Cis-platinum Diamminedichloride Research Articles

Inhibition studies of S-adenosylhomocysteine hydrolase purified from Acinetobacter calcoaceticus ULA-501

Adenosine analogs previously reported as reversible inhibitors of mammalian S-adenosylhomocysteine hydrolase (SAHase) have been found to exert similar effects on Acinetobacter calcoaceticus ULA-501 enzyme. In addition, two metal coordination compounds, cis-platinum diammine dichloride ( cis-DDP) and its trans isomer ( trans-DDP), the former well known for its employment in anticancer chemotherapy, were assayed on both bacterial and mammalian SAHases. In our conditions, trans-DDP appeared to be the strongest inhibitor toward both SAHases. Finally, treatment of the bacterial enzyme with a mixture of ATP-Mg acetate and KCl caused only a slight reversible inhibition, in contrast to the complete inactivation exerted on the mammalian SAHase.

ＨｅＬａ細胞におけるトランスフェリンレセプターの局在についての免疫電顕学的研究

Immunocytochemical localization of the transferrin receptor (TfR) using a monoclonal antibody in HeLa cells was investigated by microscopy and electron microscopy. In addition, changes in transferrin receptor localization evoked by cisplatinum diammine dichloride (CDDP) were examined. The results were as follows:1. In proliferating cells, TfR was found in the cell membrane and electron microscopic investigations revealed that TfR was localized in a scattered fashion in the cell membrane, microvillus-like projections and intercellular vesicles.2. After CDDP treatment, microvillus-like projections and intercellular vesicles were not as prominent as in the control group and the quantity of TfR decreased.3. In some relatively highly degenerated cells by CDDP, many TfRs were demonstrated, suggesting that the mechanism of TfR expression, which reflects the proliferative ability of cancer cells, should be investigated.

Proteinase inhibitory activities of antileukoprotease are represented by its second COOH-terminal domain

Antileukoprotease or secretory leukocyte proteinase inhibitor is a potent serine proteinase inhibitor produced by exocrine glands of the human body. This monomeric protein (107 amino acids) comprises two homologous domains. It is generally thought that Leu 19-Arg 20-Tyr 21 in the NH 2-terminal domain represent the trypsin inhibitory activity, whereas Leu 72-Met 73-Leu 74 in the COOH-domain represent the chymotrypsin and elastase inhibitory activity. Besides Met 73, antileukoprotease contains three additional methionine residues all located in the COOH-terminal domain. Treatment of antileukoprotease with different amounts of methionine-selective reagents such as myeloperoxidase in the presence of H 2O 2 and Cl −, or cis-platinumdiammine dichloride resulted in a dose-dependent inactivation of all inhibitory activities, suggesting that methionine residues are involved in these activities. By using specific synthetic substrates, it was observed that elastase is able to displace trypsin from the inhibitor molecule, indicating that the trypsin and elastase inhibitory sites are located close to each other or at the same site. Incubation of antileukoprotease or its recombinant COOH-terminal domain with an antileukoprotease-specific monoclonal antibody (MoAb15) resulted in a strong selective increase of the trypsin inhibitory activity. The results presented reveal strong evidence that the inhibitory activities of antileukoprotease against trypsin, chymotrypsin and elastase are represented by its COOH-terminal domain, and that methionine residues are involved in interactions with these proteinases.

Optimization of the efficiency of cross-linking PtIIoligonucleotide phosphorothioate complexes to complementary oligonucleotides

We have investigated the efficiency with which PtII complexes cross-link phosphorothioates of oligonucleotides to complementary DNA targets. The A and G residues 2-5 bases downstream from the 5'-phosphorothioate group are preferred sites for cross-linking. Replacement of residues in this part of the target by T residues results in greatly decreased cross-linking when cis platinum diammine dichloride (cisPtII) or potassium platinous chloride (K2PtCl4) are used. Trans platinum diammine dichloride (transPtII) forms cross-links with T residues if A and G residues are absent from the susceptible region of the target. Oligomers containing an internal phosphorothioate group can also be linked to their templates with transPtII, but not with cisPtII or K2PtCl4. Cross-linking via an internal phosphorothioate group tends to be less efficient than cross-linking via a 5'-terminal phosphorothioate. The Sp isomers of internal phosphorothioates are cross-linked more efficiently than the Rp isomers. Preliminary experiments suggest that the efficiency of cross-linking to RNA targets will prove similar to that found for DNA targets.

The Syndrome of Inappropriate Antidiuretic Hormone Secretion Associated With Induction Chemotherapy for Squamous Cell Carcinoma of the Head and Neck

Two patients with squamous cell carcinoma of the head and neck are reported in whom the syndrome of inappropriate antidiuretic hormone (SIADH) secretion occurred transiently during the rapid cytolytic phase of tumor destruction after chemotherapy with cis-platinum diamminedi-chloride and bleomycin. Immunoperoxidase staining for ADH of the original biopsy specimens from both patients was negative. Possible mechanisms for and the implications of the production of SIADH in this setting are discussed.

Current status of systemic chemotherapy in the treatment of advanced ovarian cancer with emphasis on CHAP-5

In patients with advanced ovarian cancer, initial treatment with combination chemotherapy, including cyclophosphamide and cis-platinum diamminedichloride (cis-platinum), produces response and progression-free survival results which are superior to those achieved with alkylating single-agent chemotherapy. Unfortunately most schedules have not resulted in a statistically significant improvement of overall survival. So far one of the most effective combination regimens is the four-drug regimen CHAP-5 that consists of cyclophosphamide, hexamethylmelamine, adriamycin, and cis-platinum. This regimen is the first schedule to result in significant improved survival times compared with a second combination schedule, i.e. Hexa-CAF, which is at least as good as alkylating therapy alone. The CHAP-5 regimen was rather toxic but it was manageable and easy to apply in daily practice. Further improvement of the treatment results in advanced ovarian carcinoma will be difficult because no effective new drugs are available. In future clinical research it must be tried to decrease the toxicity and morbidity of the current schedules without reducing efficacy and survival.

A review of clinical experience with cis-platinum diammine dichloride : 1972–1978

A review of clinical experience with cis-platinum diammine dichloride : 1972–1978

High dose Cis-platinum diammine dichloride.Amelioration of renal toxicity by mannitol diuresis

A clinical trial was undertaken to improve the therapeutic index of cis-platinum diammine dichloride with a concomitantly administered mannitol induced diuresis. Sixty patients, heavily pretreated, were entered; fifty-one are evaluable. The technique of concomitant osmotic diuresis and CPDD administration is described in detail. Doses ranged from 3 mg/kg to 5 mg/kg. At 5 mg/kg, dose-limiting renal, marrow and ototoxicity were seen, and resulted in one drug death. Marrow toxicity was moderate. Renal toxicity was limited to transient elevations in serum creatinine levels, except in some patients who had renal impairment prior to CPDD treatment. These patients had moderate renal toxicity. Serial treatments as frequently as once every 3 weeks were used to maintain responses. Serial high dose CPDD produced only mild renal dysfunction. Ototoxicity, usually subclinical, was quantitated audiometrically, and found to be dose related, but not clinically prohibitive at 4 mg/kg or less. The overall response rate (PR/MR) was 42%. Clinically significant responses in epidermoid carcinoma of the head and neck, adenocarcinoma of the ovary, and germ cell tumors of the testis were seen. All six responding patients with germ cell tumor of the testis, had been resistant to low dose (1mg/kg) CPDD. Two responding patients with ovarian adenocarcinoma had been resistant to alkylating agents.