No abstract

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...

Summary.-We investigated the metastasizing capacity of spontaneous lung metastases from the MN/MCA1 and mFS6 sarcomas, the B16 melanoma and colon 26 carcinoma. Spontaneous metastases at other visceral organs (liver, spleen, kidney, ovary, uterus) from the M5076/73A (M5) ovarian carcinoma and colon 26 carcinoma were also studied. Tumour cells from individual spontaneous metastases were used immediately after isolation from the normal parenchyma (mFS6, M5 and colon 26) and/or after 1 s.c. passage in syngeneic mice (MN/MCA1, mFS6, B16 and M5). Spontaneous metastases were examined for all tumours and their secondaries after i.m. or s.c. inoculation of tumour cells; artificial lung colonies were measured after i.v. injection only of cells from the primary mFS6 and MN/MCA1 and B16 or their spontaneous metastases.Individual spontaneous metastases were to some extent heterogeneous in their metastatic potential, a minority of the secondaries having greater or lesser metastatic capacity than the appropriate primary. Overall, tumour cells from spontaneous metastases did not show greater metastasizing capacity than primary neoplasms, nor was there evidence that metastases from specific organs (e.g. spleen and kidney) tended to home to the specific anatomical sites from which they were originally isolated.These observations in a series of murine tumours of different histology, transplantation history and pattern of metastasis, do not support the hypothesis that metastases are the ultimate expression of strong selection of variant cells with greater intrinsic metastatic potential, pre-existing within the primary tumour.

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)

Soluble polymer conjugates have only recently been introduced into clinical practice. They can be subdivided into 2 main categories: polymer-protein conjugates, so far the most widely studied; and polymer-drug conjugates, particularly those containing conventional antitumour agents, that are still at an early stage of development. Polymer conjugation can be used to alter the biodistribution, elimination and rate of metabolism of covalently bound drugs. In the case of protein adducts, polymer conjugation prolongs the protein plasma elimination half-life (5- to 500-fold increases in elimination half-life have been reported), reduces proteolytic degradation and has the added benefit of reducing immunogenicity. Cellular uptake of low molecular weight drugs convalently bound to polymeric carriers is restricted to the endocytic route. Thus, the organ and subcellular distribution of the drug can be modified. Cellular uptake has been used to facilitate drug targeting and decreased toxicity. In this review, the theoretical rationale for polymer conjugation is described, as is the limited clinical pharmacokinetic experience with polymer conjugates. As an alteration of the pharmacokinetic profile of a drug was one of the underlying arguments for creation of polymeric conjugates, more clinical pharmacokinetic studies are urgently needed to permit the validation of appropriate pharmacokinetic models that can be used in the future to assist in the optimisation of clinical protocols, and improved conjugate design.