RESUMO
Conjugates of 1-beta-D-arabinofuranosylcytosine (araC) with two polysaccharides such as polygalacturonic acid (PGA) and carboxymethylated yeast beta-D-glucan (CMG) were tested for their antileukemic activity in vitro on a L1210 cell line in suspension culture, in soft agar assay and in vivo on L1210, L1210/araC- and P388-leukemia-bearing mice. Both conjugates showed high activity in vitro in soft agar assay, compared with araC. Single administration of PGA-araC or CMG-araC increased the survival time 1.5 x or 1.7 x, respectively, compared with araC in vivo in L1210-leukemia-bearing mice. The conjugates were not active against araC-resistant leukemia line L1210/araC. The marked effect of both PGA-araC and CMG-araC against leukemia L1210 and P388 is probably due to the prolonged release of free araC from conjugates caused by hydrolysis.
Assuntos
Citarabina/análogos & derivados , Glucanos/uso terapêutico , Leucemia L1210/tratamento farmacológico , Leucemia P388/tratamento farmacológico , Pectinas/uso terapêutico , beta-Glucanas , Animais , Citarabina/uso terapêutico , DNA/biossíntese , Feminino , Leucemia L1210/metabolismo , Leucemia P388/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBARESUMO
1. Conjugates of 1-beta-D-arabinofuranosylcytosine (araC) with polysaccharides containing carboxyl groups, such as polygalacturonic acid (PGA) and carboxymethylated yeast beta-D-glucan (CMG) were prepared. 2. Activation of the polysaccharidic carboxyl group by isobutylchloroformiate and formation of a peptide bond via 4-NH2 group of araC was used for a coupling reaction. 3. Elementary analysis, u.v. and i.r. spectra confirmed the structures of the conjugates. 4. The conjugates were most stable against the hydrolysis under the mild acid conditions. 5. It was also shown that under the physiological conditions trypsin catalyze the conjugate hydrolysis and the catalytic effect is higher than that of chymotrypsine. 6. It is suggested that trypsin or trypsin-like proteases could participate in the hydrolysis of the conjugates in vivo. PGA-araC and CMG-araC showed 1.5- or 2.5-times higher antileukemic activity than both free araC or polysaccharides.
Assuntos
Antineoplásicos/uso terapêutico , Citarabina/metabolismo , Glucanos/metabolismo , Leucemia L1210/tratamento farmacológico , Pectinas/metabolismo , beta-Glucanas , Animais , Antineoplásicos/química , Citarabina/análogos & derivados , Citarabina/química , Citarabina/uso terapêutico , Feminino , Glucanos/química , Glucanos/uso terapêutico , Hidrólise , Masculino , Camundongos , Camundongos Endogâmicos DBA , Nitrogênio/análise , Pectinas/química , Pectinas/uso terapêutico , Espectrofotometria Infravermelho , Espectrofotometria UltravioletaRESUMO
The following platinum complexes have been tested: cis-DDP--cis-diamminedichloroplatinum(II), Platinex--1,2-diaminocyclohexaneplatinum(II)citrate, Platuran--1,2-diaminocyclohexaneplatinum(II)-glucarate , TMA--1,2-diaminocyclohexaneplatinum(II)-4-carboxyphthalate,o xo-PT--cis-diamminedichloro-trans-dihydroxyplatinum(IV), CHIP--cis-dichloro-bis-(isopropylamine)-trans-dihydroxyplatinum(IV ), CBDCA--cis-diammine-cyclobutane-1,1-dicarboxylatoplatinum(II ). The activity of all tested complexes againt L1210 cells was higher in soft agar colony assay when compared with suspension culture of the same target cells. Using various doses and schedules oxo-Pt, CBDCA and cis-DDP exhibited the highest in vivo activity against P388 leukemia.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia L1210/tratamento farmacológico , Leucemia P388/tratamento farmacológico , Leucemia Experimental/tratamento farmacológico , Compostos Organoplatínicos/uso terapêutico , Platina , Animais , Carboplatina , Linhagem Celular , Cisplatino/análogos & derivados , Cisplatino/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Feminino , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos DBARESUMO
In vitro drug resistance was induced against cis-diamminedichloroplatinum(II) (cis-DDP), 1,2-diaminocyclohexaneplatinum-(II)citrate (PEX) and 1,2-diaminocyclohexaneplatinum(II)glucarate (PTU) in L1210 leukemia cell line. Using the resistant sublines cross-resistance was found between cis-DDP and cis-diamminecyclobutane-1,1-dicarboxylatoplatinum(II) (CBDCA) and between the three 1,2-diaminocyclohexane (DACH) derivatives tested. No (or low degree) cross-resistance was found between cis-DDP and DACH derivatives.