Combination radioimmunotherapy with local hyperthermia: increased delivery of radioimmunoconjugate by vascular effect and its retention by increased antigen expression in colon cancer xenografts

Enhanced Efficacy of Radioimmunotherapy Combined with Systemic Chemotherapy and Local Hyperthermia in Xenograft Model

“…Intestinal absorbed dose with 131 I-A7 at MTD was estimated, in the previous studies, to be less than 1 Gy, which was not affected by local HT to the tumor-bearing leg or by the administration of 5-FU. 15,21) Local HT did not affect systemic circulation and, therefore, would not increase the distribution of 5-FU to the intestine. 15) These findings indicate that intestinal toxicity should not be an obstacle to combining these three modalities in this animal model.…”

“…We previously found a 2.25-fold increase of tumor absorbed dose with 131 I-A7 by local HT, and suggested that this improvement was due to the hyperthermic effect on tumor vasculature-increase of blood flow and vascular permeability-as well as on antigen expression, which was 2.66-fold enhanced 2 days after heating. 15) The increased blood flow to the tumor may also be of benefit in improving the oxygenation of tumor tissues and thus enhancing radiation-induced toxicity with 131 I-A7. In addition, this study revealed a more uniform intratumoral distribution of 131 I-A7 in the heated tumors than in the control tumors, which would be of great benefit in enhancing the RIT efficacy.…”

“…pentobarbital anesthesia was conducted at 43°C for 1 h using a circulating water bath. 15) In the combined therapy, HT was conducted immediately after the mAb injection. A dose of 30 mg/kg/day of 5-FU (Wako Pure Chemical Industries, Ltd., Osaka) dissolved in 0.9% saline was i.p.…”

“…[1][2][3][4][5] Its outcome, however, has been inadequate except for malignant lymphoma, 3,4) mainly because of limited delivery of radiation ranging around only 0.005-0.01% of the injected dose per gram of tumor. 6) Therefore, several kinds of strategies have been examined to improve its efficacy, including the use of biological response modifiers to increase tumor targeting of labeled monoclonal antibodies (mAbs), [7][8][9] the use of a pretargeting system to obtain a better therapeutic ratio to normal tissues 10,11) and combination with other therapeutic modalities such as hyperthermia (HT) [12][13][14][15] and chemotherapy. [16][17][18][19][20][21] Our previous study demonstrated that HT enhanced the absorbed dose with 131 I-A7 anti-colorectal cancer mAb to colon cancer xenografts and significantly improved the therapeutic efficacy of RIT.…”

“…6) Therefore, several kinds of strategies have been examined to improve its efficacy, including the use of biological response modifiers to increase tumor targeting of labeled monoclonal antibodies (mAbs), 7-9) the use of a pretargeting system to obtain a better therapeutic ratio to normal tissues 10,11) and combination with other therapeutic modalities such as hyperthermia (HT) [12][13][14][15] and chemotherapy.…”