Chemo combo fights cancer

Bacteria that can cause deadly infections in humans and animals have shown promise in treating cancer by “eating” tumors from the inside out. Now, two new studies at the Johns Hopkins Kimmel Cancer Center have demonstrated that, combined with specially-packaged anti-cancer drugs, the bacterial therapy’s prospects for cancer eradication have dramatically improved.

In mouse experiments reported in the November 24 issue of Science, the Hopkins researchers demonstrated that genetically-modified bacteria called Clostridium novyi-NT (C.novy-NT) have a special taste for oxygen-starved environments much like those found in the core of cancer cell clusters. The modified bacteria themselves are relatively harmless, but their unmodified counterparts produce poisons that have killed some humans and cattle when introduced into the bloodstream.

“It is not difficult to kill cancer cells. The challenge is killing them while sparing normal cells,” says Bert Vogelstein, M.D., professor and co-director of the Ludwig Center and Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center.

The bacteria’s cancer-killing effects were first discovered five years ago by the Hopkins team who noticed the germ’s ability to grow and spread in the oxygen-poor core of mouse tumors and the blackened scars signaling that most of the cancer cells had been destroyed. Normal surrounding cells were largely unaffected. But the bacteria failed to kill cancer cells at the still oxygen-rich edge of the tumors.

In response, the Hopkins team added specially-packaged chemotherapy to the bacterial attack speculating that certain properties of the bacteria would improve the drug’s effectiveness, according to Shibin Zhou, M.D., Ph.D., assistant professor of oncology at the Johns Hopkins Kimmel Cancer Center.

The combo approach temporarily wiped out both large and small tumors in almost 100 mice and permanently cured more than two-thirds of them.

The likely explanation for the greater cancer cell kill by the combination treatment is that the bacteria expose the tumors to six times the amount of chemotherapy than is usually the case by improving the breakdown and dispersal of the chemotherapy’s fatty package at the tumor site.

The investigators repeated experiments using two packaged chemotherapy drugs -- doxorubicin and irinotecan -- and observed similar tumor-killing effects of both when used in combination with the bacteria.

“Packaged” cancer drugs currently are available in microscopic fatty capsules called liposomes which gravitate to tumors because they are too large to fit through the skins of tightly-woven blood vessels surrounding normal tissue and small enough to get through tumor vasculature.

Combining C.novyi-NT and liposomes filled with chemotherapy seems to have its synergistic effect on tumors owing to the presence of an enzyme found lurking in C. novyi-NT cultures, which Ian Cheong, Ph.D., in the Vogelstein lab dubbed liposomase. It destroys fatty membranes and may disrupt the outer layer of liposomes releasing their drug contents.

“Drugs contained in these ‘Trojan horse’ compartments are specifically released at the tumor site by the C-novyi-NT bacteria which may improve the effectiveness and safety of the therapy,” says Cheong who is the lead author of the study.

The scientists note that liposomase could be used in a variety of other targeted therapies besides the bacteria combination. Such approaches could include attaching liposomase to antibodies that have an affinity for specific tumors or adding its DNA code to gene therapy. As many drugs can be packaged within liposomes, the investigators say the approach could have general utility.

In a companion study published in the November 19 online issue of Nature Biotechnology, the Hopkins team decoded the entire C.novyi-NT genome which Zhou says “was instrumental in identifying liposomase and will help improve our bacterial-based therapies.”

Preliminary safety tests of injected C. novyi-NT alone are under way in a small number of cancer patients.

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The research was funded the Virginia and D.K. Ludwig Fund for Cancer Research, the Commonwealth Foundation, Miracle Foundation, and the National Institutes of Health.

Co-authors include Xin Huang, Chetan Bettegowda, Luis A. Diaz., Jr., and Kenneth W. Kinzler at the Johns Hopkins Kimmel Cancer Center.

1 Cheong, I., et al. A C.novyi Protein Enhances the Release and Efficacy of Liposomal Cancer Drugs. Science online, November 24, 2006.

2 Bettegowda, C., et al. The Genome and Transcriptomes of the Anti-Tumor Agent Clostridium novyi-NT. Nature Biotechnology online, Nov 17, 2006.

On the Web: www.hopkinskimmelcancercenter.org


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