lead-radioisotopes and Carcinoma

Recent studies from this laboratory with (212)Pb-trastuzumab have shown the feasibility of targeted therapy for the treatment of disseminated peritoneal disease using (212)Pb as an in vivo generator of (212)Bi. The objective of the studies presented here was improvement of the efficacy of alpha-particle radioimmunotherapy using a chemotherapeutic agent.. In a series of experiments, a treatment regimen was systematically developed in which athymic mice bearing i.p. LS-174T xenografts were injected i.p. with gemcitabine at 50 mg/kg followed by (212)Pb radioimmunotherapy.. In a pilot study, tumor-bearing mice were treated with gemcitabine and, 24 to 30 h later, with 5 or 10 muCi (212)Pb-trastuzumab. Improvement in median survival was observed at 5 microCi (212)Pb-trastuzumab in the absence (31 days) or presence (51 days) of gemcitabine: 45 and 70 days with 10 microCi versus 16 days for untreated mice (P < 0.001). Multiple doses of gemcitabine combined with a single (212)Pb radioimmunotherapy (10 microCi) administration was then evaluated. Mice received three doses of gemcitabine: one before (212)Pb-trastuzumab and two afterwards. Median survival of mice was 63 versus 54 days for those receiving a single gemcitabine dose before radioimmunotherapy (P < 0.001), specifically attributable to (212)Pb-trastuzumab (P = 0.01). Extending these findings, one versus two treatment cycles was compared. A cycle consisted of sequential treatment with gemcitabine, 10 microCi (212)Pb radioimmunotherapy, then one or two additional gemcitabine doses. In the first cycle, three doses of gemcitabine resulted in a median survival of 90 versus 21 days for the untreated mice. The greatest benefit was noted after cycle 2 in the mice receiving 10 microCi (212)Pb-trastuzumab and two doses of gemcitabine with a median survival of 196.5 days (P = 0.005). Pretreatment of tumor-bearing mice with two doses of gemcitabine before (212)Pb radioimmunotherapy was also assessed with gemcitabine injected 72 and 24 h before (212)Pb-trastuzumab. The median survival was 56 and 76 days with one and two doses of gemcitabine versus 49 days without gemcitabine. The effect may not be wholly specific to trastuzumab because (212)Pb-HuIgG with two doses of gemcitabine resulted in a median survival of 66 days (34 days without gemcitabine).. Treatment regimens combining chemotherapeutics with high-LET targeted therapy may have tremendous potential in the management and care of cancer patients.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma; Deoxycytidine; Female; Gemcitabine; Humans; Lead Radioisotopes; Linear Energy Transfer; Mice; Mice, Nude; Peritoneal Neoplasms; Radiation-Sensitizing Agents; Radioimmunotherapy; Receptor, ErbB-2; Survival Analysis; Trastuzumab; Treatment Outcome; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

A simple and rapid procedure was developed for the purification of cyclotron-produced 203Pb via the 203Tl(d,2n) 203Pb reaction. A Pb(II) selective ion-exchange resin, with commercial name Pb Resin from Eichrom Technologies, Inc., was used to purify 203Pb from the cyclotron-irradiated Tl target with excellent recovery of the enriched Tl target material. The purified 203Pb was used to radiolabel the monoclonal antibody Herceptin. The in vitro and in vivo properties of the 203Pb radioimmunoconjugate were evaluated.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Carcinoma; Cell Line, Tumor; Colonic Neoplasms; Cyclotrons; Female; Humans; Isotope Labeling; Lead Radioisotopes; Metabolic Clearance Rate; Mice; Mice, Nude; Organ Specificity; Radioimmunotherapy; Radiopharmaceuticals; Tissue Distribution; Trastuzumab

We are investigating the potential use of short-lived alpha-emitting radionuclides for the treatment of ovarian carcinoma. These radionuclides transfer dense high ionizing linear energy (high LET) over a short path length without dependence upon cellular oxygen. The alpha-emitting radionuclides chosen were lead-212 and bismuth-212 which are readily available. The radiosensitivities of two ovarian carcinoma cell lines (OVC-1 and OVC-2) was greater with 212Pb and 212Bi than with X-ray therapy. D0, inversely related to the radiosensitivity, was 155 and 240 rads for OVC-1 and OVC-2, respectively. With 212Pb or 212Bi, the slope of the survival curves was steeper. The D0 was 75 and 70 rads after 212Pb and 85 and 95 rads after 212Bi treatment for OVC-1 and OVC-2, respectively. The relative biological effectiveness with alpha irradiation was two to four times greater than with X rays. Unlike low-LET irradiation (i.e., X rays and gamma emitters) the cells had no ability to accumulate or repair sublethal damage. From these experiments it is concluded that a greater therapeutic advantage may be gained with alpha-emitting radionuclides than X rays. Further development of these nuclides may provide for a new form of therapy.

Topics: Bismuth; Carcinoma; Cell Line; Cell Survival; Energy Transfer; Female; Humans; Lead Radioisotopes; Ovarian Neoplasms; Radioisotope Teletherapy; Radioisotopes; Tumor Cells, Cultured