d.d. 29 december 2003:

Mei 2003 bracht The Journal of the National Cancer Institute een bericht dat een virus onder de naam Delta-24-RGD bij muizen met ingebrachte kwaadaardige hersentumoren (Glioma's) een zeer positief effect had. Tot onze verbazing krijgen we bij zoeken op internet te lezen dat al in 2002 in de VU-Amsterdam zeer geslaagde proeven zijn gedaan met dit virus, ook bij muizen met kwaadaardige hersentumoren, zowel met het virus alleen als in combinatie met bestraling. En met groot succes, want bij alle 10 behandelde muizen met de combinatie virus en bestraling verdwenen de hersentumoren volledig, aldus studie gepubliceerd in Pubmed, lees hieronder abstract daarvan. Nu zijn de proeven nog wel op kleine schaal maar het NCI meldt wel dat al in 2004 trials met patiënten zullen worden opgezet dus hopelijk doet de VU-Amsterdam ook mee. We zullen daar begin januari navraag voor gaan doen. Hier achtereenvolgens, na tip van bezoeker van onze site overigens, waarvoor dank, het bericht van mei 2003 en het abstract van de studie gedaan in de VU-Amsterdam. 

Cold virus rids mice of brain cancer 

Tim Radford, science editor
Wednesday May 7, 2003
The Guardian 

In an experiment that may have implications for cancer treatment, American and Spanish scientists have used the common cold virus to eradicate brain tumours in mice. 

They report today in the Journal of the National Cancer Institute that they chose an adenovirus - a virus of the respiratory tract - which targets only cancerous cells, and which spreads like a wave through malignant glioma, the most lethal form of brain cancer. 

They injected it into laboratory mice implanted with human glioblastoma tumours. Untreated mice died in three weeks, but treated mice survived for more than four months. When they examined the survivors, investigators found only empty cavities and scar tissues where the brain tumours had been. 

"We believe this therapy has a lot of potential, but one that needs much more study," said Juan Feyo of the University of Texas MD Anderson cancer centre. "We've never seen this kind of response before with any other treatment tested in either animals or humans." 

The US National Cancer Institute is to produce a drug to test in humans late in 2004. The virus, known so far by the clumsy name of Delta-24-RGD, replicates only in cancer cells, not healthy tissue. 

It reproduces itself by killing its host cells and moving on to contaminate other tumour cells. When there are no more cancer cells to infect, it dies. 

As there is no successful treatment for malignant glioma, the researchers have in effect turned an unstop pable infection into a weapon against an incurable disease. 

"Cancer can be devious, in that it does everything possible to evade destruction. But viruses are equally tricky in their quest to invade cells and propagate," said Frederick Lang, one of the investigators. "In this experimental war between cancer and a viral therapy, the virus won. Of course, we hope to obtain similar results when patients are tested, but we cannot predict such success based on animal studies." 

Viruses hijack their hosts' DNA to multiply. Cancer is above all a DNA disease, and the cancer genome project in Cambridge has found more than 100 genetic mutations associated with cancer. The reasoning is that if humans can identify a cancer cell by its DNA, then so can a virus. 

Researchers have proposed an altered HIV virus for gene therapy in haemophilia, cystic fibrosis and heart disease. Other teams have experimented with bacteriophages - viruses that prey on bacteria - to defeat antibiotic-resistant infection. Cell biologists experimented with an altered virus to deliver growth factor to wasting muscles, and mutant common cold viruses have been used to shrink tumours in prostate cancer and head and neck cancer. 

But most experiments have been with mice, and most are rated only "promising" so far. The cooperation between the University of Texas, the University of Alabama at Birmingham, and the Catalan cancer institute in Barcelona, Spain, has achieved more than that. 

Cancer Res. 2002 Oct 15;62(20):5736-42. 


Potential of the conditionally replicative adenovirus Ad5-Delta24RGD in the treatment of malignant gliomas and its enhanced effect with radiotherapy.

Lamfers ML, Grill J, Dirven CM, Van Beusechem VW, Geoerger B, Van Den Berg J, Alemany R, Fueyo J, Curiel DT, Vassal G, Pinedo HM, Vandertop WP, Gerritsen WR.

Department of Neurosurgery, VU University Medical Center, 1007 MB Amsterdam, the Netherlands. 

The use of replication-competent adenoviruses (Ads) for cancer therapy is receiving widespread attention, especially for the treatment of tumors refractory to current treatments such as glioblastoma. AdDelta24, which carries a 24-bp deletion in E1A and replicates in cells with a retinoblastoma-defective pathway, produced a strong antitumor effect in glioma. To improve infection efficiency of primary glioma cells, which express low levels of coxsackie adenovirus receptor (CAR), the tropism of AdDelta24 was expanded toward alphav integrins by insertion of an Arg-Gly-Asp (RGD) motif into the fiber knob (Ad5-Delta24RGD). We show that Ad5-Delta24RGD had a stronger oncolytic effect than the non-RGD-expressing variant on a broad panel of primary glioma cells, in particular on those with low CAR expression. The effects of Ad5-Delta24RGD were also assessed on a panel of primary organotypic glioma spheroids. In all cases, Ad5-Delta24RGD strongly decreased the viability of these small tumor nodules in vitro. In s.c. glioblastoma xenografts expressing low levels of CAR, five intratumoral injections of 1 x 10(7) plaque-forming units Ad5-Delta24RGD resulted in complete tumor regression in 9 of 10 mice and long-term survival in all treated mice. Preclinical evaluations and clinical trials of replication-competent Ad have shown more promising results when combined with conventional therapeutics. Therefore, we assessed the effects of Ad5-Delta24RGD in combination with radiotherapy. Low-dose irradiation before Ad5-Delta24RGD infection decreased viability of glioma cells more effectively than Ad5-Delta24RGD alone with effects ranging from additive to supra-additive. In addition, combination treatment with Ad5-Delta24RGD and irradiation was studied in glioma xenografts. Five injections of 1 x 10(6) plaque-forming units Ad5-Delta24RGD induced significant tumor growth delay of >119 days compared with untreated controls and led to long-term survival in 6 of 9 mice. When viral treatment was combined with irradiation, tumor regression occurred in all mice resulting in long-term survival without evidence of tumor regrowth in 10 of 10 cases. This study thus provides evidence that Ad5-Delta24RGD has strong antitumor activity in malignant glioma, which can be additionally enhanced by irradiation such that the same therapeutic effect is achieved when a 10-fold lower viral dose is applied. These results support further development of Ad5-Delta24RGD in combination with radiation therapy for treatment of these highly malignant tumors.

PMID: 12384532 [PubMed - indexed for MEDLINE]