Whole-body low dose irradiation promotes the efficacy of conventional radiotherapy for cancer and possible mechanisms - PubMed (original) (raw)
Whole-body low dose irradiation promotes the efficacy of conventional radiotherapy for cancer and possible mechanisms
S Z Jin et al. Dose Response. 2007.
Abstract
The purpose of the present study was to explore the possibility of establishing cancer radiotherapy protocols that could promote treatment efficacy at a reduced radiation dose. Mouse models of melanoma (B16) and Lewis lung carcinoma (LLC) were used in the experiments. Conventional local radiotherapy was combined with low dose whole-body irradiation (LDWBI) in the presence or absence of gene therapy by intratumor injection of a recombinant plasmid Egr-mIL-18-B7.1 (E18B). After a number of trials with different combinations it was found that a protocol of 2-week treatment with 2 x (E18B + 2 Gy + 0.075 Gy x 2) was found to be able to promote treatment efficacy at a reduced radiation dose. In this protocol local irradiation with 2Gy was administered 24h after intratumor injection of 10 microg of the plasmid E18B followed by LDWBI with 0.075 Gy every other day for 2 sessions in 1 week, and the procedure was repeated for another week. When this combined treatment was compared with conventional radiotherapy, i.e., 2Gy every other day 3 times in one week repeated for 2 weeks, the treatment efficacy was improved, as judged by increased average survival rate, reduced mean tumor weight, reduced pulmonary metastasis and suppressed intratumor capillary growth with a 2/3 reduction of radiation dose. Immunologic studies showed stimulated natural killer (NK) and cytotoxic T lymphocyte (CTL) activity as well as increased interferon-gamma (IFN-gamma) secretion in this combined treatment group as compared with the group receiving local treatment alone. It is suggested that up-regulation of host anticancer immunity by LDWBI and the initiation of expression of immune genes by both the local large dose and LDWBI are important factors in the realization of improved cancer control.
Keywords: cancer; conventional radiotherapy; gene therapy; low dose whole-body irradiation.
Figures
FIGURE 1
Combined treatment of B16-bearing mice with 1-week protocol. Left panel: Tumor growth curves of gene radiotherapy with or without 0.1 Gy WBI; Right panel: Changes in immuno-logic parameters of the spleen 1 day after termination of treatment.
FIGURE 2
Tumor growth curves of Lewis lung cancer treated with a 2-week regimen of 5 Gy sessions. LLC model was used in the trial of a protocol with 2-week treatment and observation of tumor growth for one month after treatment as shown in the left upper panel. In order to discern the effect of combination of local high dose irradiation and LDWBI with or without the introduction of gene therapy with E18B plasmid, the left and right lower panels are shown with statistical analysis which illustrated that in the presence or absence of gene introduction, substitution of 4 local doses of 5 Gy with 4 doses of WBI of 0.075 Gy exerted the same efficacy of tumor control.
FIGURE 3
Tumor growth curves of Lewis lung cancer treated with a 2-week regimen of 2 Gy sessions with or without gene therapy and LDWBI (explanation in text).
FIGURE 4
Immunological changes in the spleen of LLC-bearing mice after termination of radiotherapy and gene radiotherapy with or without LDWBI. Left upper panel: NK activity on d1; Right upper panel: CTL activity on d5; Left lower panel: IFN-γ secretion on d1, d3 and d5; Right lower panel: Lamp-1 expression on splenic lymphocytes on d1, d3, d5. For all panels: A=normal mice; B=tumor-bearing mice without treatment; C=tumor-bearing mice with local radiotherapy 2 Gy × 6; D=tumor-bearing mice with 2 × (2 Gy + 0.075 Gy × 2); E: tumor-bearing mice with 2 × (E18B + 2 Gy × 3); F: tumor-bearing mice with 2 × (E18B + 2Gy + 0.075 Gy × 2)
References
- Alter G, Malenfant JM, Altfeld M. CD107a as a functional marker for the identification of natural killer cell activity. J Immunol Methods. 2004;294:15–22. -PubMed
- Gilligan MG, Knox P, Weedon S, Barton R, Kerr DJ, Searle P, Young LS. Adenoviral delivery of B7-1 (CD80) increases the immunogenicity of human ovarian and cervical carcinoma cells. Gene Ther. 1998;5:965–974. -PubMed
- Jin GH, Jin SZ, Liu Y, Pan XN, Xu RM, Liu SZ. Therapeutic effect of gene therapy in combination with local X-irradiation in a mouse malignant melanoma model. Biochem Biophys Res Commun. 2005;330:975–981. -PubMed
- Liu SZ. On radiation hormesis expressed in the immune system. Crit Rev Toxicol. 2003;33:431–441. -PubMed
- Liu WH, Yang YG. Measurement of cytotoxicity and lymphokines. In: Gong SL, Zhang M, editors. Practical Experimental Techniques in Basic Medicine. Changchun: Jilin Science and Technology Press; 1991. pp. 189–196.
LinkOut - more resources
Full Text Sources