RESUMEN
This paper reports the synthesis and characterization of a new class of tetrabenzoporphyrins bearing glucosyl or polyamine units on meso positions to improve the targeting of cancer cells. Photocytotoxic activity of these photosensitizers was tested on cell lines HaCaT and MCF-7 and compared to Photofrin II.
Asunto(s)
Derivados del Benceno/química , Glucosa/química , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/uso terapéutico , Poliaminas/química , Porfirinas/química , Animales , Derivados del Benceno/síntesis química , Derivados del Benceno/farmacología , Derivados del Benceno/uso terapéutico , Bioensayo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Glucosa/análogos & derivados , Glucosa/farmacología , Glucosa/uso terapéutico , Humanos , Modelos Químicos , Fármacos Fotosensibilizantes/farmacología , Poliaminas/farmacología , Poliaminas/uso terapéutico , Porfirinas/farmacología , Porfirinas/uso terapéuticoRESUMEN
Porphyrin-polyamine conjugates bearing two (cis or trans position) or four spermidine or spermine units were synthesized. We studied the photostability, the hydrophilic/lipophilic balance of porphyrin-polyamine derivatives and the production of singlet oxygen. All these compounds possess physicochemical features required for their use in PDT. Then, we investigated the photocytotoxic efficacy of these porphyrin-polyamine derivatives and the cell death pathway implicated. All compounds appear to be more efficient than Photofrin® to induce HaCat and MCF7 cell death, essentially by apoptosis. Collectively, these data show that porphyrin-polyamine conjugates could be promising phototherapeutic agents.
Asunto(s)
Apoptosis/efectos de los fármacos , Fotoquímica/métodos , Fármacos Fotosensibilizantes/farmacología , Poliaminas/farmacología , Porfirinas/farmacología , Apoptosis/efectos de la radiación , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular , Línea Celular Tumoral , Femenino , Humanos , Queratinocitos/citología , Queratinocitos/metabolismo , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Fototerapia/métodos , Poliaminas/síntesis química , Poliaminas/química , Porfirinas/síntesis química , Porfirinas/química , Espermidina/química , Espermidina/farmacología , Espermina/química , Espermina/farmacología , EstereoisomerismoRESUMEN
The more distal enhancers of the immunoglobulin heavy-chain 3' regulatory region, hs3b and hs4, were recently demonstrated as master control elements of germline transcription and class switch recombination to most immunoglobulin constant genes. In addition, they were shown to enhance the accumulation of somatic mutations on linked transgenes. Since somatic hypermutation and class switch recombination are tightly linked processes, their common dependency on the endogenous locus 3' enhancers could be an attractive hypothesis. VDJ structure and somatic hypermutation were analyzed in B cells from mice carrying either a heterozygous or a homozygous deletion of these enhancers. We find that hs3b and hs4 are dispensable both for VDJ assembly and for the occurrence of mutations at a physiologic frequency in the endogenous locus. In addition, we show that cells functionally expressing the immunoglobulin M (IgM) class B-cell receptor encoded by an hs3b/hs4-deficient locus were fully able to enter germinal centers, undergo affinity maturation, and yield specific antibody responses in homozygous mutant mice, where IgG1 antibodies compensated for the defect in other IgG isotypes. By contrast, analysis of Peyer patches from heterozygous animals showed that peanut agglutinin (PNAhigh) B cells functionally expressing the hs3b/hs4-deficient allele were dramatically outclassed by B cells expressing the wild-type locus and normally switching to IgA. This study thus also highlights the role of germinal centers in the competition between B cells for affinity maturation and suggests that membrane IgA may promote recruitment in an activated B-cell compartment, or proliferation of activated B cells, more efficiently than IgM in Peyer patches.