found in pigs given 10(2) or 10(3) cfu of M. bovis int. Lesions ranged from well-organized tubercles with coagulative necrosis, epithelioid macrophages, and fibrosis to large expansive tubercles with liquefactive necrosis and extracellular growth of M. bovis. Tuberculous meningitis was observed in animals given M. bovis i.v. Swine infected with M. bovis are a useful animal model for elucidating the mechanisms of pathogenesis and host defense to tuberculosis in humans.

Background: Both cell-associated and cell-free HIV virions are present in semen and cervical secretions of HIVinfected individuals. Thus, topical microbicides may need to inactivate both cell-associated and cell-free HIV to prevent sexual transmission of HIV/AIDS. To determine if the mild acidity of the healthy vagina and acid buffering microbicides would prevent transmission by HIV-infected leukocytes, we measured the effect of pH on leukocyte motility, viability and intracellular pH and tested the ability of an acidic buffering microbicide (BufferGel ® ) to prevent the transmission of cell-associated HIV in a HuPBL-SCID mouse model.