RESUMO
The murine antibody 30.6 recognizes an antigen that is expressed on a high proportion of colorectal carcinomas and their metastases. We report the results of single-dose escalation studies of the chimeric 30.6 (c30.6) monoclonal antibody in metastatic colorectal cancer, to evaluate its safety, pharmacokinetics, and biodistribution. Recombinant c30.6 (IgG1kappa) antibody was secreted from Chinese hamster ovary cells and purified by a multistep chromatography process. Seventeen patients with metastatic colorectal cancer were enrolled in this dose escalation study. The first four patients were treated with 3 mg of 123I-labeled c30.6, whereas the next 13 received a single dose of unlabeled antibody (maximum dose, 50 mg/m2). The most frequent side effect was a novel syndrome of severe burning and erythema of the face, chest, neck, ears, palms, soles, and genitalia. The frequency of this syndrome was markedly reduced in those patients premedicated with high doses of histamine receptor 1 and histamine receptor 2 blockers. Other side effects were mild and predictable. Biodistribution studies showed a rapid and intensive hepatic uptake. At the 50 mg/m2 level the half-life and maximum serum concentration were 81 +/- 15 h and 7.9 microg/ml, respectively. One patient developed a low-level human anti-c30.6 response. Tumor response was assessed by computed tomography, positron emission tomography scanning, and serial carcinoembryonic antigen measurements. There were no partial responses, although positron emission tomography scanning demonstrated some reduction in tumor activity in three individuals. The chimerized c30.6 antibody is not immunogenic in humans and appears worthy of further study. It does, however, produce a unique profile of side effects that can be well controlled with premedication.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/terapia , Adulto , Idoso , Animais , Anticorpos Monoclonais/efeitos adversos , Células CHO , Cromatografia , Cromatografia em Gel , Cricetinae , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Radioisótopos do Iodo/metabolismo , Fígado/efeitos dos fármacos , Masculino , Camundongos , Pessoa de Meia-Idade , Metástase Neoplásica , Fatores de Tempo , Tomografia Computadorizada de Emissão , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Disease-oriented panels of human tumor cell lines used by the National Cancer Institute for large-scale in vitro anticancer drug screening were evaluated for multidrug-resistant phenotype at the functional (in vitro drug sensitivity) and molecular levels. The cell line panels manifested a broad range of sensitivities to drugs typically associated with multidrug resistance (MDR) as well as to drugs not associated with MDR. Individual cell lines displayed unique and characteristic profiles of response. Patterns of correlated response were observed among, but not between, MDR and non-MDR drugs. Strong evidence of correlated response was limited to drugs sharing an intracellular mechanism of action. Several tumor cell lines exhibited a high degree of resistance to MDR drugs and relative sensitivity to non-MDR drugs, contained high levels of MDR-1 mRNA, and expressed cell surface P-glycoprotein detectable with one or more monoclonal antibodies. Parallel expression of all of these features representing the classic MDR phenotype was observed among members of the colon and renal tumor panels. Certain individual cell lines among other panels (lung, ovarian, melanoma, and central nervous system) also manifested some aspects of the MDR phenotype to various extents. Identification of MDR cell lines used for large-scale in vitro anticancer drug screening will facilitate interpretation of data in a way which may allow identification of new drug leads of potential value in treatment of MDR tumor cell populations.
Assuntos
Antineoplásicos/farmacologia , Resistência a Medicamentos/genética , Ensaios de Seleção de Medicamentos Antitumorais , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Anticorpos Monoclonais , Sequência de Bases , Linhagem Celular , DNA de Neoplasias/genética , Humanos , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/genética , Dados de Sequência Molecular , Neoplasias , Oligodesoxirribonucleotídeos , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
A sensitive DNA dot-blot assay for repetitive human DNA sequences was developed and applied to the quantitative determination of spontaneous metastases of a human melanoma in various tissues of nude mice. The assay was useful for defining the time course and pattern of tissue distribution of metastatic cells as well as for assessing response to therapy. The methodology is relatively simple, can be performed using nonradioactive DNA probes, and should be broadly applicable to studies of metastasis of human tumors in nude mice.
