Optimal Timing of Administration of Hyperthermia in Combined Radioimmunotherapy

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Abstract
Local hyperthermia (HT) may enhance the efficacy of radioimmunotherapy (RIT). However, the optimal timing of HT relative to administration of antibody is unknown. Human colon cancer xenografts (290 ± 26 mm3) were treated with 4.63 MBq 131 I-A 7 monoclonal antibody (MAb) anti-Mr 45,000 glycoprotein antigen on colorectal cancer, and HT at 43 °C for 1 h was administered at: (A), 2 days after the 131 I-A 7 injection at the maximum 131 I-A7 tumor accumulation (radiation); (B), soon after the 13l I-A7 injection aiming to increase the tumor accumulation of131 I-A 7 due to HT vascular effects; or (C), 2 days before the 131 I-A 7 injection in an attempt at injecting 131 I-A 7 when increased antigen expression could be expected. Specific growth delay (SGD) of tumors was calculated as (Tq,treat-Tqcontrol)/Tqcontrol where Tq was tumor quadrupling time. The biodistribution and intratumoral distribution of13l I-A 7 were investigated to explore the mechanism of tumor response among the different HT regimens. HT alone produced some antitumor effect (SGD 1.90 ±0.26), which was less effective than RIT (3.11± 0.50). HT soon after 131 I-A 7 RIT (B) significantly enhanced RIT efficacy (6.57±0.51, p < 0.0001) whereas neither HT at 2 days after RIT (A) nor at 2 days before RIT (C) did so. Biodistribution study revealed that HT soon after RIT (B) increased the tumor radiation absorbed dose by a factor of 2.4, while HT after RIT (A) did not increase radiation dose and HT before RIT (C) decreased it. Radioluminograms of tumor sections indicated that HT soon after RIT (B) improved the uniformity of131 I-A 7 distribution whereas HT after RIT (A) did not and HT before RIT (C) diminished the uniformity of A7 distribution. In conclusion, the best therapeutic efficacy was obtained when HT was combined soon after the initiation of RIT with 13,I-A 7. The increased tumor radiation absorbed dose and the uniform intratumoral distribution of13l I-A 7 were important factors underlying this improvement, and the additive cytotoxicity of HT is suspected to some extent. HT-induced radiosensitization of tumor was not apparent in this model when HT was given 2 days after 131 I-A7 MAb.