Novel therapies for renal cell carcinoma

Metastatic renal cell cancer remains a disease which is difficult to treat medically. Prognosis often depends more on intrinsic disease features than on treatment choices. In this review, we examine novel therapies and scientific directions surrounding the RCC treatment problem. Reports relating chromosomal aberrations and of comparative gene expression analyses relating to RCC, are reviewed briefly. The central role of the von Hippel Lindau protein in clear cell RCC pathogenesis is evident. The limited contribution of conventional cytotoxic chemotherapy is mentioned. Some clinically applied agents whose clinical results are highlighted include 5-FU, retinoids, thalidomide, razoxane and IL-12. Features of the pathophysiology of von Hippel Lindau protein are described, with attention to potential novel therapies targeting HIF-1α, VEGF, TGF-β1 and TGF-α pathways. Immunotherapy is being explored in many angles. Most basic are cytokine therapies incorporating new IL-2 and IFN-α schedules. Newer cytokine-based drugs include pegylated forms and IL-12. Allogeneic mini-transplantation has generated much interest. Tumour-associated antigens are being used to direct therapy using both identified and non-identified epitopes. A variety of tumour-cell vaccine and dendritic-cell vaccine clinical approaches are discussed. Finally, nephrectomy for known metastatic disease has been demonstrated to be helpful in retrospective and now prospective trials. Resection of metastases is also discussed. We are optimistic that the further clinical development among these novel therapies will improve the outlook for metastatic RCC.     

右丙亚胺对表柔比星所致心脏毒性防治作用的观察

目的:观察右丙亚胺对表柔比星所致心脏毒性的防治作用。方法:对84例应用含表柔比星方案化疗的患者,以心电图作为观察指标,先单独化疗4个周期,然后将已出现心电图异常者归入右丙亚胺治疗组、心电图正常者分为单独化疗组及右丙亚胺联合化疗组继续单独化疗或用右丙亚胺联合化疗2个周期,观察心电图变化。结果:单独化疗4个周期过程中,心电图异常发生率为26.2%(22/84)。继续化疗2个周期,单独化疗组心电图异常发生率为38.7%(12/31),右丙亚胺联合化疗组心电图异常发生率为16.1%(5/31),RIDIT公式统计,u=1.977,P<0.05,差异有统计学意义;右丙亚胺治疗组有13.6%(3/22)患者异常心电图转为正常,有18.2%(4/22)患者异常心电图保持稳定,其余68.2%患者心脏损害加重。结论:右丙亚胺对表柔比星所致心脏毒性的发生有一定的防护作用,并且对已经形成的损害有一定的治疗作用。     

Measurement of renal tumour and normal tissue perfusion using positron emission tomography in a phase II clinical trial of razoxane

Measurement of tumour and normal tissue perfusion in vivo in cancer patients will aid the clinical development of antiangiogenic and antivascular agents. We investigated the potential antiangiogenic effects of the drug razoxane by measuring the changes in parameters estimated from H(2)(15)O and C(15)O positron emission tomography (PET) to indicate alterations in vascular physiology. The study comprised 12 patients with primary or metastatic renal tumours >3 cm in diameter enrolled in a Phase II clinical trial of oral razoxane. Perfusion, fractional volume of distribution of water (VD) and blood volume (BV) were measured in tumour and normal tissue before and 4-8 weeks after treatment with 125 mg twice-daily razoxane. Renal tumour perfusion was variable but lower than normal tissue: mean 0.87 ml min(-1) ml(-1) (range 0.33-1.67) compared to renal parenchyma: mean 1.65 ml min(-1) ml(-1) (range 1.16-2.88). In eight patients, where parallel measurements were made during the same scan session, renal tumour perfusion was significantly lower than in normal kidney (P=0.0027). There was no statistically significant relationship between pretreatment perfusion and tumour size (r=0.32, n=13). In six patients scanned before and after razoxane administration, there was no statistically significant change in tumour perfusion: mean perfusion pretreatment was 0.81 ml min(-1) ml(-1) (range 0.46-1.26) and perfusion post-treatment was 0.72 ml min(-1) ml(-1) (range 0.51-1.15, P=0.15). Tumour VD and BV did not change significantly following treatment: mean pretreatment VD=0.66 (range 0.50-0.87), post-treatment VD=0.71 (range 0.63-0.82, P=0.22); pretreatment BV=0.18 ml ml(-1) (range 0.10-0.25), post-treatment BV=0.167 ml ml(-1) (range 0.091-0.24, P=0.55). Tumour perfusion, VD and BV did not change significantly with tumour progression. This study has shown that H(2)(15)O and C(15)O PET provide useful in vivo physiological measurements, that even highly angiogenic renal cancers have poor perfusion compared to surrounding normal tissue, and that PET can provide valuable information on the in vivo biology of angiogenesis in man and can assess the effects of antiangiogenic therapy.     

Phase II trial of ICRF-187 in children with solid tumors and acute leukemia

Summary ICRF-187 is the (+) enantiomer of the racemic mixture razoxane (ICRF-159). This compound is much more water soluble and thus could be formulated for parental use. The maximum tolerated dose in children after phase I trials was determined to be 3500 mg/M²/day × 3 days. A phase II trial of ICRF-187 was done in 21 children with solid tumors and 35 children with acute leukemia. All these patients were < 21 years of age, had recovered from previous chemotherapy, had normal liver and kidney functions, and had a life expectancy of greater than 4 weeks. ICRF-187 was administered at a dose of 3 g/M²/day for 3 days as a 4 hour infusion each day. In patients with leukemia, no objective response was seen in the bone marrow although a few patients had a decrease in peripheral blast count. There were no measurable responses seen in patients with a solid tumor. ICRF-187 was well tolerated. The major toxicity was hematopoietic depression. Significant but rare toxicities included moderate to severe nausea and vomiting, and elevation of bilirubin and transaminases. Although inactive in the current study, ICRF-187 might be more active in another schedule. Address for offprints: T. Vats (POG #8462), POG Operations Office, 4949 West Pine Boulevard, Suite 2A, St. Louis, MO 63108, USA     

微波辐射加热法合成乙亚胺

[目的]探讨微波辐射加热法合成乙亚胺的优越性。[方法]通过调整原料比例、微波功率和反应时间,确定最佳反应条件。然后,以传统方法合成乙亚胺,并将其结果与微波合成的结果相比较。[结果]微波辐射加热合成产物、传统方法合成产物、及标准品进行红外鉴定,确定它们为同一物质。在420 W的功率下,以甲酰胺∶乙二胺四乙酸（EDTA）=10.5∶1的比例反应12.5 min有最高产率,为75.6%。传统方法合成乙亚胺的产率为69.3%。相对于传统方法将反应时间缩短至原来的3.8%,并节约了46%的甲酰胺。[结论]微波合成乙亚胺相对于传统合成方法产率有所提高,并且大大缩短了反应时间,提高了原料甲酰胺的利用率。     

吗丙嗪和雷佐生抑制兔红细胞膜钙调蛋白活力的比较

比较了抗癌结构类似物吗丙嗪和雷佐生对红细胞膜钙调蛋白 (CaM)活性的影响 .观察兔红细胞膜Ca2 +,Mg2 + ATP酶 (CaM的靶酶 )活性反映膜CaM激活ATP酶的活性 .结果显示吗丙嗪 ( 0 .1～ 1mmol·L- 1)浓度依赖性抑制CaM激活ATP酶活性 (下降11%～ 32 % ) .雷佐生在高浓度 ( 0 .5mmol·L- 1)仍未显示抑制CaM激活ATP酶活性的作用 .吗丙嗪在低浓度 ( 0 .0 2～ 0 .1mmol·L- 1)能增加N 乙酰神经氨酸( 0 .2mmol·L- 1)抑制CaM激活ATP酶活性的作用 .结果表明吗丙嗪对CaM活性的抑制作用强于雷佐生 ,因而可能在CaM介导的抑瘤途径的作用较雷佐生强 ,且其作用可能与神经氨酸 (唾液酸 )有关     

Combined Razoxane and Radiotherapy for Melanoma Brain Metastases. A Retrospective Analysis

Summary We retrospectively compared the efficacy of razoxane and radiotherapy with radiotherapy alone or in combination with a non-razoxane based medication in patients with melanoma brain metastases. From 19 assessable patients receiving whole brain irradiation with or without a boost (mean total dose 40.5 Gy) for measurable brain metastases, 8 patients underwent an additional razoxane therapy with 125 mg per os twice daily started 5 days before radiotherapy and given throughout the whole radiation period. The median razoxane dose was 6.25 g (range 3.2–8.0 g). Endpoints included radiation response rates, median survival time and 1-year survival rates. To generate reliable prognostic parameters for this non-randomized study population, the Score Index for Stereotactic Radiosurgery and the Radiation Therapy Oncology Group Recursive Partitioning Analysis score were applied. Radiotherapy with razoxane led to higher response rates (62% vs. 27%) and a lower percentage of progressive disease (12.5% vs. 36%) if compared with radiotherapy alone or with a non-razoxane based medication. This combination was associated with a longer median survival (5 months vs. 2.2 months; P=0.052) and a 1-year survival rate of 37.5% vs. 0% (P=0.027). Both treatment groups belonged to similar prognosis subsets. The treatment was well tolerated. Taken together our data support the therapeutic concept of a combined razoxane radiation therapy in melanoma patients with brain metastases. The favorable treatment effects are probably due to the radiosensitizing and the cytorallentaric mode of action of razoxane. Since the patient numbers are low, confirmatory studies are certainly necessary.     

乙双吗啉致急性白血病6例临床分析

目的 :探讨乙双吗啉引起急性白血病的临床特点。方法 :观察 6例乙双吗啉引起急性白血病患者的临床表现及预后。结果 :6例患者 ,2例诱导缓解阶段死亡 ,1例 5个诱导方案未缓解 ,2例缓解后 18、2 4个月复发 ,1例未治。结论 :乙双吗啉引起的急性白血病治疗效果差 ,预后欠佳 ,应引起临床医生注意     

三个哌嗪二酮类化合物对Lewis癌体内肺转移的影响

目的　比较吗丙嗪 (Pro) ,乙双吗啉 (Bim)和丙亚胺(Raz)对动物肿瘤肺转移的影响。方法　用生物接种法进行Lewis癌肺转移的观测。结果　Pro和Bimd 2起给药和d 8起给药对Lewis癌肺转移均有抑制 ,Raz仅d 2起给药对Lewis癌肺转移有影响 ,Pro在等毒性剂量下对Lewis癌肺转移疗效优于Bim。结论　Pro的抗Lewis癌肺转移疗效优于Raz可能是由于其存在新的分子药理机制。