Concurrent Cisplatin, Prolonged Oral Etoposide, and Vincristine plus Chest and Brain Irradiation for Limited Small Cell Lung Cancer: A Phase II Study of the Southwest Oncology Group (SWOG-9229)

Purpose: The primary objectives of the study were to evaluate the efficacy and safety of prolonged oral (PO) etoposide as part of cisplatin-based chemotherapy plus concurrent chest/brain irradiation induction, followed by CAV consolidation, in the treatment of patients with limited-stage small cell lung cancer (SCLC-LD) within a cooperative group setting.

Methods and Materials: Fifty-six eligible patients with SCLC-LD received three 28-day cycles of cisplatin 50 mg/m² i.v. (days 1, 8; 29, 36; and 57, 64), PO etoposide 50 mg/m² (days 1–14, 29–42, and 57–70), and vincristine 2 mg i.v. (days 1, 29, and 57). Thoracic irradiation (TRT) was administered at 1.8 Gy in 25 daily fractions to a total dose of 45 Gy via an AP:PA arrangement, to begin concomitantly with induction chemotherapy. Prophylactic cranial irradiation (PCI) was started on day 15 of induction therapy. Fifteen daily fractions of 2.0 Gy were administered to the entire brain to a total dose of 30 Gy to finish at approximately the same time as TRT. Two 21-day cycles of consolidation cyclophosphamide 750 mg/m² i.v., doxorubicin 50 mg/m² i.v., and vincristine 2 mg i.v. (all on days 1 and 22), were given beginning on day 106 or week 16, from the start of induction therapy.

Results: Among 56 eligible patients, 93% had SWOG performance status 0–1. All had adequate organ function and had not received prior therapy. The overall confirmed response rate was 46%, including 16% complete responders and 30% partial responders. After a minimun follow-up duration of 17 months, the Kaplan-Meier median progression-free (PFS) and overall survival (OS) were 10 and 15 months, respectively. Two-year survival is 28%. Only 28 of 56 patients (50%) completed chemotherapy per protocol, while 52 of 56 patients (93%) completed radiation per protocol. Eleven patients (20%) discontinued secondary to toxicity and two patients died from treatment. The major toxicity was hematologic. The two deaths were secondary to infection. Of the nonhematologic toxicities, there were 10 cases of pulmonary fibrosis (including one Grade 3) and six cases of pneumonitis (including one Grade 3).

Conclusion: Concomitant chemoradiation with oral etoposide as part of a platinum-based chemotherapy and TRT induction regimen is toxic. The CR rate is not better than our prior best group-wide experience. The progression-free and overall survival are similar to published trials utilizing short-course i.v. etoposide. As in chemotherapy for extensive-stage SCLC, there is no apparent advantage to prolonged exposure to etoposide, and toxicity resulted in an inferior therapeutic index compared to programs with shortened exposure.     

姜黄素体外增敏抗肿瘤药物作用

目的 探讨姜黄素与抗癌药物长春新碱、阿霉素合用对KB及KBv200细胞的体外杀伤作用。方法 采用MIT法测定药物的体外杀伤作用，用荧光分光光度法进行细胞内阿霉素蓄积测定。结果 姜黄素与长春新碱、阿霉素合用，在KB及KBv200细胞中均有增敏作用。蓄积实验说明，在KBv200细胞，其增敏作用与增加细胞内阿霉素蓄积有关；而在KB细胞中的增敏作用与细胞内阿霉素蓄积量无关。结论 姜黄素通过不同机理增敏抗癌药对敏感细胞KB及其耐药细胞KBv200的毒性。     

关于CEP72 rs924607 TT基因型和长春碱类相关外周神经毒性的meta分析

目的 评价CEP72 rs924607 TT基因型对急性淋巴细胞白血病(ALL)患儿长春碱类药物相关外周神经毒性发生的影响.方法 在Pubmed、Embase、Cochrane、中国知网、万方、维普、中国生物医学文献数据库中检索"acute lymphoblastic leukemia","vincristine","...     

长春新碱诱导的自噬性凋亡与细胞内游离Ca~(2+)浓度的相关性研究

目的　研究长春新碱 (VCR)诱导的L 0 2细胞自噬性凋亡时细胞内游离钙离子浓度 ([Ca2 +]i)的变化 ,以及自噬特异性抑制剂 3 methyladenine(3MA)对此自噬性凋亡和 [Ca2 +]i的影响。方法　应用已建立的VCR诱导L 0 2细胞自噬性凋亡模型 ,使用电镜、流式细胞术检测细胞凋亡 ;用Fluo 3/AM荧光探针经流式细胞仪测定L 0 2细胞平均 [Ca2 +]i。结果　电镜及流式细胞术检测证实VCR诱导L 0 2细胞发生了自噬性凋亡 ,此凋亡过程中 [Ca2 +]i明显升高 ,以凋亡早期更为明显 :3MA可显著抑制VCR所致的 [Ca2 +]i升高并能降低凋亡细胞比例。结论　在体外条件下VCR可以诱导L 0 2细胞自噬性凋亡 ,其发生可能与VCR导致 [Ca2 +]i升高有关 ;3MA可能通过抑制 [Ca2 +]i升高而抑制自噬及VCR所致的自噬性凋亡。     

Loss of singing ability caused by vincristine

Two patients who received vincristine therapy for lymphoma suffered marked impairment of ability to sing as a consequence of neurotoxicity. Slow recovery occurred on drug withdrawal.     

Dual agents loaded PLGA nanoparticles: Systematic study of particle size and drug entrapment efficiency

PLGA nanoparticles simultaneously loaded with vincristine sulfate (VCR) and quercetin (QC) were prepared via O/W emulsion solvent evaporation. Six independent processing parameters and PLGA characteristics were assessed systematically to enhance the incorporation of the dual agents with different properties (VCR and QC, hydrophilic and hydrophobic molecule, respectively) into PLGA nanoparticles and control particle size. Approaches investigated for the enhancement of drug entrapment efficiencies and the controlling of particle size included the influence of the molecular weight (MW) of PLGA and the lactide-to-glycolide (L:G) ratio of PLGA, PLGA concentration, PVA concentration, initial QC content, acetone-to-dichloromethane (A/D) volume ratio, aqueous phase pH and aqueous to organic phase (W/O) volume ratio. The nanoparticles produced by optimal formulation were submicron size (139.5+/-4.3 nm, n=3) with low polydispersity index (0.095+/-0.031, n=3). Nanoparticles observed by transmission electron microscopy (TEM) showed extremely spherical shape. The entrapment efficiencies determined by high performance liquid chromatography (HPLC) by ultracentrifuge method were 92.84+/-3.37% for VCR and 32.66+/-2.92% for QC (n=3). The drug loadings were 0.0037+/-0.0001% for VCR and 1.36+/-0.12% for QC (n=3).     

长春新碱和甲氨蝶呤行口腔鳞癌术前新辅助化疗的临床研究

目的:观察长春新碱(vincristine)和甲氨蝶呤(methotrexate)新辅助化疗方案(VM方案)在口腔鳞状细胞癌治疗中的临床疗效.方法:对联合应用长春新碱和甲氨蝶呤行新辅助化疗的45例口腔鳞癌患者(辅助化疗组)和既往术前未作任何辅助治疗的50例口腔鳞癌患者(对照组)进行回顾性分析,辅助化疗组术前接受1个疗程的VM方案化疗后进行手术,术后两组接受同样治疗.统计辅助化疗组化疗疗效、术后肿瘤复发率、不良反应和生存质量评分,比较两组患者的术后肿瘤复发率和生存质量评分.结果:经1个疗程VM化疗方案治疗后,45例口腔鳞癌患者中临床部分缓解26例(57.8%),稳定19例(42.2%),化疗总有效率57.8%.VM方案不良反应小,不影响患者接受手术治疗.随访期间辅助化疗组出现肿瘤复发10例(22.2%)、肿瘤远处转移4例(8.9%),对照组出现复发21例(42.0%),转移14例(28.0%),组间比较差异有显著性.结论:术前应用长春新碱和甲氨蝶呤联合化疗在口腔鳞癌治疗中疗效显著,能提高患者生存质量.     

Vincristine treatment in steroid-dependent nephrotic syndrome

Treatment of children with steroid-dependent nephrotic syndrome (SDNS) continues to be a challenge when relapses recur after treatment with cyclophosphamide and side effects or non-compliance make steroids and cyclosporin unsatisfactory. We treated 12 patients with intravenous vincristine for SDNS in a regime of 1–1.5 mg/m² weekly for 4 weeks then monthly for 4 months. Four of the 5 patients in relapse when commencing vincristine remitted within 2 doses. Comparing relapse frequency in the 12 months before and after vincristine, there was a reduction from 4 to 1.5 (p=0.004) relapses per year. Median sustained remission was 5 months, but 1 frequently relapsing patient remains in remission 4 years after vincristine. Vincristine was also successfully used in 1 or 2 doses at weekly intervals for subsequent relapses in 5 patients. Side effects were minimal in most cases. Abdominal pain occurred in 2 patients who commenced vincristine at 1.5 mg/m², but resolved when continued at 1 mg/m². We felt vincristine had a role in a subset of children with challenging SDNS administered as 1 mg/m² weekly for 4 weeks then 1.5 mg/m² monthly for 4 months. Vincristine allowed steroid- and cyclosporin-sparing, contributed to long-term remission in some patients, and was especially valuable in children with poor compliance with oral medication. Many patients expressed a preference for a few doses of vincristine rather than a standard course of oral prednisolone or cyclosporin.     

ABT-594 (a nicotinic acetylcholine agonist): anti-allodynia in a rat chemotherapy-induced pain model

ABT-594 ((R)-5-(2-azetidinylmethoxy)-2-chloropyridine) represents a novel class of broad-spectrum analgesics whose primary mechanism of action is activation of the neuronal nicotinic acetylcholine receptors. The present study characterized the effects of ABT-594 in a rat chemotherapy-induced neuropathic pain model, where it attenuated mechanical allodynia with an ED50 = 40 nmol/kg (i.p.). This anti-allodynic effect was not blocked by systemic (i.p.) pretreatment with naloxone but was blocked completely with mecamylamine. Pretreatment with chlorisondamine (0.2-5 micromol/kg, i.p.) only partially blocked the effects of ABT-594 at the higher doses tested. In contrast, central (i.c.v.) pretreatment with chlorisondamine completely blocked ABT-594's anti-allodynic effect. Taken together, the data demonstrate that ABT-594 has a potent anti-allodynic effect in the rat vincristine model and that, in addition to its strong central site of action, ABT-594's effects are partially mediated by peripheral nicotinic acetylcholine receptors in this animal model of chemotherapy-induced neuropathic pain.     

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