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Bacterial toxins for the treatment of cancer - Page 2

© David Olle

Recombinant toxins

Recombinant toxins are prepared by genetic engineering, and consist of a modified bacterial toxin fused with either an antibody or an interleukin. The antibody or interleukin component binds to specific receptors on the cancer cell, with the subsequent release of toxin that kills the cell. Kreitman 2 provided a recent review on the subject. Phase 1 clinical trials are underway to study the effects of recombinant toxins against malignant glioblastoma or astrocytoma (brain tumors).

Combination therapy

Combination therapy is based on the use of bacteriological methods to complement either chemotherapy or radiation to improve clinical outcome. Chemotherapy generally acts preferentially on the more rapidly dividing cancer cells, but also act upon the rapidly dividing hair follicles and intestinal lining as well. Radiation focuses a beam directly on the tumor, and attempts to minimize exposure to normal tissue.

When the tumor grows rapidly, however, the vascular network is poorly developed and inadequate to supply nourishment to the cells. As a result, the tumor environment is hypoxic (lack of oxygen), and there is typically an inner core of necrotic (dead) cells. This environment reduces the effectiveness of radiation therapy, since its killing power is dependent on the oxygen concentration. Likewise, the poor vascular system can limit the entry of chemotherapeutic drugs at effective concentrations in the tumor.

Vogelstein and associates at the Johns Hopkins School of Medicine 1recognized this problem, and developed a less toxic strain of Clostridium novyi that grows well under hypoxic conditions. Tumors were established in mice following injection of colon cancer or melanoma cells. Spores of the Clostridium strain were then injected, and the spores germinated and bacteria spread throughout the poorly vascularized tumor. The workers observed that the treatment left a ring of viable cancer cells at the periphery of the tumor that were inaccessible to the bacteria. Follow-up studies, therefore, added a combination of low molecular weight chemotherapeutics and an antivascular agent. As the name indicates, the antivascular agent shuts down additional regions of the vascular system thereby increasing the region of the tumor accessible to the bacteria. The results on tumor destruction were dramatic; in many cases, the large quantity of tumor cells dying posed a toxicity problem. Although the studies were very encouraging, many problems need to be solved before the procedure can reach the clinic.

References

1. Dang, L. et. al. Combination bacteriolytic therapy for the treatment of experimental tumors. Proc Nat Ac Sci, Vol. 98, No. 26, pp. 15155-15160 (Dec. 18, 2001)

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