RESUMO
Matrix metalloproteinase (MMP)-activated prodrugs were formed by coupling MMP-cleavable peptides to doxorubicin. The resulting conjugates were excellent in vitro substrates for MMP-2, -9, and -14. HT1080, a fibrosarcoma cell line, was used as a model system to test these prodrugs because these cells, like tumor stromal fibroblasts, expressed several MMPs. In cultured HT1080 cells, simple MMP-cleavable peptides were primarily metabolized by neprilysin, a membrane-bound metalloproteinase. MMP-selective metabolism in cultured HT1080 cells was obtained by designing conjugates that were good MMP substrates but poor neprilysin substrates. To determine how conjugates were metabolized in animals, MMP-selective conjugates were given to mice with HT1080 xenografts and the distribution of doxorubicin was determined. These studies showed that MMP-selective conjugates were preferentially metabolized in HT1080 xenografts, relative to heart and plasma, leading to 10-fold increases in the tumor/heart ratio of doxorubicin. The doxorubicin deposited by a MMP-selective prodrug, compound 6, was more effective than doxorubicin at reducing HT1080 xenograft growth. In particular, compound 6 cured 8 of 10 mice with HT1080 xenografts at doses below the maximum tolerated dose, whereas doxorubicin cured 2 of 20 mice at its maximum tolerated dose. Compound 6 was less toxic than doxorubicin at this efficacious dose because mice treated with compound 6 had no detectable changes in body weight or reticulocytes, a marker for marrow toxicity. Hence, MMP-activated doxorubicin prodrugs have a much higher therapeutic index than doxorubicin using HT1080 xenografts as a preclinical model.
Assuntos
Doxorrubicina/análogos & derivados , Fibrossarcoma/tratamento farmacológico , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Metaloendopeptidases/metabolismo , Fragmentos de Peptídeos/farmacologia , Pró-Fármacos/farmacologia , Animais , Doxorrubicina/síntese química , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Fibrossarcoma/metabolismo , Humanos , Metaloproteinases da Matriz Associadas à Membrana , Camundongos , Neprilisina/farmacologia , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Reticulócitos/efeitos dos fármacos , Reticulócitos/metabolismo , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
This study assessed the behavior of infants whose mothers had a drug history by using the Neonatal Behavioral Assessment Scale. Data were collected via retrospective chart review (N = 103). Urine testing was only reported for 66 mothers during pregnancy and at birth. Infants performed within normally expected ranges for all items, except consolability and self-quieting. These findings support the use of NBAS in assessing newborn behavior because the information gained assists the parent in providing a supportive care giving environment that will not only help the infant recover but also enhance interaction between infant and parent.
