Vinorelbine and the topoisomerase 1 inhibitors: Current and potential roles in breast cancer chemotherapy

Summary Vinorelbine is a semi-synthetic vinca alkaloid which was initially developed in France in the 1980's. Due to its unique structure it is considerably less neurotoxic than vincristine. Several phase II studies have shown that vinorelbine is active in metastatic breast cancer therapy with response rates of 20–30% in pretreated and 40–50% in nonpretreated patients respectively. Higher response rates have been noted when vinorelbine is used in combination regimens. The main dose-limiting toxicity seen with this agent has been neutropenia; neurotoxicity manifest as symptomatic paresthesia can be seen in 10% of treated patients. Oral and implantable forms of the drug have also been investigated.The topoisomerase 1 inhibitors topotecan and camptothecin 11 (CPT-11) have been less extensively evaluated in breast cancer therapy. Preclinical studies have indicated that both of these agents are active against breast cancer and some responses have been seen in phase 1 trials of topotecan. An 8% response rate was noted in a phase II trial of CPT-11 in patients with pretreated metastatic breast cancer. Further phase II trials are ongoing at present with both agents.Presented by R.C. Donehower at the 16th Annual San Antonio Breast Cancer Symposium, San Antonio TX, November 4, 1993; Mini-symposium on New Agents in Breast Cancer (supported by an educational grant from Rhône-Poulenc Rorer).     

10-羟基喜树碱衍生物的合成及体外抑制肿瘤活性

目的寻找高效低毒的喜树碱类抗肿瘤新药。方法合成7个喜树碱衍生物（3~9），经¹HNMR，IR，MS分析确证了所合成化合物的结构，经MTT法筛选了对宫颈癌Hela、肝癌BEL-7402、胃癌7901和大肠癌CCL-187瘤株的体外抑制肿瘤活性。结果7个化合物分别对前三种瘤株有效，其中化合物4对前三种瘤株均有较好的体外抑制肿瘤细胞活性，尤其对宫颈癌Hela细胞的抑制活性大于10-羟基喜树碱。结论该类化合物的抗癌活性值得进一步研究。     

羟基喜树碱联合顺铂和平阳霉素治疗Ⅳ期食管癌临床分析

目的评价羟基喜树碱联合顺铂和平阳霉素治疗Ⅳ期食管癌的疗效和毒性。方法经病理证实的46例Ⅳ期食管癌病人,采用羟基喜树碱 顺铂 平阳霉素方案:羟基喜树碱10m g连续7天;顺铂30m g/m2,第1~3天应用;平阳霉素16m g,第1.8天应用,21天为1周期。结果完全缓解(CR)2例,部分缓解(PR)20例,稳定(SD)18例,进展(PD)6例,总有效率47.8%。初治25例中,CR PR 15例,有效率为60.0%。复治21例中CR PR 6例,有效率达28.6%。两组差异有显著性(P<0.05)。毒副反应为骨髓抑制和胃肠道反应。结论羟基喜树碱联合顺铂和平阳霉素对Ⅳ期食管癌疗效较好,毒副反应可以耐受。     

Second-line treatment of small-cell lung cancer with the camptothecin-derivative GI147211: A study of the EORTC Early Clinical Studies Group (ECSG)

Background:GI147211, a 10,11-ethylenedioxy substituted analogueof camptothecin (CPT), was brought into clinical development because of itshigher water solubility and greater potency as compared to topotecan (TPT).The antitumor activity of GI147211 as second-line therapy in small-cell lungcancer (SCLC) was assessed after stratification of patients in refractory (noresponse to initial treatment or relapse within three months from last cycle)and chemosensitive (relapse more than three months from last cycle). Patients and methods:Sixty-seven patients were entered in thestudy and sixty-two were evaluable for response, twenty-eight in therefractory and thirty-four in the chemosensitive group. All patients hadreceived 1 line of chemotherapy; radiation had also been given in 29 cases,6 in the refractory and 23 in the chemosensitive group. GI147211 wasadministered at 1.2 mg/m²/day as 30-min infusion for fiveconsecutive days every three weeks. Results:The overall response rate was 16.6% (11 of 66patients; 95% confidence interval (95% CI):8.5%–27.5%), 10.3% (3 of 29 patients; 95%CI: 2.2%–27%) in the refractory and 21.1% (8 of 37patients; 95% CI: 9.5%–37%) in the chemosensitivegroup. Only partial responses (PR) were observed with a median duration of PRof 4.8 months (5.7 months in the refractory and 5.2 in the chemosensitivegroup). Hematological toxicity consisted mainly of neutropenia (grades3–4 in 25% of cycles) and thrombocytopenia (grades 3–4 in23% of cycles); non-hematological toxicity was mild to moderate andconsisted of nausea (22% of cycles), vomiting (11%), malaise(34%). Conclusions:At the dose and schedule tested GI147211 is an activenew agent for second-line treatment of SCLC; the antitumor activity andtoxicity profile are comparable to those observed with TPT which remains theleading CPT analogue for salvage treatment. Interest has been renewed in theclinical development of GI147211 by preclinical data with the liposomalformulation showing an increased therapeutic index.     

Camptothecin and taxol: Discovery to clinic

Camptothecin (CPT) is a pentacyclic alkaloid isolated from wood and bark of Camptotheca acuminata. Initially it was found to be highly active in a number of mouse in vivo cancer assays. Subsequently, CPT was found to uniquely inhibit an enzyme, topoisomerase I, which is involved in DNA replication. A number of CPT analogs are in advanced clinical trial, and two, Topotecan and CPT-11, have been approved for marketing by the FDA. Taxol, a taxane alkaloid, was isolated from Taxus brevifolia. Taxol is a highly cytotoxic compound active in several mouse antitumor assays. It was subsequently found to uniquely inhibit tubulin, a protein involved in mitosis. After clinical evaluation, it has become the drug of choice for treatment of ovarian cancer. © 1998 John Wiley & Sons, Inc. Med Res Rev, 18, No. 5, 299–314, 1998.     

Plasma Pharmacokinetics of the Lactone and Carboxylate Forms of 20(S)-Camptothecin in Anesthetized Rats

20(S)-Camptothecin exists in equilibrium between its lactone (CPT) and its carboxylate forms (Na-CPT) under simulated physiological conditions, with the equilibrium favoring the carboxylate form. The rates of lactone hydrolysis were studied in plasma, serum albumin, and blood and were found to be faster than in aqueous buffers at equivalent pH values. From mechanistic information and in vivo activity data, the lactone appears to be the active form of the drug. It has been argued, therefore, that if an equilibrium existed between the lactone and the carboxylate, Na-CPT could be used to deliver the lactone effectively. In the present study, plasma pharmacokinetics were performed in sodium pentobarbital-anesthetized rats treated with both CPT (lactone) and the sodium salt of camptothecin (carboxylate, Na-CPT) and the lactone and carboxylate, as well as the total drug, concentration versus time profiles were assessed. It was found that plasma concentrations and AUC values for the lactone were significantly higher after dosing with CPT than after dosing with Na-CPT. After i.v. administration, the ratio of plasma lactone to carboxylate was skewed by the apparent rapid and extensive uptake of the lactone into tissues and the rapid clearance of both species. From our results, it appears that the lower in vivo activity of Na-CPT compared to that from CPT administration might be attributed to the altered conversion of carboxylate into lactone in vivo compared to that predicted from in vitro data.     

Partial characterization of human leukemia U-937 cell sublines resistant to 9-nitrocamptothecin P

Abstract: Human leukemia U-937 cell sublines exhibiting various levels of resistance to 9-nitrocamptothecin (9NC) were developed after exposure to progressively increased 9NC concentrations. Increases in 9NC resistance of the cells were accompanied by decreases in proliferation rate; appearance of morphological and functional features that correlate with granulocytic maturation; decreased synthesis of topoisomerase I; increased synthesis of topoisomerase II; and inability or decreased ability to induce tumors when xenografted in nude mice. 9NC-resistant cells, transferred and propagated in 9NC-free media for 6 months, continue to exhibit resistance and other features similar to cells propagated in continual presence of 9NC. Finally, 9NC-resistant U-937 cells respond to physiological and non-physiological agents of cell differentiation, indicating that alternative treatments can be successfully used to inhibit growth of 9NC-resistant U-937 cells and tumors.     

氮素水平对喜树幼苗喜树碱含量的影响

目的:探讨氮素营养水平对喜树幼苗喜树碱含量的影响。方法:在温室中对砂培喜树幼苗进行5种氮素水平处理,用HPLC测定了喜树幼苗各器官中喜树碱含量,观察了幼叶中喜树碱含量的动态变化过程。结果:不同氮素水平下喜树幼苗幼叶中喜树碱含量均明显高于其他器官的(P<0.01)。喜树幼苗幼叶中的喜树碱含量在不同氮素水平下随时间进程均呈明显的单峰曲线,处理的第50天达到高峰;幼叶的喜树碱含量随氮素水平的增加而明显减小,氮素水平为4 mmol.L^-1时幼叶的喜树碱含量最高(6.72‰),是16 mmol.L^-1的1.1倍。结论:适宜的供氮水平对于喜树幼苗幼叶中的喜树碱含量极为重要,适当的低氮胁迫能够显著地增加喜树幼苗幼叶的喜树碱含量。     

Thiocolchicine dimers: a novel class of topoisomerase-I inhibitors

During a cellular screening of thiocolchicine analogs, thiocolchicine dimers resulted particularly active in cisplatin-resistant A2780-CIS cells. In order to discover by which mechanism(s) thiocolchicine dimers overcame cisplatin resistance, p53, p21waf1 and MLH1 were assessed by Western blot. Results pointed out that, when combined with cisplatin, dimers increased the amount of all the three proteins with respect to the levels obtained by single drug exposure, thereby suggesting an interference in the process of repair of the cisplatin-induced DNA lesions. Moreover, in isolated nuclei drugs were able to produce DNA breaks, as demonstrated by Comet assay, thereby proving that the compounds were able to target cell nucleus independently from microtubules. Since Topo-I (topoisomerase I) is directly involved in the DNA repair and such activity is overexpressed in cisplatin-resistant cells, Topo-I was investigated as a potential target. Using DNA relaxation assay, thiocolchicine dimers inhibited Topo-I, a property not shared by thiocolchicine. At variance with camptothecin, dimers did not produce cleavable complexes, thereby indicating that Topo-I inhibition occurs upstream of the religation step. To assess the mechanism of inhibition, an electrophoretic mobility shift assay between DNA and Topo-I was performed and revealed that thiocolchicine dimers specifically interfere with binding of Topo-I to DNA. The interference is specific since the same compounds did not modulate DNase activity and did not act as intercalating agents in the DNA unwinding assay. Finally, behaviour of dimers as spindle poisons was investigated and no relevant changes with respect to thiocolchicine in terms of interaction with microtubules were found.