Summary Inhibition of angiogenesis through blocking of growth factors involved in this process could be a novel therapeutic approach in several important pathologies, neoplasia among them. Suramin has recently been described to possess antineoplastic activity in animals and humans, and it has been proposed that an important role in this activity is played by antagonism of growth factors and especially bFGF. To investigate this hypothesis in vivo, we used gelatin sponges loaded with bFGF and implanted subcutaneously in mice. Suramin showed an inhibitory activity on bFGF-induced angiogenesis, whereas it was inactive in the case of heparin-complexed bFGF. Suramin was also studied in an in vivo model of tumour-induced angiogenesis using the murine M5076 reticulosarcoma, a tumour producing significant levels of bFGF. Suramin was able to reduce tumour growth and tumour induced angiogenesis, and exogenous administration of bFGF countered suramin effects.Physiologically, angiogenesis (i.e. the formation of new capillary vessels), is an important event in embryonic development and in the adult female reproductive cycle (Gospodarowicz & Thakral, 1978). Under pathological conditions neovascularisation occurs during the wound healing process (Knighton, 1981) and in a variety of diseases ranging from diabetic retinopathy to psoriasis and several types of chronic inflammations (Goldie, 1969). It has also been shown that the process of solid tumours growth is angiogenesisdependent (Gullino, 1978;Folkman, 1990). Several substances of different chemical nature and cellular origin, including growth factors produced by the neoplastic cells themselves, have been described to be involved in tumourinduced neoangiogenesis (Shing et al., 1985;Folkman & Klagsbrun, 1987) by directly and/or indirectly stimulating endothelial cells proliferation and/or migration (Ausprunk & Folkman, 1977). One of the better characterised among such angiogenic factors is basic Fibroblast Growth Factor (bFGF) (Rifkin & Moscatelli, 1989), whose presence in a large number of normal and malignant cells is well established, and that has been implicated as a major contributing factor in both physiological and pathological neovessel formation (Folkman et al., 1988;Klagsbrun et al., 1986;Thompson et al., 1988;Hayek et al., 1987). Since solid tumour growth and progression are strictly dependent from neovessel formation (Folkman et al., 1989;Brem et al., 1977) interfering with this process by counteracting the effect of angiogenic growth factors could represent a novel and selective therapeutic approach to malignancy.Suramin, a polysulphonated trypan red derivative used in the past as antitrypanosomic agent (Hawking et al., 1987), has recently generated interest as an antinoplastic agent (Stein et al., 1989;Myers et al., 1990; Richard, 1990;Hosang, 1985;Mills et al., 1990) to their cell surface receptors through direct complexation of the growth factors and/or via a modification of the cell receptor (Coffey et al., 1987). This activity could explain suramin inhibitio...
A rat model was used to evaluate the general acute toxicity and the late cardiotoxicity of 4 mg/kg doxorubicin (DOX) given either as free drug or in the form of three N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates. In these HPMA copolymers, DOX was covalently bound via peptide linkages that were either non-biodegradable (Gly-Gly) or degradable by lysosomal proteinases (Gly-Phe-Leu-Gly). In addition, one biodegradable conjugate containing galactosamine was used; this residue was targeted to the liver. Over the first 3 weeks after the i.v. administration of free and polymer-bound DOX, all animals showed a transient reduction in body weight. However, the maximal reduction in body weight seen in animals that received polymer-bound DOX (4 mg/kg) was significantly lower than that observed in those that received free DOX (4 mg/kg) or a mixture of the unmodified parent HPMA copolymer and free DOX (4 mg/kg; P less than 0.01). Throughout the study (20 weeks), deaths related to cardiotoxicity were observed only in animals that received either free DOX or the mixture of HPMA copolymer and free DOX; in these cases, histological investigations revealed marked changes in the heart that were consistent with DOX-induced cardiotoxicity. Sequential measurements of cardiac output in surviving animals that received either free DOX or the mixture of HPMA copolymer and free DOX showed a reduction of approximately 30% in function beginning at the 4th week after drug administration. The heart rate in these animals was approximately 12% lower than that measured in age-matched control rats (P less than 0.05). Animals that were given the HPMA copolymer conjugates containing DOX exhibited no significant change in cardiac output throughout the study (P less than 0.05). In addition, no significant histological change was observed in the heart of animals that received DOX in the form of HPMA copolymer conjugates and were killed at the end of the study. However, these animals had shown a significant increase in heart rate beginning at 8 weeks after drug administration (P less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)
FCE 24157 (chemically (beta-[1-methyl-4-(1-methyl-4--[1-methyl-4-(4-N,N- bis(2-chloroethyl) amino-benzene-1-carboxy-amido) pyrrole-2-carboxiamido]pyrrole-2-carboxyamido)pyrrole-2-c arboxyamido]) propionamidine, hydrochloride) is a distamycin A (Dista A) derivative bearing a benzoyl mustard moiety instead of the formyl group at the N-terminal. Contrary to Dista A, FCE 24517 has been found to display potent cytotoxic activity on human and murine tumour cell lines. The compound maintains activity on melphalan (L-PAM)-resistant cells, whereas cross-resistance is observed on doxorubicin-(DX)-resistant cells. In vivo, FCE 24517 was found to possess evident antineoplastic activity on a series of murine transplanted solid tumours and human tumour xenografts. The following neoplasms were in fact found to be sensitive to FCE 24517 treatment: M14 human melanoma xenograft, N592 human small cell lung carcinoma, MTV murine mammary carcinoma, Colon 38 murine carcinoma, PO2 murine pancreatic carcinoma and M5076 murine reticulosarcoma. Lower effectiveness was observed against the murine P388 and Gross leukaemia, Lewis lung murine carcinoma, LoVo human colon carcinoma xenografts and A459 human lung adenocarcinoma. Against the murine L1210 leukaemia, FCE 24517 displayed a clear activity only when the tumour was transplanted i.p. and treatment was given i.p., whereas only marginal activity was seen against this leukaemia if transplanted i.v. and the drug was given i.v. As true also in vitro, FCE 24517 was effective against i.p. implanted L1210 leukaemia resistant to L-PAM. The mode(s) of action of this new compound is under active investigation.
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