Effect of metal containing compounds on superoxide release from phorbol myristate acetate stimulated murine peritoneal macrophages: inhibition by auranofin and spirogermanium.

A variety of metal containing compounds were examined for their ability to inhibit the respiratory burst of murine peritoneal macrophages. Auranofin (AF), a gold containing complex used in the treatment of rheumatoid arthritis, is a potent inhibitor of the macrophage respiratory burst. Ten rhodium, iridium, osmium and ruthenium containing complexes were inactive in inhibiting superoxide production. The only active nongold organometallic complex was spirogermanium which had an equivalent IC50 for activity as AF. The inhibitory activity of AF, but not spirogermanium, was reduced in the presence of the sulfhydryl reducing agent dithiothreitol. This suggests that interactions other than those with sulfhydryl groups may be involved in the action of spirogermanium.

Advances in platinum cancer chemotherapy. Advances in the design of cisplatin analogues.

In the past 4 years substantial progress has been made in the development of platinum cancer chemotherapy. A number of drug candidates have undergone clinical trials and one 'second generation' platinum drug, carboplatin, has been approved for use in the treatment of ovarian and small cell lung cancer. This review covers the major developments since the last international conference on Platinum Chemotherapy in Vermont, and attempts to highlight the primary factors that appear to be influencing the synthesis and screening of potential third generation platinum drugs. A predominant feature in the evaluation of analogues has been the emphasis on chelating diamine complexes, in particular those of diaminocyclohexane, which show activity in L1210 tumours that are resistant to cisplatin, and the use of a wide range of carboxylate ligands as a means of circumventing solubility and toxicity problems inherent in the parent compounds. There has also been an increased effort in studies relating to complexes containing mixed amines and functionalised amines, building on the assumption, which remains valid to date, that two amines are a necessary requirement for anti-tumour activity. Efforts have also been made to address the use of complexes containing biologically active ligands, and the concept of targeting compounds to specific organs and formulating drugs to achieve more specific activity or controlled release of drugs with lower toxicities. These may provide a viable route to drugs that can be administered more easily, for example by an oral route, or show a different spectrum of activity. However, it may prove difficult to adequately characterise these more complex systems. The major problem encountered in evaluating cisplatin analogues, as with other prospective cancer drugs, is finding reproducible anti-tumour screens that are predictive of the behaviour of the drugs in the clinic. Progress is being made in the development of sensitive and resistant human tumour xenograft lines and this area should be monitored with interest, as it may provide a key to the development of a future platinum drug, hopefully with a wider range of activity than either cisplatin or carboplatin.

Antileukemia (L1210) activity and toxicity of cis-dichlorodiammineplatinum(II) analogs.

cis-Dichlorodiammineplatinum(II) (cis-platinum) and 40 of its analogs were evaluated for antitumor activity in BDF1 mice implanted ip with 10(6) L1210 leukemia cells. Several of these analogs were also evaluated for their ability to cause elevation in BUN and to produce leukopenia in normal BDF1 mice. In 11 experiments, cis-platinum given on Day 1 or Days 1--9 after implant produced T/C (treated/control) values between 164% and 214% and 157% and 285% respectively. On the basis of single experiments, 13 analogs were judged to be comparable to cis-platinum in that they produced T/C values greater than or equal to 167% after a single dose or greater than or equal to 200% after daily doses for 9 days. These active compounds included various substituted amine derivatives of dichloroplatinum(II), malonatoplatinum(II), aquasulfatoplatinum(II), and chloroacetatoplatinum(II) and derivatives of dihydroxydichloroplatinum(IV). Twelve of these active analogs and cis-platinum were evaluated for toxicity at doses ranging from near the optimal therapeutic dose to greater than or equal to the LD50. Only five of the 12 analogs and cis-platinum caused an increase in BUN to greater than 30 mg/100 ml, while eight of the analogs produced leukopenia comparable in incidence and severity to that produced by cis-platinum.