Structure activity studies on leaving group derivatives of [meso-1,2-bis-(2,6-dichloro-4-hydroxyphenyl)ethylenediamine] platinum(II).

The spatial structures of leaving group derivatives of [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]platinum(II) (meso-1-PtL2; L2 = SO4, Cl2, I2, CBDC (cyclobutane-1,1-dicarboxylate)) were investigated by NMR methods and correlated with their reactivity against nucleophiles, their estrogenic potency, and their activity on the hormone dependent MCF-7 mammary carcinoma cell line. It was demonstrated that beside the non-leaving group meso-1 the PtL2 moiety of meso-PtL2 complexes is important for the estrogen receptor binding. Among the tested complexes meso-1-PtI2 possesses the highest affinity for the estrogen receptor (RBA = 2.6) and represents a strong estrogen on the MCF-7-2a cell line. The use of CBDC as leaving group decreases the effects. Meso-1-PtCBDC shows an RBA of 0.06 and has only half of the estrogenic activity. Both complexes are sufficiently stable under physiological conditions, so a transformation into the dichloroplatinum(II) complex prior to the binding to the estrogen receptor can be excluded. Due to their high stability meso-1-PtI2 and meso-1-PtCBDC were only marginally active on the human estrogen receptor positive MCF-7 cell line, while meso-1-PtSO4 and meso-1-PtCl2 reduced the cell growth to T/Cmax = 45% and 25%, respectively.

[meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine] sulfatoplatinum(II)--pharmacokinetic studies.

The maximally attainable level of the non-plasma protein bound fraction of a single 10.0 mumol/kg i.p. dose of [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine] sulfatoplatinum(II), a drug active on the murine, hormone-sensitive MXT-M-3.2 breast cancer, lies markedly below the concentration causing a significant cytotoxic effect on a cell line derived from this tumor. This result confirms our opinion that the strong in vivo activity of this drug on hormone-sensitive breast cancers is mediated by its estrogenic potency by analogy with high dosed steroidal and non-steroidal estrogens. A specific cytotoxic effect utilizing the estrogen receptor as carrier, as formerly postulated, is unlikely.

Stability and cellular studies of [rac-1,2-bis(4-fluorophenyl)-ethylenediamine][cyclobutane-1,1- dicarboxylato]platinum(II), a novel, highly active carboplatin derivative.

The synthesis of the diastereomeric [1,2-bis(4-fluorophenyl)ethylenediamine][cyclobutane-1, 1-dicarboxylato]platinum(II) complexes, rac- and meso-4F-Pt(CBDC), the evaluation of their structures, their tumor-inhibiting properties and their stability in physiological environment are described (reference complexes: the dichloro- and sulfatoplatinum(II) analogues, carboplatin and cisplatin). The most interesting diastereomer, rac-4F-Pt(CBDC), equals cisplatin and surpasses carboplatin in its effect on human breast cancer cell lines (MCF-7 and MDA-MB-231). Rac-4F-Pt(CBDC) is largely insensitive against attack of nucleophiles e.g. Cl-, a prerequisite for sufficient stability in vivo and for fewer side effects. In accordance with this, in vitro studies on the binding of rac-4F-Pt(CBDC) to albumin, the main plasma protein, show that the free, non-protein-bound fraction is relatively high, coming close to that of carboplatin. These properties are of importance for the transferability of the promising effects found in the cell culture experiments to in vivo conditions. The distinctly better anti-breast cancer activity of rac-4F-Pt(CBDC) than of carboplatin has been attributed to its ability to accumulate in the tumor cells. The human ovarian cancer cell line NIH-OVCAR-3 is also strongly inhibited by rac-4F-Pt(CBDC).

Synthesis and antitumor activity of [1,2-bis(4-fluorophenyl)ethylenediamine][dicarboxylato]platinum(II) complexes.

The synthesis of the diastereomeric [1,2-bis(4-fluorophenyl)-ethylenediamine][dicarboxylato]platinum(I I) complexes, rac- and meso-4F-Pt(X) [X: oxalato (Ox), malonato (Mal), hydroxymalonato (OHMal), phenylmalonato (PhMal), tetrahydro-4H-pyran-4,4-dicarboxylato (Thpdc)], the evaluation of their structure, water solubility, resistance against attack by nucleophiles, and growth inhibiting properties on the human MCF-7 breast cancer cell line are described [parent compounds: rac-4F-Pt(CBDC) and meso-4F-Pt(CBDC); reference complexes: carboplatin, cisplatin, rac- and meso-4F-PtCl2]. The most active 4F-Pt(X) complexes, rac-4F-Pt(Mal), rac-4F-Pt(OHMal) and rac-4F-Pt(Thpdc), equal the parent compound rac-4F-Pt(CBDC) as well as cisplatin and surpass carboplatin in their effect on the MCF-7 breast cancer cell line. Their water solubility, which is of importance for an application in the cancer chemotherapy, is higher than that of rac-4F-Pt(CBDC), especially in the case of rac-4F-Pt(OHMal) and rac-4F-Pt(Thpdc). In comparison to the dichloroplatinum(II) analogue (4F-PtCl2) the stability of the three compounds in the presence of the strong nucleophile iodide is markedly enhanced, which means a reduction of the protein bound drug fraction in the blood and tissue compartments accompanied by an increase of the active, free drug level. The found physiochemical properties of these compounds meet the requirements for the transferability of their promising breast cancer inhibiting effects detected in cell culture experiments to in vivo conditions.

Development of a parenterally administrable hydrosol preparation of the "third generation platinum complex" [(+/-)-1,2-bis(4-fluorophenyl)ethylenediamine]dichloroplatinum(II). Part 1. Preparation and studies on the stability and antitumor activity.

The development of a galenical formulation for poorly water soluble dichloroplatinum(II) complexes suitable for the parenteral administration in cancer chemotherapy is described. The procedure, which we elaborated for [(+/-)-1,2-bis(4-fluorophenyl)ethylenediamine]dichloroplatinum(II) (rac-4F-PtCl2), is based on the reaction of a soluble diaquaplatinum(II) salt with sodium chloride in water in the presence of pluronic F 68 as stabilizer and results in a sufficiently stable colloidal solution (i.e. hydrosol). In contrast to the poorly water soluble synthetic rac-4F-PtCl2, which was ineffective towards the hormone sensitive MXT-M-3.2 breast cancer of the mouse, its hydrosol formulation proved to be highly active and was very well tolerated.

Histological appearance of the synovium in early rheumatoid arthritis.

This report reviews and discusses studies on the synovial fluid and biopsy specimens of synovial membrane obtained during the first 6 weeks of synovitis that evolved into rheumatoid arthritis (RA). Five previously unreported cases are described. Early changes in the microvasculature and synovial lining seem to antedate the classical chronic inflammation of established RA. Further characterization in the joint tissues in very early RA offers opportunities for identification of exogenous triggers and may allow more appropriate targeting of early therapy to potentially reversible aspects of pathogenesis.

Chrysotherapy in psoriatic arthritis. Efficacy and toxicity compared to rheumatoid arthritis.

Chrysotherapy was given to 14 patients with refractory psoriatic polyarthritis and to a comparable group of 42 patients with rheumatoid arthritis. The psoriatic patients had a higher rate of remission on gold and less severe toxicity than the rheumatoid arthritis patients. Psoriatic skin lesions were not affected by chrysotherapy.

Eosinophilic fasciitis.

A detailed evaluation of the clinical and histologic manifestations of eosinophilic fasciitis is described in a 22-year-old woman. Scleroderma-like skin involvement is associated with eosinophilia and hypergammaglobulinemia. Visceral and serologic manifestations of a generalized scleroderma are lacking. Results of a biopsy showed severe thickening of the deep fascia accompanied by an infiltration of lymphocytes and plasma cells. This syndrome must be differentiated from generalized scleroderma because eosinophilic fascitis has a benign course and may benefit from systemic corticosteroid therapy.

The arthritis of Sweet's syndrome.

A detailed evaluation of the articular manifestations of Sweet's syndrome is described in a 24-year-old man. Fever, mild leukocytosis, tender cutaneous erythematous plaques or nodules with neutrophilic infiltration were accompanied by multiple painful, swollen joints. A knee effusion contained 1,575 leukocytes with many large phagocytic cells. Since it may include significant articular disease, rheumatologists should be aware that this syndrome does exist.