Experimental investigations on a sequential combination chemotherapy protocol

Summary This paper deals with experimental investigations concerning the composition of a cytostatic three-drug-protocol in diploid Ehrlich-Ascites-Tumor (EAT) cells in vivo at a far advanced stage of the disease. Hydroxyurea (HU) and vincristine (VCR) were used in very low doses to induce a modification of the growth pattern of tumor cells alike partial synchronization. Adriamycin (ADM) was selected as cytocidal drug during DNA synthesis of the partially synchronized cells. It was found that the sequential combination of HU and VCR (first HU and 12h thereafter VCR) caused the greatest alteration of growth pattern compared with other combination protocols. A further statistically significant increase of the degree of synchrony was observed after a second VCR administration—22 h after HU. By means of this protocol the EAT was subdivided into two proliferating subpopulations, a diploid and a tetraploid one. the tetraploid population resulted from surviving cells being not able to perform cytokinesis correctly, so that polynuclear cells and cells with a large single nucleus containing tetraploid DNA values were created. With respect to therapy, the administration of ADM at the time of DNA synthesis of the partially synchronized cells resulted in a statistically significant prolongation of the mean survival time and in 30% of cures of the animals. The dosage of ADM was 2.6 mg/kg, i.e., a nonlethal dose (50% of the LD₁₀). Other combinations, i.e., simultaneous or reversed sequential combinations, did not show any therapeutic improvement compared to single drug therapy of ADM.the present time visiting professorship at the Medical Clinic of the University of CologneSupported by Deutsche Forschungsgemeinschaft     

Retinal changes induced by treatment with vincristine and vinblastine

The mitosis-inhibiting Vinca-alkaloids vincristine sulphate and vinblastine sulphate were injected into the vitreous body. This treatment resulted in ultrastructural changes in the retina within an hour. The retinal nerve cells showed a marked increase in the number of cell organelles, including the 100 Å filaments found in their perikarya. The microtubules disappeared and crystalloid structures appeared within an hour. The axons became distended by accumulated cell organelles, usually surrounding a crystalloid. The synaptic bodies, especially the presynaptic ones, often contained crystalloids, and showed a transient increase in the number of synaptic vesicles. The inner segments of the photoreceptor cells showed similar ultrastructural alterations, and, in addition, stacks of membranous structures. The outer segments decreased in length, and only rudiments of these structures remained one week after the intravitreal injection. The non-pigmented epithelial cells and the Müller's neuroglial cells also showed marked structural alterations.These ultrastructural changes are consistent with the biochemical and fluorescence microscopic observations that vincristine and vinblastine both inhibit the intracellular flow of cell constituents, as previously demonstrated to be the case with colchicine. It is proposed that the structural changes in the individual cells reflect the drug-induced imbalance between the inhibited intracellular transport and the continued formation of the cell constituents characteristic of the afflicted cell.This study was supported by grants from M. Bergwalls Stiftelse, W. and M. Lundgrens Stiftelse, H. Hiertas Stiftelse, Swedish Medical Research Council (B 72-12 X-2543-04 A) and the Swedish National Cancer Society (265 - B 70-02 X).     

肝癌细胞自噬性凋亡过程中caspase-3基因的克隆与鉴定

目的从长春新碱诱导发生自噬性凋亡的肝癌细胞系HepG2中克隆caspase-3基因。方法提取细胞总RNA,采用RT-PCR技术扩增目的片段,构建重组克隆载体,测序鉴定及分析。结果经RT-PCR获得了预期的扩增产物即caspase-3基因625bp的核苷酸片段,其测序结果与文献报道一致。结论初步证明该caspase-3基因片段参与了长春新碱诱导的HepG2细胞自噬性凋亡过程。     

Analgesic Effects of Dexmedetomidine in Vincristine-Evoked Painful Neuropathic Rats

Dexmedetomidine, which is a selective α2-adrenoceptor agonist, was recently introduced into clinical practice for its analgesic properties. The purpose of this study was to evaluate the effects of dexmedetomidine in a vincristine-evoked neuropathic rat models. Sprague-Dawley rats were injected intraperitoneally with vincristine or saline (0.1 mg/kg/day) using a 5-day-on, 2-day-off schedule for 2 weeks. Saline and dexmedetomidine (12.5, 25, 50, and 100 µg/kg) were injected to rats developed allodynia 14 days after vincristine injection, respectively. We evaluated allodynia at before, 15, 30, 60, 90, 120, 180, and 240 min, and 24 hr after intraperitoneal drug (normal saline or dexmedetomidine) injection. Saline treatment did not show any differences for all the allodynia. Maximal paw withdrawal thresholds to mechanical stimuli were 3.0 ± 0.4, 9.1 ± 1.9, 13.0 ± 3.6, 16.6 ± 2.4, and 24.4 ± 1.6 g at saline, 12.5, 25, 50, and 100 µg/kg dexmedetomidine injection, respectively. Minimal withdrawal frequency to cold stimuli were 73.3 ± 4.2, 57.1 ± 6.8, 34.3 ± 5.7, 20.0 ± 6.2, and 14.3 ± 9.5 g at saline, 12.5, 25, 50, and 100 µg/kg dexmedetomidine injection, respectively. Dexmedetomidine shows a dose-dependent antiallodynic effect on mechanical and cold stimuli in vincristine-evoked neuropathic rat models (P < 0.05).     

两种化疗方案超选择动脉灌注治疗颅内恶性肿瘤的疗效及并发症比较

目的：比较表阿霉素（组）、长春新碱（组）分别联合卡铂、VP16超选择动脉灌注化疗治疗脑恶性肿瘤的疗效及并发症。方法：超选择动脉灌注化疗治疗脑恶性肿瘤30例，随机使用表阿霉素（组）、长春新碱（组）分别联合卡铂、VP16治疗并比较其疗效。结果：两组有效率（CR＋PR）分别为55．6％（10／18）和58．3％（7／12）(P＞0．05），均无严重并发症。结论：两组联合治疗方案的疗效相当，但表阿霉素组脱发更为明显，且价格昂贵，临床应用受一定限制。     

Sensorineural hearing loss associated with vincristine treatment

Summary We describe a 64-year-old patient with multiple myeloma who developed a sudden sensorineural hearing loss shortly after receiving chemotherapy with vincristine. Ototoxicity is not a known side effect of this drug. It would be of interest to perform repeated audiograms on patients receiving vincristine, in order to appreciate the actual ototoxicity of this drug.     

Degradation kinetics of vincristine sulphate and vindesine sulphate in aqueous solutions

The degradation kinetics of the antineoplastic drugs, vincristine and vindesine, have been studied in the pH range from − 2 up to 11 at 80°C. A stability-indicating HPLC system with UV detection was utilized for the analysis of vincristine and vindesine in the reaction solutions. The influences of external factors (e.g. pH, buffer concentrations, ionic strength and temperature) on the degradation rate have been studied systematically. The relationship between pH and log k_obs was modelled by using a non-linear least-squares curve-fitting computer program. From this plot thepK_a values of vindesine have been calculated. This plot also showed that vincristine was most stable at pH 4.8 and vindesine at pH 1.9.     

NGF prevention of neurotoxicity induced by cisplatin, vincristine and taxol depends on toxicity of each drug and NGF treatment schedule:: In vitro study of adult rat sympathetic ganglion explants

The simultaneous administration of nerve growth factor (NGF) has been found to prevent experimental neuropathies induced by anti-cancer drugs such as cisplatin, vincristine and taxol. However, it is clinically important to know whether NGF is beneficial once the neuropathy is already manifest. We established a bioassay system to examine the preventive effects of NGF in various treatment schedules. NGF significantly prevented the inhibition of neurite outgrowth by vincristine and taxol regardless of treatment schedules. The pre-treatment and co-treatment schedules were effective against cisplatin, but the post-treatment schedule was not. With regard to the neurite and nerve cell population densities, only the cisplatin group treated with NGF showed lower values than the control. These results indicate that NGF-treatment is effective for the toxic sympathetic nerve injury induced by vincristine and taxol regardless of the treatment schedule, but is not protective against cisplatin-induced nerve cell injury.     

Studies on the use of antimitotic drugs entrapped within liposomes and of their action on a human glioma cell line

The optimal conditions have been determined for producing the maximum incorporation within liposomes of two cell cycle-specific antimitotic drugs (bleomycin and vincristine) used in the treatment of human cerebral gliomas. Under these conditions the subsequent rate of release of these two drugs was studied in vitro. Neither cell fusion nor endocytosis could be demonstrated between liposomes of the size distribution used in these experiments (0.1-15 micron) and a human glioma cell line (U.251-MG) using a variety of marker techniques. Dose-response curves were similar for the two drugs whether free or entrapped within liposomes when applied to this cell line. These results suggest that drugs entrapped within liposomes may be useful as a potential depot preparation in the treatment of human gliomas.