Intracellular metabolism of the new antiviral compound 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine

1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine [HPMP-5-azaC], the 5-azacytosine analogue of cidofovir (HPMPC), represents a new acyclic nucleoside phosphonate with pronounced activity against DNA viruses, and a selectivity index superior to that of cidofovir. Here we investigated the intracellular metabolic pathway of [6-³H]-HPMP-5-azaC. By comparing the metabolism in mouse lymphosarcoma S49-wild type (S49-WT) and mutant cells deficient for dCMP deaminase, we identified the mono- and diphosphate metabolites generated from HPMP-5-azaC and its deaminated product HPMP-5-azaU. In human lung carcinoma A549 cells, the relative formation of the deaminated metabolites was only 6%, implying that deamination plays a minor role in the overall metabolism of HPMP-5-azaC. The diphosphorylated metabolite of HPMP-5-azaC accounted for 60% of the total radioactivity, and reached intracellular levels which were 60-fold higher in absolute value than the corresponding diphosphate levels obtained with cidofovir. Consequently to its increased activation, HPMP-5-azaC showed about 45-fold higher incorporation into cellular DNA than cidofovir. Herpes-, pox- or adenovirus infection had no marked influence on the metabolism of HPMP-5-azaC. The HPMP-5-azaC-diphosphate metabolite was shown to have long intracellular stability (half-life: 63 h), suggesting that infrequent administration of HPMP-5-azaC should be possible. HPMP-5-azaC represents a new acyclic nucleoside phosphonate compound with promising anti-DNA virus activity and a favorable metabolic profile that is characterized by low sensitivity to catabolic deamination and a high rate of phosphorylation and DNA incorporation.     

新型膦酸酯类化合物DHBMGP2的免疫抑制作用

目的从细胞和整体动物水平研究新型膦酸酯类化合物DHBMGP2免疫抑制活性。方法分离正常BALB/c小鼠脾淋巴细胞,与DHBMGP2共培养72 h,用[3H]TdR掺入法测定淋巴细胞增殖反应;染料排斥法检测24 h细胞存活率,观察淋巴细胞毒性。雄性BALB/c小鼠用二硝基氯苯(DNCB)皮肤致敏2次(间隔1周),制备小鼠迟发型超敏反应模型,初次致敏当天开始ig给药,每天1次,连续10 d,第11天处死动物测定耳肿胀度。雌性BALB/c小鼠足跖sc注射鸡卵清蛋白(OVA)免疫2次(间隔2周),制备致敏模型,首次免疫当天开始ig给药,每天1次,连续4周,每周眼球后静脉丛采血,ELISA法检测血清OVA特异性IgG,IgG1和IgG2a抗体水平,[3H]TdR掺入法检测OVA抗原特异性T细胞反应。结果 DHBMGP2 1～100μmol.L-1体外应用可明显抑制小鼠脾淋巴细胞增殖反应,对脾淋巴细胞24 h存活率无明显影响。DHBMGP2 20,40和80 mg.kg-1可以减轻DTH模型小鼠耳肿胀度,耳肿胀度由模型组的(8.1±3.4)mg分别降低为(5.2±2.1)(,5.1±1.0)和(5.4±1.3)mg,抑制其迟发型超敏反应。ig给予DHBMGP2 40和80 mg.kg-1可以明显抑制OVA致敏小鼠抗原特异性T细胞反应,[3H]TdR掺入值由模型组的(975±46)cpm分别降低为(769±30)和(601±45)cpm,但对血清OVA特异性抗体水平无明显影响。结论 DHBMGP2体内外应用对细胞免疫反应具有抑制作用,对体液免疫反应无明显影响。     

Synthesis and preclinical pharmacological evaluation of 99mTc‐TEDP as a novel bone imaging agent

The detection of bone metastasis in early stages requires the development of high‐affinity bone imaging radiopharmaceuticals for the improvement of the diagnostic accuracy of routine bone scanning and effective management of these medical cases. This study aimed to provide a convenient synthesis of 1‐thioethylidene‐l,l‐disodiumphosphonate (TEDP) and an improved preparation of its ^99mTc‐TEDP complex. The results showed that the radiochemical purity of ^99mTc‐TEDP was found to be 95 ± 2% and that its stability was up to 6 h. Biodistribution study showed high and long uptake of ^99mTc‐TEDP in bone starting from 15 min (39 ± 4 ID/g) to 3 h (53 ± 2.4 ID/g) showing high affinity of ^99mTc‐TEDP complex to bones. This research could introduce a novel radiopharmaceutical that could be used in scanning body bones starting from 15 min between injection of ^99mTc‐TEDP and bone imaging, minimizing the burden on patients in terms of the total length of the examination and the dose of radiation absorbed and showing high specificity and efficacy in bone scintigraphy.     

α-(2-苯并噻唑氧基)烃基膦酸酯的波谱性质

通过α－（２－苯并噻唑氧基）烃基膦酸酯的１ＨＮＭＲ，１３ＣＮＭＲ谱的分析，讨论了中心磷原子对α烷氧基和烷基质子的裂分以及Ｐ－Ｏ－Ｃ旋转受阻现象。分析了化合物（１－８）的质谱特征，并加以解析     

丹参（冻干粉针）结合唑来膦酸治疗恶性肿瘤骨转移临床研究

目的：观察丹参（冻干粉针）结合唑来膦酸治疗恶性肿瘤骨转移对患者生活质量的影响。方法：将60例患者随机平均分为两组,治疗组采用丹参（冻干粉针）结合唑来膦酸治疗,对照组单用唑来膦酸治疗。结果：两组生存质量量表EORTCQLQ-SF-36调查问卷评分比较,生活质量治疗组优于对照组（P〈0.05）;而认知功能、社会功能比较,差异无统计学意义（P〉0.05）;治疗组症状较治疗前有显著改善（P〈0.05）;对照组治疗后与治疗前比较,差异无统计学意义（P〉0.05）,治疗组优于对照组。不良反应比较,治疗组低于对照组（P〈0.05）。结论：丹参（冻干粉针）结合唑来膦酸治疗恶性肿瘤骨转移疼痛,能改善临床症状,减少不良反应,提高生活质量。     

Multicentre trial on the efficacy and toxicity of single-dose samarium-153-ethylene diamine tetramethylene phosphonate as a palliative treatment for painful skeletal metastases in China

A multicentre trial was organized in China as part of an international coordinated research project to study the efficacy and toxicity of single-dose samarium-153 ethylene diamine tetramethylene phosphonate (EDTMP) as a palliative treatment for painful skeletal metastases. One hundred and five patients with painful bone metastases from various primaries were treated with ¹⁵³Sm-EDTMP at a dose of 37 MBq/kg(group I) or 18.5 MBq/kg (group II). The effects were evaluated according to change in daily analgesic consumption, pain score, sum of effect product (SEP), Physician’s Global Assessment (PGA), blood counts, and organ function tests conducted regularly for 16 weeks. Fifty-eight of 70 patients in group I and 30 of 35 in group II had a positive response, with SEPs of 22.29±14.47 and 20.13±13.90 respectively. Of 72 patients who had been receiving analgesics, 63 reduced their consumption. PGA showed that the Karnofsky score (KS) increased from 58.54±25.90 to 71.67±26.53, indicating improved general condition, but the difference was not significant. Among subgroups of patients, only those with breast cancer showed a significant change in the Karnofsky score after treatment. Inter-group differences were found for net change in KS between patients with lung and patients with breast cancer, and between patients with lung and patients with oesophageal cancer. Seventeen patients showed no response. No serious side-effects were noted, except for falls in the white blood cell (nadir 1.5×10⁹/l) and platelet (nadir 6.0×10¹⁰/l) counts in 44/105 and 34/105 cases, respectively. Ten patients had an abnormal liver function test. Response and side-effects were both independent of dose. In conclusion, ¹⁵³Sm-EDTMP provided effective palliation in 83.8% of patients with painful bone metastases; the major toxicity was temporary myelosuppression. Further studies are needed to identify better ways of determining the appropriate dose in the individual case and the efficacy of treatment. Received 4 July and in revised form 6 September 1998     

The broad-spectrum anti-DNA virus agent cidofovir inhibits lung metastasis of virus-independent,FGF2-driven tumors

The FDA-approved anti-DNA virus agent cidofovir (CDV) is being evaluated in phase II/III clinical trials for the treatment of human papillomavirus (HPV)-associated tumors. However, previous observations had shown that CDV also inhibits the growth of vascular tumors induced by fibroblast growth factor-2 (FGF2)-transformed FGF2-T-MAE cells. Here, we demonstrate that CDV inhibits metastasis induced by FGF2-driven, virus-independent tumor cells. Pre-treatment of luciferase-expressing FGF2-T-MAE cells with CDV reduced single cell survival and anchorage-independent growth in vitro and lung metastasis formation upon intravenous inoculation into SCID mice. This occurred in the absence of any effect on homing of FGF2-T-MAE cells to the lungs and on the growth of subconfluent cell cultures or subcutaneous tumors in mice. Accordingly, CDV protected against lung metastasis when given systemically after tumor cell injection. Lung metastases in CDV-treated mice showed reduced Ki67 expression and increased nuclear accumulation of p53, indicating that CDV inhibits metastasis by affecting single cell survival properties. The anti-metastatic potential of CDV was confirmed on B16-F10 melanoma cells, both in zebrafish embryos and mice. These findings suggest that CDV may have therapeutic potential as an anti-metastatic agent and warrants further study to select those tumor types that are most likely to benefit from CDV therapy.