Friday, July 31, 2009

‘Trojan’ cells take on drug-resistant tumours

JUST one imitation horse was enough to conquer Troy, but it takes two waves of “Trojan” cell fragments to destroy drugresistant tumours in mice. The first wave releases RNA to disrupt drug resistance, making the tumours vulnerable, and the second delivers a fatal dose of chemotherapy. Himanshu Brahmbhatt and Jennifer MacDiarmid of the company Engeneic in Sydney, Australia, had already coaxed bacteria such as E. coli into dividing at their ends, rather than in the middle. This way they produce tiny buds of cytoplasm devoid of chromosomes and other organelles. After washing these “minicells” clear of bacterial toxins , the team loaded them up with chemotherapy drugs and tagged them with antibodies that bind only to tumours. When injected, the minicells destroyed tumours in animals .

However, because many tumours eventually become resistant to chemotherapy, the next step is to find ways to overcome drug resistance. One way cancer cells develop resistance is by overproducing a protein called MDR1, which helps pump the drugs out of the cell, reducing their toxicity. Brahmblatt’s team wondered if they could also use the minicells to block production of this protein. To find out, they created strands of small interfering RNA (siRNA) with a sequence designed to block the expression of the gene for MDR1, and loaded these into the minicells.

Next they injected these minicells into mice with a range of drug-resistant human cancers, including breast, colon and uterine tumours. The minicells were engulfed by the cancer cells, where they released the strands of siRNA (see diagram). The second wave of minicells containing high doses of the cancer drug doxorubicin was then injected, and the tumours shrank, indicating that the first batch had indeed blocked MDR1 (Nature Biotechnology, DOI: 10.1038/ nbt.1547). All of the treated mice were still alive 110 days after being implanted with the tumours, while a group of untreated mice had died by then. Brahmblatt says that the cancer cells engulf the minicells in their cell membranes – a process called endocytosis. Many different cells take in foreign cells or proteins this way, but it wasn’t clear that cancer cells would be capable of absorbing two rounds of minicells. “The first Trojan horse goes in and the cancer cell opens its door,” says Brahmbhatt. “The cell then regenerates its entire machinery for the next Trojan horse to come in and release a different payload.” Brahmbhatt adds that the minicells could be loaded with different drugs depending on the type of cancer and with different siRNAs to block the production of proteins responsible for other forms of drug resistance.

Double whammy to kill cancer cells

They could also be used to treat other diseases. siRNAs have been touted as a way to block a range of disease-causing genes but researchers have struggled to get them across cell membranes efficiently. “This is an exciting, novel technology with potential applicability to a number of different delivery problems,” agrees Daniel Anderson, who researches drugs delivery at the Massachusetts Institute of Technology. Linda Geddes

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