Pharmacokinetics,tissue distribution,and in vivo antitumor effects of the antimelanoma immunotoxin ZME-gelonin

Antibody ZME-018 is directed against the gp240 glycoprotein on the surface of more than 80% of human melanoma cell lines and fresh biopsy specimens. Previous studies in our laboratory described the in vitro cytotoxicity and specificity of an immunoconjugate composed of mAb ZME-018 and the plant toxin gelonin. The present study describes the in vivo pharmacokinetics and therapeutic effects of ZME-gelonin in human xenograft/nude mouse models. Pharmacokinetic studies of¹²⁵I-labeled ZME-018 and ZME-gelonin demonstrated a shorter terminal-phase plasma half-life of the immunoconjugate than native ZME (20.6 h compared to 41.3 h). The initial volume of distribution of the ZME-gelonin was also higher compared to that of ZME alone (2.85 ml compared to 1.91 ml) suggesting an enhanced distribution of the conjugate outside the vasculature. The corresponding area under the concentration/time curve for the ZME-gelonin conjugate was 40% lower than that of ZME alone (80.8 compared to 139.6 μCi·ml^?1 x min). In nude mice bearing well-developed human tumor A375 melanoma xenografts, administration of¹²⁵I-labeled ZME and ZME-gelonin resulted in tumor-to-blood ratios of 1.9±0.5 and 1.5±0.6 respectively by 72 h. Compared with ZME, ZME-gelonin conjugate caused an increase in the content of radiolabel in kidney, spleen and liver. Treatment of nude mice bearing well-developed (150 mm³) s.c. A375-M xenografts with divided doses of ZME-gelonin, ZME, gelonin, or saline resulted in suppression of tumor growth in the immunotoxin group but virtually no retardation of tumor growth in the control groups. Using a murine model for a rapidly growing lethal metastatic human melanoma, treatment with ZME-gelonin resulted in a mean survival of 44 days, a 213% increase in mean survival time compared with the saline treatment (14.2±2 day survival). Given these encouraging results, we are proceeding with further preclinical development of this immunotoxin.     

Dancing The Past Into Life: The Rasa,Nrtta and Rāga of Immigrant Existence.

This paper attempts to explore the significant place that Indian ‘classical’ dance has held, both in postcolonial Indian nationalism, and in the middle‐class Indian diaspora's efforts to transmit the cultural past. While arguing that this orientation towards culture as a set of representations signals a fundamental breakdown in a more primary relation to the past, the paper turns to Indian dance and music for a language with which to appreciate both the full magical force of representations and the persistence of a level of embodied experience which is coherent and meaningful without being representational. If the past were available to us only in the form of express recollections, we should be continually tempted to recall it in order to verify its existence, and thus resemble the patient mentioned by Scheler, who was constantly turning round in order to reassure himself that things were really there—whereas in fact we feel it behind us as an incontestable acquisition. (Merleau‐Ponty, 1986:418)     

Untimeliness as Moral Indictment: Tamil Agricultural Labouring Women's Use of Lament as Life Narrative

How do Dalit women forge certain forms of critical perspectives in relation to their existence? This paper explores the very particular poetics that shape the women's responses to an invitation by the ethnographer to tell her their life stories. Their narratives made use of several dominant discourses in south India that ritually construct a woman's life as a teleology of an unfolding essence, an embodied force that comes into flower and fruition, and must be socially shaped and tended in order to bring about an auspicious confluence for both woman and the social order. The women also made use of the structure and tropes of several styles of performance that have tragedy at their emotional heart, and which gain their force against the normative construction of life cycle as temporality. By using these forms, women were able to bring into discourse several aspects of their experience of marriage that would otherwise gain no social recognition. In particular, they highlighted the prematurity of their marriage, having wed while still children themselves. The wider argument of this paper engages with two very different versions of agency—one predicated on the use of reason and consent by the individual, the other derived from an examination of the Dalit women's narratives.     

Sequences in the human immunodeficiency virus type 1 U3 region required for in vivo and in vitro integration.

A series of mutants with alterations in the U3 region of the human immunodeficiency virus type 1 long terminal repeat were made, and the effects of these mutations were evaluated both in vitro and in vivo. When the subterminal 6 to 8 nucleotides of the U3 long terminal repeat were mutated, the resulting provirus was unable to efficiently replicate in vivo, and a mutant oligonucleotide which mimicked the mutation could not be efficiently cleaved but could be joined to target DNA by wild-type recombinant integrase protein in vitro. These results suggest that this region is important in the specific recognition of the viral DNA by the integrase protein.     

Protection against X-ray radiation-induced cellular damage of human peripheral blood lymphocytes by an aminothiazole derivative of dendrodoine

The present study was aimed to evaluate the radioprotective efficacy of dendrodoine analog (DA), an aminothiazole derivative against X-ray radiation-induced cellular damage in cultured human peripheral blood lymphocytes. Different concentrations of DA (2, 4, 6, 8, 10 μg/ml or 6.15, 12.29, 18.44, 24.59, 30.73 μM) were pre-incubated with lymphocytes for 30 min prior to irradiation [4 Gy] and the micronuclei (MN) scoring and comet assay were performed to fix the effective concentration of DA against 4 Gy irradiation-induced cellular damage. The results indicated that among all the concentrations, 6 μg/ml concentration of DA showed optimum protection by effectively decreasing the MN frequencies and comet attributes. Based on the above results, 6 μg/ml concentration of DA was fixed as the effective dose to further investigate its radioprotective efficacy. This was carried out by pre-incubating the lymphocytes with 6 μg/ml concentration of DA followed by exposure of the lymphocytes to different doses (1, 2, 3 and 4 Gy) of radiation and investigating the radiation-induced genetic damage (MN, comet assay, DNA fragmentation assay) and biochemical changes (changes in the level of enzymic and non-enzymic antioxidants, lipid peroxidation). The results indicated a dose-dependent increase in both genetic damage and thiobarbituric acid reactive substances (TBARS), accompanied by a significant decrease in the antioxidant status in the irradiated groups compared to DA treated groups which modulated the toxic effects through its antioxidant potential. Thus the current study shows DA to be an effective radioprotector against X-ray radiation induced in vitro cellular damage in lymphocytes.