Biomedical subjects
Publications and source records attributed to R D Blumenthal.
Mouse ovarian tumor (MOT) cells have been grown in C3HeB/FeJ mice as an ascites and as a subcutaneous tumor and in cell culture as a suspension. These cells contain saturable, high-affinity, specific progesterone receptors. Estrogen receptors were not detectable in these cells. MOT cells can be used as both an in vivo and an in vitro model for progestin-mediated radiotherapy.
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Pretargeting methodologies can produce high tumor:blood ratios, but their role in cancer radioimmunotherapy (RAIT) is uncertain. A pretargeting method was developed using a streptavidin (StAv) conjugate of MN-14 IgG, an anti-carcinoembryonic antigen (CEA) murine monoclonal antibody (mab) as the primary targeting agent, an anti-idiotype antibody (WI2 IgG) as a clearing agent, and DTPA- or DOTA-conjugated biotin as the radiolabeled targeting agent. A variety of reagents and conditions were examined to optimize this method. At 3 h, 111In-DTPA-peptide-biotin tumor uptake was 3.9 +/- 0.8% per gram and tumor:blood ratios were > 11:1. By 24 h, this ratio was 178:1, but tumor accretion declined in accordance with the gradual loss of StAv-MN-14 from the tumor. Tissue retention was highest in the liver and kidneys, but their tumor:organ ratios were > 2:1. Dosimetry predicted that radiolabeled MN-14 alone would deliver higher tumor doses than this pretargeting method. Increasing the specific activity and using DOTA-biotin in place of DTPA increased tumor uptake nearly 2-fold, but analysis of StAv-MN-14's biotin-binding capacity indicated over 90% of the initial biotin-binding sites were blocked within 24 h. Animals fed a biotin-deficient diet had 2-fold higher 111In-DOTA-biotin uptake in the tumor, but higher uptake also was observed in all normal tissues. Although exceptionally adept at achieving high tumor:blood ratios rapidly, the tumor uptake of radiolabeled biotin with this pretargeting method is significantly (p < 0.0001) lower than that with a radiolabeled antibody. Endogenous biotin and enhanced liver and kidney uptake may limit the application of this method to RAIT, especially when evaluating the method in animals, but with strategies to overcome these limitations, this pretargeting method could be an effective therapeutic alternative.
Understanding the changes in tumor biology following cytotoxic therapy may lead to a better understanding of the properties of surviving tumor cell populations and to an improved ability to target and treat these cells. This report addressed the time-dependent dynamic alterations in the expression of three tumor-associated antigens: carcinoembryonic antigen (CEA), colon-specific antigen (CSAp) and mucin-1 (MUC-1) following chemotherapy with 5-fluorouracil (5-FU) or radioimmunotherapy (RAIT; (131)I-labeled anti-CEA IgG) in human colonic tumor xenografts. Immunoassay results show that CEA and MUC-1 expression all increase rapidly after either 5-FU or RAIT. GW-39 tumors show a 2.7-fold increase in CEA expression after a maximum tolerated dose of RAIT, being highest after 21 days, while LS174T and HT-29 tumors maximally increase expression 8.3- and 2.6-fold on day 7 after RAIT, respectively. The change in LS174T is short-term, whereas the change in HT-29 is maintained for at least 4 weeks. Serum CEA levels in these tumor- bearing mice also increase in parallel to the changes observed in tumor. MUC-1 increases 2.5-fold by day 5-7 following RAIT in LS174T tumors and 6-fold by day 14 following RAIT in GW-39 tumors, with a corresponding increase in serum MUC-1. Dramatic increases in CSAp after RAIT were also demonstrated in GW-39 tissue by immunohistochemistry. Thus, these data indicate that the response of tumor cells to low-dose-rate radiation from RAIT or to chemotherapy is associated with an increase of CEA, MUC-1 and CSAp.
INTRODUCTION: Radioimmunotherapy (RAIT) has been shown to enhance the efficacy of chemotherapy in a variety of tumor models. When multiple drugs are available for a given tumor type, several questions arise, such as how one selects the appropriate drug to be used with RAIT, in what sequence to administer the two therapeutic agents and how to space the two modalities. Unique molecular characteristics affecting chemo- and radiosensitivity are found in every tumor. We postulated that the agents and dose scheduling of bimodal RAIT plus chemotherapy might have to be tailored to each tumor based on the expression of specific relevant genes. MATERIALS AND METHODS: To determine whether a single choice of agents and sequence and spacing of agents would be effective in 4 established human ovarian cancer cell lines, the cytotoxic effect of four standard first- and second-line chemotherapeutic agents used to treat ovarian cancer (doxorubicin, carboplatin, paclitaxel, or topotecan) or radioimmunotherapy (90Y-RS-7 IgG anti-EGP1) were evaluated as single agents or as a bimodal therapy. The four human ovarian cancer lines differed with respect to expression of p53 and drug resistance proteins: SKOV3 (p53null, mdr-, mrp+), A2780 (p53wt, mdr+, mrp), IGROV-1 (p53mut, mdr, mrp+), and OVCAR3 (p53mut, mdr-, mrp-). RESULTS: The profile of chemo- and radiosensitivity for the 4 drugs and for RAIT was unique for each of the four tumor lines. As a result, combinations of radio-antibody and chemotherapy that resulted in good growth inhibition in one tumor line were ineffective in another. Several specific synergistic and antagonistic combinations were identified for each of the ovarian cancer cell lines studied. CONCLUSION: These studies provide evidence that individualized bimodal RAIT and chemotherapy has to be used for each tumor. Therefore, the influence of individual molecular traits on growth inhibition effects from different combinations of agents needs to be studied. This work should then permit rational choices of which drug to add to RAIT, which dose-schedule to use (sequential with RAIT first or sequential with drug first) and how to space the two modalities, based on certain phenotypic markers of the tumors.