Combined ⁹⁰Yttrium‐DOTA‐labeled PAM4 antibody radioimmunotherapy and gemcitabine radiosensitization for the treatment of a human pancreatic cancer xenograft

Combination Therapy Using Gemcitabine and Radioimmunotherapy in Nude Mice with Small Peritoneal Metastases of Colonic Origin

“…To date, four reports have been published on the combination of experimental RIT and gemcitabine, three of which are in animal models of pancreatic cancer, [5][6][7] and one in an animal model of colon cancer. 11 The group of Goldenberg published three reports on the efficacy of combination therapy using 131 I-labeled or 90 Y-DOTA-labeled chimeric PAM4 MAb and gemcitabine in nude mice bearing s.c. CaPan1 human pancreas carcinoma xenografts.…”

“…injections of gemcitabine (6 mg/mouse, which equals 1000 mg/m 2 /week), or combination therapy. 7 Both RIT and gemcitabine monotherapy, when given as monotherapy, had some antitumor effects. When combined, however, there was a supra-additive antitumor effect, at the cost of only minimal toxicity to normal tissues, as evidenced by an average loss in body weight of less than 2% for all treatment groups.…”

“…The dose levels chosen in both MTD studies were based on the doses utilized in the above-mentioned studies, in which gemcitabine was combined with RIT. Cardillo et al 5 and Gold et al 7 administered gemcitabine i.p. every 3rd day for a total of 5 administrations at 2 mg/mouse and reported a maximum mean weight loss of only 4.5% Ϯ 5.5% on day 7.…”

“…Several innovative approaches have been pursued with the aim to improve the efficacy of RIT. These include strategies to improve the localization and retention of radiolabeled MAbs in the tumor (e.g., using high-affinity MAbs 2 ), strategies to accelerate the blood clearance of the radiolabel (e.g., using antibody fragments 3 or the pretargeting method 4 ), and strategies to increase the sensitivity of the tumor cells to radiation (e.g., using radiosensitizers [5][6][7] ).…”

“…10 Although in most chemoradiotherapy studies gemcitabine was combined with external beam radiation, in recent years, a few studies have been published reporting radiosensitizing effects of gemcitabine when combined with RIT in animal models of pancreatic cancer and colon cancer. [5][6][7]11 We have previously characterized a nude mouse model for RIT of small-volume peritoneal carcinomatosis of colorectal origin using the human colon carcinoma cell line, LS174T. 12 RIT using the radiolabeled anti-CEA MAb MN-14 proved very effective in inhibiting the growth of intraperitoneally (i.p.)…”