Improvement of Clostridium tumour targeting vectors evaluated in rat rhabdomyosarcomas

Abstract

Previous studies have demonstrated the feasibility of using apathogenic clostridia as a promising strategy for hypoxia-specific tumour targeting. The present study shows that the use of the vascular targeting compound combretastatin A-4 phosphate could significantly (P<0.001) increase the number of Clostridium vegetative cells in rat rhabdomyosarcomas with sizes between 0.2 cm(2) and 3 cm(2). Furthermore, this study showed that administration of metronidazole for a 9-day period was sufficient to eliminate systemically administered Clostridium from the tumour. Moreover, previous Clostridium spore administration did not effect tumour colonisation, regardless of the immune response status of the host.

Repeated cycles of Clostridium-directed enzyme prodrug therapy result in sustained antitumour effects in vivo

“…Overall, this indicates that maturation of inactive spores into vegetative rods following a first cycle does not eliminate the activity of subsequent administrations. Our data are in line with our own previously reported results (Theys et al, 2001b) and with the observations of Liu et al (2002) showing no reduction in numbers of vegetative cells g À1 tumour occurring between 7 and 14 days after a single spore injection. This is not limited to animals with an immunocompromised immune system since it was demonstrated some 25 years ago that repeated clostridial spore administration could be performed in tumourbearing rats (Gericke et al, 1979).…”

“…Clearance of the bacteria from the animal not only allowed recovery after the treatment cycle, it also enabled a precise and direct quantification of the antitumour effect. In order to minimise all secondary effects that could be potentially involved in mediating the antitumour effect, we chose immunocompromised mice as a model, although there is no evidence for an immune response as shown earlier in immunocompetent rats (Theys et al, 2001b). Our results clearly demonstrate that intravenously administered spores of C. sporogenes expressing NTR-H produce Figure 3A).…”

“…Although the observed effects of the therapy were significant, additional efficacy would be predicted when combined with radiotherapy and/or conventional chemotherapy. Other potential combined treatment modalities include specific targeting of the structurally abnormal tumour blood vessels with vascular targeting agents as we (Theys et al, 2001b) and others (Dang et al, 2001) have already successfully reported. In addition, more soluble derivatives of CB1954 that cause more effective tumour regression have recently been described (Wilson et al, 2002) and since 5-FU and CB1954 have been shown to act synergistically (Palmer et al, 2003), the combinatorial use of prodrug activating enzymes (CDase and NTR) might be a promising option for CDEPT.…”

Systemic administration of attenuated Salmonella choleraesuis carrying thrombospondin-1 gene leads to tumor-specific transgene expression, delayed tumor growth and prolonged survival in the murine melanoma model

“…Indeed, it has been demonstrated that vascular collapsing agents increase the germination of bacterial spores in tumors. 33 Dolastatin, a vascular collapsing agent, has been shown to enhance the ability of Clostridium novyi spores to lyse tumors. 6 Several activities of TSP-1 may contribute to its antitumor effect.…”

Radio-responsive recA promoter significantly increases TNFα production in recombinant clostridia after 2 Gy irradiation

“…Since anaerobic bacteria like Clostridium may colonise other hypoxic/necrotic tissues besides tumoral, such as for instance abscesses and infarcted tissues, spatial control of gene expression would be advantageous. Further benefiting the treatment plan, Clostridium can be completely eradicated by the administration of antibiotics, 23 suggesting that complete control of gene expression can be obtained; radiation will switch it on, and, if necessary, antibiotics can switch it off.…”