meat-eating bacteria and cancer

Posted by
KB on Jan 06, 2002 at 21:59
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Therapeutics: Taking a bite out of tumours
KRISTINE NOVAK


Although many drugs are effective in killing rapidly dividing cancer cells, it is difficult to deliver these drugs to the poorly vascularized, hypoxic regions inside large tumours. Bert Vogelstein's group at Johns Hopkins University have developed an 'inside-out' therapy to destroy the oxygen-deprived necrotic areas of tumours using meat-eating bacteria.



Clostridium novyi bacteria (green) destroying colorectal cancer cells (red). Image courtesy of Long H. Dang and Bert Vogelstein, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

Although tumours induce formation of new blood vessels to deliver nutrients and oxygen to the growing tumour, angiogenesis does not keep pace with the growth of the neoplastic cells. This results in large hypoxic areas throughout the tumour. Cancer cells in these areas are not killed by ionizing radiation, which depends on oxygen, or by chemotherapeutic drugs, which do not reach these regions.

In the 27 November issue of Proceedings of the National Academy of Sciences, Dang et al. report an attempt to take advantage of the fact that necrotic tissues exist only in tumours and not in normal tissues. They performed a screen for anaerobic bacteria that can distribute throughout poorly vascularized regions of tumours. One of the strains they isolated, Clostridium novyi (which the authors grew on cooked meat particles) fulfilled this criteria, but was also, unfortunately, toxic to the mice. As this bacterium carries its toxin gene on a phage episome, the authors were able to isolate phage-free strains that no longer killed mice. But would these bacteria still be able to kill tumour cells?

The authors tested the ability of intravenously administered C. novyi spores to destroy colorectal tumours in a mouse xenograft model. The spores were administered with conventional chemotherapeutic agents, in the hope of killing the vascularized cancer cells located on the tumour's outside as well as the hypoxic regions inside. Treatment with chemotherapy alone usually only slows, but does not stop, tumour growth. The combination bacteriolytic therapy (COBALT), however, caused the tumours to become black necrotic masses that shrank and disappeared, whereas surrounding normal tissue remained intact. More than three-quarters of the tumours treated, including very large tumours, were completely destroyed within 24 hours, and approximately half the mice were cured with no evidence of tumour regrowth. Similar results were seen with melanomas grown in C57BL/6 mice.

Interestingly, the authors found that co-administration of the bacterial spores with D10, a chemotherapeutic drug that acts by collapsing the tumour vasculature, was the most effective antitumour combination. The authors believe that the D10-induced vascular collapse further lowers the oxygen tension near the bacteria and increases their proliferation and activity.

But can these bacteria be used to treat human cancers? Future experiments are required to answer safety questions, as the rapid destruction of large tumours was toxic and caused the death of some animals. It will also be important to determine the mechanism by which C. novyi selectively destroys viable tumour cells that are adjacent to hypoxic areas. The authors also point out that not all tumours will be susceptible to COBALT, and they will have to determine which chemotherapeutic drugs act synergistically with bacteria against human tumours.

Kristine Novak is senior editor of Nature Reviews Cancer




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