Monolithic triglyceride matrices: a controlled-release system for proteins

Matrices made of glyceryl trimyristate as a bioerodible and biocompatible material were manufactured by compression in dimensions that would still allow an application via injection. Pyranine, as a low molecular hydrophilic compound with a low detection limit, and tetramethylrhodamine labeled bovine serum albumin (TAMRA-BSA), as a high molecular weight (66 kDa) protein compound, served as model drugs for release investigations. In vitro studies with pyranine revealed that release depends substantially on the gelatin content of the matrices, which proved to be a useful tool as a release modifier. The duration of the drug release period can be adjusted to a desired time interval ranging from days to weeks by choosing the right gelatin content. Moreover, results illustrated the importance of the molecular weight and the nature of the compound to be incorporated into such matrices, since investigations with TAMRA-BSA showed a more pronounced burst release and altered release profiles and periods. Experiments with hyaluronidase, which served as a model enzyme to assess the problem of protein integrity in such matrices, suggested that proteins may display sufficient stability during the manufacturing procedure of the cylinders or while in contact with the triglyceride matrices. In addition to in vitro investigations, a study in mice revealed that after 15 days of subcutaneous implantation the matrices showed a good in vivo stability. The main conclusion that could be drawn from these results was that triglycerides are a promising alternative to biodegradable polymers for the development of parenteral release systems for protein and peptide drugs

Hyaluronidase enhances the activity of adriamycin in breast cancer models in vitro and in vivo

The effect of hyaluronidase and a combination of hyaluronidase with Adriamycin was investigated on several breast cancer models in vitro and in vivo. In vitro enzyme treatment (using concentrations up to 80,000 IU/1) of murine (MXT-, MXT +/-, and MXT+) and human (MCF-7, ZR-75-1 and T-47-D) breast cancer cell lines did not inhibit tumour cell proliferation (measured by a kinetic crystal violet assay) in either case. Although high-dose hyaluronidase (1.2 x 10(6) IU/kg) was ineffective, when administered peritumourally to the MXT M3.2 mammary carcinoma of the B6D2F1 mouse, it is remarkable that five "megadoses" were excellently tolerated. However, the antineoplastic activity of Adriamycin against the oestrogen-receptor-positive variant of the MXT tumour was significantly enhanced by combination with concentrations of hyaluronidase that were inactive per se, both in vitro and in vivo. Interestingly, the enhancement of the in vivo antitumour activity was not compromised by toxic side-effects

DNA-Interaction, Estrogen Receptor Affinity, and Cytostatic Activity of 1,3-Diphenylpropane-1,3-diamine-Pt(II) Complexes

The Pt(II) complexes of 1,3-diphenylpropane-1,3-diamines (part IV 2)) were tested for DNA interaction (UV-difference spectroscopy, Tables 1 and 2), for affinity to the estrogen receptor (calf uterus cytosol; scarcely any affinity), and for cytostatic activity at estrogen independent MDA-MB 231 cells (Tables 3 and 4) and estrogen dependent MCF-7 cells (Tables 5 and 6). The data are compared with those reported for the analogous 1,2-diphenylethane-1,2-diamine-Pt(II) complexes: most probably, the cytostatic activity is not mediated by the estrogen receptor. Die in der 4. Mitt. 2) beschriebenen 1,3-Diphenylpropan-1,3-diamin-Pt(II)-Komplexe wurden auf Wechselwirkungen mit DNS (UV-Differenzspektroskopie, Tab. 1 und 2), auf Affinität zum Estrogenrezeptor (Kalbsuterus-Cytosol, fast keine Affinität) und auf cytostatische Aktivität an der Estrogen-unabhängigen MCF-MB 231 Zellinie (Tab. 3 und 4) bzw. an Estrogen-abhängigen MCF-7 Zellen (Tab. 5 und 6) geprüft. Die Ergebnisse werden mit Lit. Angaben über die analogen 1,2-Diphenyllethan-1,2-diamin-Pt(II)-Komplexe verglichen: die cyostatische Aktivität ist sehr wahrscheinlich nicht Estrogenrezeptor-vermittelt

Platinum(II) complexes interfering with testicular steroid biosynthesis: drugs for the therapy of advanced or recurrent prostate cancers? Preclinical studies

[Meso-1,2-bis(2,6-dihalo-3/4-hydroxyphenyl)ethylenediamine]platinum(II) complexes (meso-1-PtLL': 2,6-F(2),3-OH; meso-2-PtLL': 2,6-F(2),4-OH; meso-3-PtLL': 2,6-Cl(2),3-OH; meso-4-PtLL': 2,6-Cl(2),4-OH; L = OH(2), L' = OSO(3) or L,L' = Cl(2)) were designed with the aim to get drugs comprising both cytotoxic and testosterone level lowering potencies. It is assumed that such compounds are more efficient than the established endocrine therapeutic measures and can affect the development of hormone refractory prostate cancer (PC). With exception of meso-3-PtLL' all Pt-complexes and the comparison compound cisplatin significantly reduced the testosterone level in experiments on male rats. However, in the test on the Dunning R3327 PC of the rat only cisplatin and meso-4-PtLL' showed a significant anti-tumor activity at well-tolerated dose ranges. Meso-4-PtLL' also significantly extended the time to disease progression in comparison with orchiectomy in this tumor model. Interestingly, the relapsed tumor, too, responded to meso-4-PtLL' as demonstrated in a long-term study on orchiectomized rats bearing Dunning R3327 PC grafts. This effect cannot be ascribed to cytotoxic effects of meso-4-PtLL' because of its inactivity on the human LNCaP/FGC PC cell line. Therefore, the contribution of an additional mechanism to the anti-prostate cancer activity of meso-4-PtLL', presumably owing to its estrogenic potency, must be considered. This assumption was supported by test results with diethylstilbestrol (DES) (non-steroidal estrogen) on the Dunning R3327 PC of the rat relapsed after orchiectomy. This tumor model was strongly inhibited by DES. The possible mode of action of meso-4-PtLL' is thoroughly discussed