Turning drug resistance into a therapeutic advantage

Newsdesk Turning drug resistance into a therapeutic advantage Drug resistance is a major marrow) with elevated TS problem in the pharmacolevels are susceptible to the logical treatment of cancer. effects of NB1011. Many cancer drugs work by Based on these results, inhibiting enzymes that are clinical trials are due to start in critical for the proliferation of April/May this year. Raymond tumour cells, best tumour cells Poon, co-founder of Newcan outsmart this approach by Biotics (San Diego, CA, USA), expressing increased enzyme the company behind NB1011, levels. Some researchers are says: “In the very first clinical now considering a new trials, we will work with strategy; instead of inhibiting patients who have become overexpressed enzymes, they resistant to 5-FU. The agent is NB1011 is a phosphoramidate derivative of (E)-5-(2-bromovinyl)-2makes use of their activity. deoxyuridine (BVdU), an antiviral agent known to be a substrate for also indicated for patients with One of these newly designed STET. BVdU is charged and cannot enter cells efficiently, but NB1011 TS overexpression.” drugs, NB1011 (Thymectacin), can. Once inside the cell, NB1011 is converted into the Researchers at the Food has been shown to be effective monophosphate, binds to TS, and is subsequently converted into and Drug Administration in preclinical studies and is cytotoxic reaction products. (FDA, Rockville, Maryland, approximately 10 times more sensitive about to enter clinical trials. USA) are working on a similar to NB1011 than to 5-FU (Biochem NB1011 targets thymidilate approach to overcome resistance to Pharmacol. 2001; 61: 179–189). When synthase (TS), an enzyme that is 5-FU. Jerry Collins, who is leading the the same cells were grown subcutessential for DNA synthesis and is also team there, says: “Taking advantage of aneously in nude mice, NB1011 (given the target of conventional fluorothe overexpression of target enzymes is ip for 5 days and compared with 5-FU pyrimidine-based cancer chemocertainly a good idea that needs to be or excipient) completely suppressed therapy (for example with 5-FU). In popularised, because everybody else xenograft growth. It also decreased contrast to these TS inhibitors, concentrates on inhibiting overtumour volume in five out of 8 eight NB1011 is a modified substrate for TS expressed enzymes. This group has nude mice carrying xenografts of and only gets to work once it has been made a plausible case for the human breast cancer cells. converted by the enzyme into relationship between enzyme activity Toxicological studies in dogs, rats, and cytotoxic products (see figure). and cytotoxicity (Mol Pharmacol 2001; mice also looked promising, normal In vitro tests showed that 5-FU59: 446–452).” Martina Habeck cells (ie from the GI tact and bone resistant colon cancer cell lines were

Australian oncologists press for PET funding Australian cancer specialists are lobbying the Federal Health Minister to back the funding of Positron Emission Tomography (PET) equipment through the Medicare Benefits Schedule. Both the Peter MacCallum Cancer Institute (PMCI) and the Wesley Hospital in Brisbane have been lobbying the Federal Australian Government to reappraise a regulatory review, released in August last year, which states that there is limited evidence that PET scans are effective. According to cancer specialist David Ball (PMCI, Melbourne), “Due to the limited number of these machines in the country and a lack of Medicare funding, cancer patients are currently waiting for up to 6 weeks for vital information on their progress. Government ministers are still dragging their feet and it is very THE LANCET Oncology Vol 2 April 2001

frustrating for doctors. For metatastic disease, PET scans make a big difference when deciding whether to select a patient for radiation”, said Ball. A PET scan can reveal whether lung cancer has spread to the lymph glands on average 90% of the time, as compared to 60% of the time using a CAT scan, he claimed. “But we have had no response from any Government minister.” This is despite a Government review from the Department of Health and Aged Care on PET, which concluded that, “more detailed data collection are required on PET” to determine its use and funding. The review also stated that, “…there is insufficient evidence at this time from which to draw definitive conclusions about the clinical and cost effectiveness of PET”.

The review includes a section from the Medicare Services Advisory Committee (MSAC), which explains that the decision to restrict Medicare funding is based on six clinical indications. These include: preoperative staging of non-small-cell lung cancer, potentially resectable melanoma, residual/recurrent mass in patients treated for malignant glioma and suspected recurrence of colorectal cancer. There are four operational PET facilities in Australia: the Royal Prince Alfred Hospital in Sydney, the Austin and Repatriation Hospital and the Peter MacCallum Cancer Institute in Melbourne, as well as the Wesley Hospital in Brisbane. Over 80% of PET examinations are currently performed in oncology. Georgina Kenyon

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For personal use only. Reproduce with permission from The Lancet Publishing Group.