RESUMO
Glucosylceramide synthase (GCS) is a key enzyme engaged in the biosynthesis of glycosphingolipids and in regulating ceramide metabolism. Studies exploring alterations in GCS activity suggest that the glycolase may have a role in chemosensitizing tumor cells to various cancer drugs. The chemosensitizing effect of inhibitors of GCS (e.g. PDMP and selected analogues) has been observed with a variety of tumor cells leading to the proposal that the sensitizing activity of GCS inhibitors is primarily through increases in intracellular ceramide leading to induction of apoptosis. The current study examined the chemosensitizing activity of the novel GCS inhibitor, Genz-123346 in cell culture. Exposure of cells to Genz-123346 and to other GCS inhibitors at non-toxic concentrations can enhance the killing of tumor cells by cytotoxic anti-cancer agents. This activity was unrelated to lowering intracellular glycosphingolipid levels. Genz-123346 and a few other GCS inhibitors are substrates for multi-drug resistance efflux pumps such as P-gp (ABCB1, gP-170). In cell lines selected to over-express P-gp or which endogenously express P-gp, chemosensitization by Genz-123346 was primarily due to the effects on P-gp function. RNA interference studies using siRNA or shRNA confirmed that lowering GCS expression in tumor cells did not affect their responsiveness to commonly used cytotoxic drugs.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/fisiologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dioxanos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glucosiltransferases/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Pirrolidinas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dioxanos/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Pirrolidinas/administração & dosagem , RNA Interferente Pequeno/farmacologia , Células Tumorais CultivadasAssuntos
Terapias Complementares/estatística & dados numéricos , Linfoma , Sobreviventes/estatística & dados numéricos , Adulto , Idoso , Criança , Comunicação , Terapias Complementares/classificação , Terapias Complementares/psicologia , Cultura , Seguimentos , Conhecimentos, Atitudes e Prática em Saúde , Necessidades e Demandas de Serviços de Saúde , Humanos , Linfoma/classificação , Linfoma/psicologia , Linfoma/terapia , Pessoa de Meia-Idade , Relações Médico-Paciente , Fitoterapia/estatística & dados numéricos , Qualidade de Vida , Inquéritos e Questionários , Sobreviventes/psicologia , Populações VulneráveisRESUMO
BACKGROUND: Non-Hodgkin's lymphoma and multiple myeloma are often incurable and respond to a limited set of treatment options. The selective expression of CD74, the invariant chain of the MHC class II molecule, in these malignancies provides an attractive target for antibody-based therapy. OBJECTIVE: This review evaluates the preclinical data for milatuzumab, a humanized antibody targeting CD74, as a treatment for non-Hodgkin's lymphomas and multiple myeloma. METHODS: A review of the literature was carried out using PubMed. Current Phase I protocols using milatuzumab are summarized. RESULTS/CONCLUSION: Milatuzumab is cytotoxic to lymphoma and multiple myeloma cell lines and mouse-human xenografts. The efficacy dramatically increases when milatuzumab is attached to a toxin or a radioactive agent. Phase I trials of milatuzumab are now underway in human subjects with lymphoma and multiple myeloma.