Pharmacokinetics of (glycolato-0,0′)-diammine platinum (II), a new platinum derivative,in comparison with cisplatin and carboplatin

Summary The pharmacokinetics of (glycolato-0,0)-diammine platinum (II) (254-S; NSC 375101D), one of the new platinum analogues, was examined in a phase I study of this drug and compared with that of cisplatin and carboplatin. All drugs were given in short-term (30-min) i.v. drip infusions; the doses of 254-S, cisplatin, and carboplatin were 100, 80, and 450 mg/m², respectively. Platinum concentrations in whole plasma, plasma ultrafiltrate, and urine were determined by atomic absorption spectrometry. After the infusion, the plasma concentration of total platinum for the three agents decayed biphasically. Ultrafilterable platinum in plasma decreased in a biexponential mode after infusions of 254-S and carboplatin, whereas the free platinum of cisplatin showed a monoexponential disappearance. The peak plasma concentrations and AUC for free platinum were 5.31 g/ml and 959 g/min per ml for 254-S, 3.09 g/ml and 208 g/min per ml for cisplatin, and 19.90 g/ml and 3446 g/min per ml for carboplatin, respectively. The mean ratio of plasma ultrafilterable platinum to total platinum were calculated, and the results showed that the protein-binding abilities of 254-S and carboplatin were almost identical. More than 50% of the 254-S was excreted in the urine within the first 480 min after its administration. Thrombocytopenia was reported as a dose-limiting toxicity for both 254-S and carboplatin. This similarity in side effects may mainly be due to the comparable pharmacokinetic behavior of these two platinum compounds.     

SieScape_(R)-全景成像术

本文介绍了一种新的超声技术,它可以完成60cm大的全景成像。借助这项技术可以完整地显示整个脏器,例如肝脏,并能显示该脏器和其周围组织的关系。和传统的超声技术一起应用,这种新技术将显示巨大的优越性。     

食管癌患者SIL_(-2R)和IL_(-6)的研究

本文对25例食管癌患者和31例健康对照者外周血单个核细胞(PBMC)经 PHA 刺激后 IL_(-6)产生能力和细胞培养上清中 SIL-_(2R)水平做了研究,同时检测了血清中 SIL_(-2R)水平。结果显示,食管癌患者产生 IL_(?)能力显著升高(P<0.001);食管癌患血清 SIL_(-2R)水平同健康者相比也显著升高(P<0.001),而细胞培养上清SIL_(-2R)浓度,两者比较差异无显著性(P>0.05)。     

CONTENTS(Vol. 5, No. 1-4, 1993)

NUMBERI,1 9931 CLONINGANDEXPRESSIONOFFabGENESOF人NTI一STOMACHCANCERMeAb3GgINE.COLI7THEPHEN0TYPE0FMASTCELLINPRIMARYADEN0IDLIVERTUM0R0FRATANDITSRELATI0NT0TUM0R CELL13 CLEAR CELL CHONDROSARCOMA OF BONE19 THE EARLY RESPONSE OF PIG SKIN TO FRACT10NATED DOSES OF 35 MeVP一Re FAST NEUTRONS IRRADIATION24 THE HBx PROTEIN EXPRESSION IN LIVER CANCER28 EXPR已粥ION OF IL一3 cDNA IN MURINE BONE…     

A new nitrosourea derivative TA-077, 1-(2-Chloroethyl)-3-isobutyl-3-(β-maltosyl)-1-nitrosourea

Summary A new water-soluble nitrosourea derivative, 1-(2-chloroethyl)-3-isobutyl-3-(-maltosyl)-1-nitrosourea (TA-077), was tested for antitumor activity against murine tumors and a human mammary carcinoma (MX-1) implanted in athymic mice, and the results were compared with those obtained with five other nitrosourea derivatives currently in clinical use: 1-(2-chloroethyl)-3-(methyl--d-glucopoyranos-6-yl)-1-nitrosourea (MCNU), 1-(2-chloroethyl)-3-(-d-glucopyranosyl)-1-nitrosourea (GANU), 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU), chlorozotocin, and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (Me-CCNU).The results indicated that TA-077 had a unique optimal treatment schedule different from other nitrosoureas. With daily IV treatments for 5 days, TA-077 showed the highest antitumor activity of all against the advanced Lewis lung carcinoma, defined by tumor weight and the survival of tumor-bearing mice. Furthermore, TA-077 given according to this treatment schedule was successful in inducing an apparent cure (complete regression and no recurrence) in all the athymic mice bearing MX-1, which the other five nitrosoureas could not. In addition, TA-077 possessed higher therapeutic indices (optimal dose/ILS₂₅) against L1210 and P388 leukemias than MCNU, which possessed the highest therapeutic index against L1210 leukemia among the five nitrosourea derivatives.     

Resveratrol induces SIRT1- and energy–stress-independent inhibition of tumor cell regrowth after low-dose platinum treatment

Purpose  

To investigate resveratrol (RSV) as a calorie restriction (CR) mimetic potentiator of platinum-based cancer drugs.     

Treatment of acute leukemia and malignant lymphoma with (2″R)-4′-O-tetrahydropyranyladriamycin

Summary Eighty-four previously treated adult patients with acute leukemia and malignant lymphoma were treated with (2R)-4-O-tetrahydropyranyladriamycin (THP). THP (10–55 mg/m²) was administered by i.v. bolus injection daily for acute leukemia, and according to three different schedules for malignant lymphoma: daily, weekly or once every 3–4 weeks. Complete and partial remission (CR and PR) were achieved by 1 (5%) and 3 of 19 patients with acute myelogenous leukemia and by 2 (13%) and 3 of 15 patients with acute lymphoblastic leukemia, respectively. All CRs were in the groups receiving 25 mg/m² THP daily. CR and PR were achieved by 6 (14%) and 8 of 42 patients with non-Hodgkin lymphoma (NHL) and by 4 (50%) and 2 of 8 patients with Hodgkin's disease (HD), respectively. No particular sensitivity was found among the subtypes of NHL and HD. Response (CR+PR) was noted in 10 (40%) of 25 patients treated every 3–4 weeks, in 1 (17%) of 6 treated weekly, and in 9 (47%) of 19 treated daily. The major side effects were myelosuppression and gastrointestinal toxicities. Alopecia was observed in only 10 (12%) patients. ECG abnormalities were observed in 7 (10%) patients, all of whom had previously been treated with other anthracyclines. No severe cardiotoxicity was observed.     

Predictive value of APE1, BRCA1, ERCC1 and TUBB3 expression in patients with advanced non-small cell lung cancer (NSCLC) receiving first-line platinum–paclitaxel chemotherapy

Purpose

Drug resistance is not only one of the major obstacles to treatment but also a poor prognosis in advanced non-small cell lung cancer (NSCLC) patients. The aim of this study was to evaluate the predictive value of APE1, BRCA1, ERCC1 and TUBB3 in advanced NSCLC patients who received platinum–paclitaxel treatment.

Methods

One hundred and thirty-six advanced NSCLC patients, who were treated with first-line platinum–paclitaxel chemotherapy, were enrolled in this study. The protein expression levels of APE1, BRCA1, ERCC1 and TUBB3 were assessed by immunohistochemistry and analyzed for the association with response to chemotherapy and progression-free survival (PFS) and overall survival (OS).

Results

Patients with negative expression of APE1, ERCC1 or TUBB3 benefited from platinum plus paclitaxel regimen chemotherapy. ERCC1-negative patients had better PFS (P = 0.016) and OS (P = 0.030) compared with positive patients. Similarly, the APE1-negative patients showed better PFS (P = 0.004) and longer OS though statistically insignificant. Multivariate analysis showed that APE1 and ERCC1 were independent predictor for PFS (HR 2.07; P = 0.004 and HR 1.66; P = 0.016) and OS (HR 1.99; P = 0.008 and HR 1.64; P = 0.040). Moreover, patients with both APE1- and ERCC1-negative or both APE1- and TUBB3-negative tumors had significantly higher response rate, longer median PFS and OS following treatment with platinum and paclitaxel (P < 0.05).

Conclusion

The data indicate that APE1, ERCC1 and TUBB3 could be a useful biomarker to predict clinical outcome in patients with advanced NSCLC receiving first-line platinum–paclitaxel chemotherapy.