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J Exp Med ; 180(3): 1047-57, 1994 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-8064224


Transforming growth factor beta 1 (TGF-beta 1) and TGF-beta 2 can reversibly inhibit the proliferation of hematopoietic progenitor cells in vivo, leading us to hypothesize that such quiescent progenitors might be more resistant to high doses of cell cycle active chemotherapeutic drugs, thereby allowing dose intensification of such agents. Initial studies showed that whereas administration of TGF-beta 1 or TGF-beta 2 did not prevent death in normal mice treated with high doses of 5-fluorouracil (5-FU), those mice that received TGF-beta 2 did exhibit the beginning of a hematologic recovery by day 11 after administration of 5-FU, and were preferentially rescued by a suboptimal number of transplanted bone marrow cells. Subsequently, it was found that the administration of TGF-beta 2 protected recovering progenitor cells from high concentrations of 5-FU in vitro. This protection coincided with the finding that significantly more progenitors for colony-forming unit-culture (CFU-c) and CFU-granulocyte, erythroid, megakaryocyte, macrophage (GEMM) were removed from S-phase by TGF-beta in mice undergoing hematopoietic recovery than in normal mice. Further studies showed that the administration of TGF-beta protected up to 90% of these mice undergoing hematologic recovery from a rechallenge in vivo with high dose 5-FU, while survival in mice not given TGF-beta was < 40%. Pretreatment of mice with TGF-beta 1 or TGF-beta 2 also protected 70-80% of mice from lethal doses of the noncycle active chemotherapeutic drug, doxorubicin hydrochloride (DXR). These results demonstrate that TGF-beta can protect mice from both the lethal hematopoietic toxicity of 5-FU, as well as the nonhematopoietic toxicity of DXR. This report thus shows that a negative regulator of hematopoiesis can be successfully used systemically to mediate chemoprotection in vivo.

Doxorrubicina/toxicidad , Fluorouracilo/toxicidad , Factor de Crecimiento Transformador beta/farmacología , Animales , Médula Ósea/efectos de los fármacos , Trasplante de Médula Ósea , División Celular/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/fisiología , Ratones , Ratones Endogámicos BALB C , Proteínas Recombinantes/farmacología
Cancer Res ; 45(3): 1058-65, 1985 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-3155990


In this report, we describe the immunomodulatory characteristics of poly(I,C)-LC, a synthetic, double-stranded nucleic acid polymer, polyinosinic-polycytidylic acid, that is complexed with poly-L-lysine and solubilized by the addition of carboxymethylcellulose. We consistently observed, both in vitro and in vivo, stimulation of macrophage cytotoxicity and augmentation of natural killer-cell activity by poly(I,C)-LC. This immunomodulator also increased the allogeneic mixed-lymphocyte response, without any blastogenic effect on responder cells cultured in the absence of allogeneic stimulator cells. Further, the addition of poly(I,C)-LC to an allogeneic mixed-lymphocyte tumor reaction did not stimulate the development of cytotoxic effector T-cells. Poly(I,C)-LC did, however, have adjuvant activity when admixed with irradiated tumor cells in the immunization of syngeneic mice. Unlike classic adjuvants, poly(I,C)-LC also enhanced the development of specific cytotoxic T-lymphocytes when it was injected either i.v. or i.p. in conjunction with a vaccine delivered at an intradermal site. The results indicate that poly(I,C)-LC has considerable potential as an immunotherapeutic agent, with the ability not only to induce macrophage and NK cell activation but also to stimulate specific cytotoxic T-lymphocytes.

Adyuvantes Inmunológicos/farmacología , Carboximetilcelulosa de Sodio/farmacología , Inductores de Interferón/farmacología , Metilcelulosa/análogos & derivados , Péptidos/farmacología , Poli I-C/farmacología , Polilisina/farmacología , Animales , Citotoxicidad Inmunológica/efectos de los fármacos , Células Asesinas Naturales/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Prueba de Cultivo Mixto de Linfocitos , Activación de Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Linfocitos T/efectos de los fármacos