|Blood flow, and lack thereof, is the Achilles heel of effective drug delivery for treating cancer. Most advanced tumors have regions that are rich in blood supply and others that are poorly vascularized. Consequently, these oxygen-starved regions cripple the cell-killing ability of conventional cancer therapies.
Ionizing radiation depends on oxygen to unleash its lethal effects, and the lack of vascular inroads to a tumor means that chemotherapeutic agents cannot reach tumor cells at sufficient concentration. This, in turn, can encourage drug-resistant cancer cells to emerge and cause more aggressive, metastatic cells to grow. Now, a team of scientists at Johns Hopkins University (Baltimore) has devised a potent strategy to overcome this hurdle by teaming up with an unlikely allyanaerobic bacteria.
The idea of putting anaerobic bacteria to the task of targeted killing of tumors dates back to the 1940s, when scientists discovered that certain microbes were particularly effective at destroying tumors in research animals. Unfortunately, nearly all the animals died from lethal toxins produced by the bacteria.
Intrigued by the idea of using bacteria for targeting tumors, Bert Vogelstein, professor of oncology at Hopkins and principal investigator of the study, decided to revisit the approach.
After screening 22 different species of anaerobes, Vogelstein and colleagues found two species that were able to germinate and spread within the hypoxic regions of melanoma and colorectal tumors generated in mice. However, the treated mice soon died. To overcome the problem, they selected Clostridium novyi, which has only a single toxin gene, and engineered the anaerobe to prevent it from making any toxin. After injection of mice with C. novyi spores, the modified bacteria were found growing extensively and leaving extensive tumor destruction in their wake (Proc. Natl. Acad. Sci. U.S.A. 2001, 98 (26), 15,15515,160). No infection or immune response was detected.
Next, the researchers combined their bacteria therapy with conventional chemotherapeutic agents. The blood vessel-collapsing agent D10 showed the greatest effect. The approach, dubbed combined bacteriolytic therapy (COBALT), was even more potent than treatment with bacteria alone. Weve always planned a double-pronged attack, says Vogelstein. Target the inside [of a tumor] with bacteria and the outside with chemotherapy. Within 24 hours, the tumors were reduced to a blackened mass of dead tissue.
Furthermore, many animals were subsequently shown to be cancer-free. Nevertheless, 1030% of the mice died from toxicity associated with rapid lysis of the tumors, a problem that Vogelstein says needs to be overcome before the approach is tested on humans.
Not all cancers will respond to COBALT, suggests Vogelstein, but he believes that it is a widely applicable approach that can be tailored to different tumor types by simply combining C. novyi with cancer- or tumor-specific chemotherapeutic agents.