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Biomedical subjects

Y Kidani

Publications and source records attributed to Y Kidani.

At least 37 records · Page 2Linked to original sources
PubMed1986

A phase I trial of trans-1-diaminocyclohexane oxalato-platinum (l-OHP).

Oxalato-platinum in a new platinum derivative which was found to be active in experimental tumors and devoid of nephrotoxicity. A phase I study was conducted in cancer patients according to a new design following the recommendations of our Institution's ethical committee to avoid the major drawback of classical phase I studies in which many patients receive the experimental drug at doses far under the potentially active dose extrapolated from experimental studies. The potentially active dose of l-OHP was determined from the Maximally Efficient Dose Range (MEDR) to be between 45 mg/m2 (subcurative dose) and 67 mg/m2 (subtoxic dose). The patients in this study received with increasing intervals 1/100, 1/10, 1/5, 1/3, 1/2, 2/3, 3/4, 1, of the low dose of the MEDR, this dose being reached after 90 to 120 days on study. 23 evaluable patients have entered the trial of which 19 reached the low dose of MEDR (45 mg/m2). Gastro-intestinal toxicity, nausea and vomiting, similar to those with CDDP occurred in all patients at or above the dose of 30 mg/m2. Renal toxicity was monitored with creatinine level and did not occur in any patient at any dose nor did significant hematologic toxicity occur. Thus nausea and vomiting appear to be the limiting toxicity of the drug. Responses were observed in this phase I study in lung cancer (1), breast cancer (1), melanoma (1) and perhaps hepatoma (major decrease in alpha FP levels) (1). The proposed starting dose for phase II studies is 45 mg/m2 but we plan to continue dose escalation during the phase II according to the design of Jones and Holland. This new study design allows each patient entering a phase I study to be treated with a potentially active dose of the drug studied.

Adult↗
PubMed1985

Interaction of zinc ions with arsanilazotyrosine-248 carboxypeptidase A.

The interaction between arsanilazotyrosine-248 carboxypeptidase A ([(Azo-CPD)Zn]) and excess zinc ions has been studied by stopped-flow and spectrophotometric methods at pH 8.2 and 7.7, I = 0.5 M (NaCl), and 25 degrees C. When excess zinc ions bind to arsanilazotyrosine-248 carboxypeptidase A, the characteristic red color, which arises from the intramolecular complex of the arsanilazotyrosine-248 residue with the active site zinc of the enzyme, changes to yellow with the inhibition of peptidase activity of the enzyme. Excess zinc ions have two binding sites for arsanilazotyrosine-248 carboxypeptidase A, and the binding constants of the first site (3.9 X 10(5) M-1 at pH 8.2; 7.1 X 10(4) M-1 at pH 7.7) are much larger than those of the second site (1.8 X 10(3) M-1 at pH 8.2; 7 X 10(2) M-1 at pH 7.7). The binding of excess zinc ions to the first site is completely correlated with the inhibition of the enzyme peptidase activity and the color change of the enzyme. The results can be understood in terms of zinc ions reacting with only one of three conformational states of arsanilazotyrosine-248 carboxypeptidase A [Harrison, L. W., Auld, D. S., & Vallee, B. L. (1975) Proc. Natl. Acad. Sci. U.S.A. 72, 4356].(ABSTRACT TRUNCATED AT 250 WORDS)

Carboxypeptidases↗
PubMed1985

Antitumor activity of l-OHP in mice.

The isomeric mixtures of platinum complexes of diaminocyclohexane (DACH) had been found active on several murine tumors. A recent separation of the oxalato-platinum complex of trans-l-DACH isomer allowed more precise screening studies and permitted the selection of one compound: l-OHP was submitted to our murine tumor screening system. The drug was given: (a) at doses of 1-12 mg/kg i.p. or i.v. on day 1, 5 and 9 compared to identical doses of cis-dichlorodiamine platinum II (CDDP) in L1210 bearing mice and (b) to AkR leukemia, LGC lymphoma, glioma 26, B16 melanoma, MA 16-C mammary carcinoma and Lewis lung carcinoma bearing mice at 2 dosages: 5 mg/kg (minimal effective dose on L1210), and 8 mg/kg (subtoxic dose in L1210). Acute LD10 and LD50 appeared similar to CDDP and l-OHP. l-OHP administered i.p. was more active on L1210 than CDDP. On L1210 grafted intracerebrally and on LGC lymphoma l-OHP increased significantly the lifespan while CDDP was inactive. On AkR leukemia, both drugs were active but l-OHP was less toxic. Both drugs were inactive on murine solid tumors. No renal toxicity was observed with l-OHP as compared to CDDP.

Animals↗
PubMed1984

Preparation of antitumor platinum(II) complexes of 1,2-diphenylethylenediamine isomers and their interactions with DNA and its purine moieties.

A series of Pt(II) complexes containing 1,2-diphenylethylenediamine (stien) isomers were synthesized and tested for their antitumor activity against leukemia L1210. Among the Pt(II) complexes examined water-soluble Pt(II) complexes with sulfate, nitrate and D-glucuronate ions as leaving groups exhibited relatively high antitumor activity. Furthermore, the interactions between calf-thymus DNA and Pt(SO4) (stein) complexes were investigated by means of circular dichroism spectrometry. Dichroism enhancements observed in the interaction between DNA and Pt(SO4) (stien) complexes were analysed to be contributable to two factors: (1) vicinal effects of DNA on the d-d transitions of Pt(II) ions and (2) conformational changes of DNA caused by the coordination of cis-configurational Pt(II) complexes.

Animals↗
PubMed1984

Selective binding behavior of zinc(II) and copper(II) ions to their native sites of apo-bovine superoxide dismutase.

The four binding constants of zinc(II) ions to apo-bovine superoxide dismutase were measured by the method of equilibrium dialysis. The binding constants (10(11.1)-10(10.9) M-1) of zinc ions to the native zinc sites were much larger than those to the native copper sites (10(7.8)-10(6.5) M-1) at pH 6.25. The competitive reaction between copper(II) and zinc(II) ions for the native copper sites of copper free bovine superoxide dismutase was also investigated. The native copper sites of bovine superoxide dismutase selectively react with copper ions, because the binding constants of copper ions for the native copper sites were much larger (10(6) times) than those of zinc ions.

Animals↗
PubMed1983

[Development of antitumor platinum complexes].

Since the discovery of the antitumor activity of cis-dichlorodiammine platinum (II) in various tumor systems by B. Rosenberg in 1969, many Pt complexes have been prepared to ameliolate DDP. It has been known to have severe nephrotoxicity, nausea and vomiting, as well as ototoxicity. However, DDP has a wide spectrum of antitumor activity, and it is specifically active against cancers in bladder, testis, ovary and, head and neck. To attenuate such toxicities, hydration prior to DDP administration and/or application of diuretics, as well as combination therapy with other antitumor agents have been developed. Various studies indicated that the nephrotoxicity was attenuated by changing carrier ligands and leaving groups. Toxicity to be removed so far is myelosuppression and vomiting. Another problem is the cross-resistance of DDP. Against L1210/DDP, amine, ethylenediamine, o-phenylenediamine and 1,2-cyclopentanediamine Pt complexes showed cross-resistance, while dach and 1,2-cycloheptanediamine Pt complexes showed no cross-resistance. In this review, the author discusses mainly preparation of the Pt complex of the 2nd generation, being now in the clinical trials and my approach to the development of the antitumor Pt complexes in my laboratory. Pt complexes being now in the advanced studies are: CBDCA, CHIP, DACCP, PYPl PHIC, TNO-6 and l-OHP. New Pt complexes are still deviced continuously. The capability of synthesizing Pt complexes which are characteristically effective against the slow-growing solid tumors, from the standpoint of the coordination chemist.

Animals↗
PubMed1983

Preferential inhibition of the activity of a stimulatory protein of eukaryotic transcription by platinum (II) complexes.

The effect of platinum(II) complexes on RNA polymerase II was studied. (D-Glucuronato)(1R,2R-cyclohexanediamine)platinum(II) nitrate (II-GHP) preferentially inhibited RNA synthesis in the presence of S-II, an essential component of eukaryotic transcription. When DNA was pretreated with I-GHP, its template activity decreased significantly, especially when assayed in the presence of S-II. The target of platinum(II) complexes is probably DNA. When DNA is modified, regulatory proteins of transcription, such as S-II, seem to lose their function preferentially on such a template, resulting in the inhibition of RNA synthesis.

HeLa Cells↗