MOLECULAK MErIICINL: TODAY. APKIL. ,‘N7 N e w s

product will therefore need to go through clinical trials before being approved for general use.

The other arm of GelMed’s current research focuses on Smart HydrogelTM, a proprietary mixture of polymers designed to exhibit a ‘reverse’ thermal response. It consists of a polyacrylic acid backbone with temperature- sensitive polymers covalently bound to the side- chains. mixed with a second polymer that acts as the carrying agent. At room temperature. a dilute solution (l-3%) of the polymer is a watery liquid, while on warming to body temperature the

solution gels, becoming viscous and clinging to surfaces in a ‘bioadhesive’ form. The hydrogel therefore provides an effective way to administer drugs, either topically or to mucosae, over longer timescales than is currently possible. by dissolving them in a solution of the hydrogel. which also contains hydrophobic regions.

GelMed believe that, by usmg existing drug formulations incorporated into the hydrogels, pharmaceutical companies will be able to Increase the efficiency, cost-effectiveness and range of applications for existing therapeutics. The

company is currently running research projects on topical anti-fungal products, osteoporosis treatments and nasal delivery systems for peptides. Clinical studies are already under way for a smart hydrogel that coats the oesophagus to prevent the damage caused by acid reflux. Late-stage pre- clmical studies are being conducted on a treatment for glaucoma. and on a topical hormone replacement therapy as an alternative to oral steroids or patches.

Claire 0’3rien

Bacterial vector for cancer therapy Vion pharmaceuticals (New Haven, CT, USA) is gearing up for human clinical hials, expected to start early in 1998, of its ~anccr therapy known as TAPFT (tumour-amplificd pmdrug enzyme therapy). The rationale of TAPET is to use bacteria as vectors to deliver therapeutic agents to tumours. Stmim of Mm4meiiu selected originally on the basis of their propensity to infect and multiply within tumour cells rather than normal cells have been genetically altered to make them nonpathogenic and to induce genes encoding protein drugs or p&g-converting enzymes. After injection into a cancer patie& the bacteria should circulate throughout the body but accumulate only within the tumour tissue, where they would multiply rapidly and release large amoullts of the therapeutic protein locally.

compared with viral vectors or liposome delivery, bacterial vectors have the advantages that (1) lhey can be engineed to carry more than one gene, (2) they are easy to produce, (3) they do not alter the genome of the recipient and (4) they can be readily elimind by antibiotics once treatment is complete. Efficient and stable expression of the thexapeutic protein is clearly essential to the success of all gene therapy approaches to cancer treatment; bactefial vectors have some advantages here too, because Vion has found that banscription tirn some bacterial promoters is enhanced severalfold in tumour tissue. Became the bacterial vecttm tnv delivered systcmicaUy, TAPET should he effective against metastases as well as primary cancers. If repeat tfeatment is necessary, the availabiity of a range of serotypes for each vectw should help to circumvent neutmhzing anti- bacterial immune responses.

The ganciclovir-hqes simplex thymidine kinase killing system is one of the prodrug systems that Vion is working on (l?g. 1). The cytotoxic drug ganciclovir is administed in its nonphosphorylated prodrug form, then TAPET is used to deliver herpes simplex thymidine kinase selectively to the -our, whew the kinase acti- the prodrug by phosphorylation. Vion has carried out trials of TAPFZ on animals with a

variety of solid tumours, including breast, lung, colon, melanoma and liver cancers. They have detected the bacteriaI vectors at concentrati0ns 200-10 OOO times higher than in normal tissues, says Vion’s Director of Biology, Ivan King, and they have observed inhibition of the growth of both the primary tumour and lung metastases in mice cmying B 16 melanomas. The enzyme cytosine deaminzz, which converts 5fluorocytosine to the antihunour agent 5-fluorouracil, has also been successfully expressed in hlmours in viva

Phase I clinical trials of TAPET will involve patients who have a variety of solid tumours. In preparation for the trials, a number of safety issues are being addressed Although the danger of sepsis with the strains selected appears to be low, Vion is carrying out additional genetic engineering to lower the risk further; for example, they are

disabling the production of endotoxins by the bacteria. Other genetic alterations have also been made to ensure that patients will be able to tolerate infection by the bacteria without adverse effects.

Other companies active in the field of targeted gene therapy for cancer are concentrating on improving approaches based on antibodies or viral vectors. ONYX Pharmaceuticals (Richmond, CA, USA), for example, has recently developed a modified adenovims that selectively infects and lyres tumour cells deficient in the protein ~53. A number of tumours injected with the virus showed signiticant shrinkage. It seems likely that targeted gene therapy using both viral and bacterial vectors will eventually find a place in clinical oncology, although routine application is probably still several years away.

AlisonStewti

HSV-TK

Cellular enzymes

Cellular enzymes A

DNA synthesis t

prodrug ganciclovir to its active, phosphorylated foml. Bacteria engineered to produce herpes simplex virus thymidlne kinase (HSV-TK) accumulate selectively In the tumour, where they enable ganciclovir to be activated

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