Multiple primary malignant neoplasms — case report

The synchronous occurence of primary carcinomas of endometrium and ovary is well recognized. Malignant peripheral nerve sheath tumours (MPNSTs) may also rarely occur in patients diagnosed with malignancies of the female genital tract. We report a rare case of synchronous primary carcinomas of endometrium and ovary, followed by a metachronous retroperitoneal MPNST. Ascites cytology and endometrial biopsy, followed by hysterectomy and bilateral adnexectomy, were performed to remove the synchronous tumors. Histology was suggestive of synchronous endometrial endometrioid carcinoma and ovarian mucinous adenocarcinoma. After the removal of the retroperitoneal tumor, a MPNST was diagnosed by immunohistochemistry. The patient developed two consecutive vaginal tumors diagnosed as metastases of the previously diagnosed endometrial carcinoma. Although synchronous tumors of endometrium and ovary were relatively early staged and consequently had a favorable prognosis, subsequently occuring implants along the lower genital tract and the metachronous MPNST added up to a poor prognosis.     

Pegylated arginine deiminase: a novel anticancer enzyme agent

Pegylated arginine deiminase (ADI-PEG20) is a novel anticancer enzyme that produces depletion of arginine, which is a nonessential amino acid in humans. Certain tumours, such as malignant melanoma and hepatocellular carcinoma, are auxotrophic for arginine. These tumours that are sensitive to arginine depletion do not express argininosuccinate synthetase, a key enzyme in the synthesis of arginine from citrulline. ADI-PEG20 inhibits human melanomas and hepatocellular carcinomas in vitro and in vivo. Phase I – II trials in patients with melanoma and hepatocellular carcinomas have shown the drug to have antitumour activity and tolerable side effects. Large Phase II trials and randomised, controlled Phase III trials are needed to determine its overall efficacy in the treatment of these malignancies and others.     

Genotoxic and cytotoxic activity of host defense peptides against human soft tissue sarcoma in an in vitro model

Soft tissue sarcomas (STSs) are a heterogeneous group of rare, mesenchymal tumors. Treatment with common chemotherapeutic drugs is consistently associated with low response rates and high rates of adverse toxic effects. Host defense peptides (HDPs) are used as part of innate immunity, and many of them act by directly lysing the target cell membrane. Studies have demonstrated high selectivity of HDP analogs against malignant cells because of a relative abundance of negative charges in malignant cell membranes, compared to normal cells. Our aim was to assess the toxic efficacy of [D]-K₆L₉, [D]-K₃H₃L₉, and Protegrin-1 against the fibrosarcoma cell line, HT1080, and primary human fibroblasts to analyze the potential of these peptides as therapeutic options against STSs. Cell proliferation of the fibrosarcoma cell line, HT1080, and human fibroblasts was determined in vitro after treatment with [D]-K₆L₉, [D]-K₃H₃L₉, and Protegrin-1. Genotoxicity was examined on the basis of the mild alkali version of single-cell gel electrophoresis (comet assay). Doxorubicin, a commonly used STS chemotherapeutic agent, served as the control. The native HDP, Protegrin-1, could show a cytotoxic tendency against malignant cells, but no selectivity in genotoxic trials. The synthetic peptide, [D]-K₆L₉, could not show any selective oncolytic activity against sarcoma cells. [D]-K₃H₃L₉ has shown a tendency for toxic selectivity against malignant cells. There is a potential of developing suitable oncolytic candidates with selectivity against malignant cells. [D]-K₃H₃L₉ showed the first promising results, but there has to be further investigation to improve the therapeutic properties of HDPs.     

Gastrocolic fistula due to gastric cancer (a case report).

Gastrocolic fistula originating from gastric cancer is a rare complication. Allison [1] collected 233 reports on patients with fistulas due to malignant tumours of the stomach and colon. In this article, a patient suffering from gastrocolic fistula as a complication of gastric carcinoma is presented.     

肿瘤的化学治疗 Ⅸ.磷酰胺及磷酸酯类氮芥的合成

双(2-氯乙基)氨基磷酰二氯与乙烯亚胺在脱水苯或对氧六环中并在三乙胺的存在下进行缩合,生成N,N-双(2-氯乙基)-N′,N″-二乙烯基-磷酰胺(Ⅳ);与双巯基或双氨基化合物作用,则生成相应的环状磷酰胺、磷酰胺酯以及磷酰胺硫代酯氮芥类化合物(Ⅴ及Ⅵ).化合物Ⅳ(AT-222)对若干动物肿瘤具有显著的抑制作用,已介绍至临床试用。     

ELECTRICAL FIELD STIMULATION IN CEREBRAL AND PERIPHERAL ARTERIES: A CRITICAL EVALUATION OF THE CONTRACTILE RESPONSE

• 1 Electrical field stimulation with recording of isometric contraction in vitro was carried out on small circular segments of pial arteries, in comparison with peripheral arteries from several regions of rat, rabbit, cow, cat, dog and man.
• 2 It was found that tetrodotoxin (TTX)-resistant contractions were obtained more readily in pial arteries of various species, including man, than in peripheral arteries of similar size. In fact, it was not possible to obtain a purely neurogenic response — without a TTX-resistant change in tone — in any pial vessels tested.
• 3 The stimulation parameters that induced TTX-resistant contraction in pial arteries were similar to those weak parameters that could reveal a purely neurogenic response in certain other arteries, such as rabbit central ear artery and rabbit and feline mesenteric arteries. In these arteries, release of noradrenaline (NA) onto postjunctional α-adrenoreceptors was found to be fully responsible for the contraction. The contractile response could be considerably potentiated by blockade of neuronal and extraneuronal uptake, prejunctional α-receptor blockade, and 4-aminopyridine (4-AP)-induced enhancement of transmitter release. Addition of compounds to prevent oxidation of released NA (EDTA by its ability to bind metal ions, and ascorbic acid-glutathione, which prevents formation of free radicals) did not enhance the neurogenic response.
• 4 However, not even under any of these conditions was it possible to reveal a purely neurogenic response in cerebral arteries. Only TTX-resistant contractions, likely to be due to direct smooth muscle activation, were obtained. The explanation may be morphological differences related to myogenic propagation, probably together with poorly sensitive α-adrenoreceptors, in these pial arteries. The situation was further complicated by the fading of the TTX-resistant contraction which often occurred upon repeated stimulation.
• 5 Therefore, acceptance of partial blockade by TTX as a criterion for a neurogenic response in cerebral vessels, as by several previous investigators, may lead to misinterpretation of the true nature of the response. Hence, when studying neurogenic mechanisms in vitro in these arteries, parameters other than vascular tone should be recorded in conjunction with electrical field stimulation, such as registration of junction potentials and measurements of released transmitter.

     

Improving the global management of the neurogenic bladder patient: part II.Future treatment strategies

ABSTRACT

Background: Patients with neurogenic bladder represent a small fraction of the total overactive bladder population.As a consequence, development of new therapies in this area has largely focused on idiopathic urinary incontinence. The absence of data for patients with neurological disease has far-reaching implications, affecting reimbursement and physicians’ willingness to prescribe therapies, and limiting access of potential valuable treatments to patients whose lives are significantly impaired by inadequately managed bladder symptoms.

Scope: The range of new therapies is increasing. Although many reviews of the overall safety, efficacy and mode of action of such treatments are available, there is limited information on how these treatments will best be used in clinical practice. We considered the current benefits and limitations of the various new licensed and unlicensed therapies and what role each would have in the future management of neurogenic urinary incontinence.

Conclusions: A wide range of new treatments have been investigated for the management of overactive bladder; few, however, have been evaluated extensively in neurogenic urinary incontinence. Further studies are required to determine the optimal dosing regimes and formulations for individual sub-populations of neurogenic bladder patients and to determine the cost-effectiveness of these interventions. With the current experience available, two treatment algorithms for a subset of patients with neurological disease have also been proposed, which suggest at which stage of management and in which patients individual therapies for neurogenic urinary incontinence could be used.     

Silencing Op18/stathmin by RNA Interference Promotes the Sensitivity of Nasopharyngeal Carcinoma Cells to Taxol and High‐Grade Differentiation of Xenografted Tumours in Nude Mice

Nasopharyngeal carcinoma (NPC) is a refractory tumour, and chemotherapy is one of the primary treatment modalities. Oncoprotein 18 (Op18)/stathmin is a conserved small cytosolic phosphoprotein and highly expressed in tumours, which plays a vital role in maintaining the malignant phenotype of tumours. Taxol is a clinically widely used chemotherapeutic agent for a broad range of taxol‐resistant tumours. This study showed that Op18/stathmin silencing by RNA interference (RNAi) combined taxol cooperatively improved cellular apoptosis in CNE1 cells mainly via initiating endogenous death receptor pathway, impaired the capabilities of cellular proliferation and cellular migration and down‐regulated the half maximal inhibitory concentration (IC₅₀) of taxol, meanwhile decreased the expression of the upstream extracellular regulated kinase 1 (ERK1) in vitro. Evidence also showed that taxol cytotoxicity was markedly augmented for Op18/stathmin RNAi in other NPC cells. In vivo animal experiments have demonstrated that early combination of Op18/stathmin silencing and taxol evidently inhibited tumourigenicity of CNE1 cells and growth of xenografted tumours in nude mice. Remarkably, silencing Op18/stathmin by RNAi still promoted transformation of late‐stage CNE1 cells in NPC‐xenografted tumours from moderately to highly differentiated and inhibited the pleiotropic cytokine interleukin‐10 (IL‐10) autocrine by transplanted tumours. These findings suggest that silencing Op18/stathmin by RNAi promotes chemosensitization of NPC to taxol and reverses malignant phenotypes of NPC, which provides a new clue for treating drug‐resistant tumours.     

Minocycline inhibits neurogenic inflammation by blocking the effects of tumor necrosis factor‐α

It has been well established that neurogenic inflammation is one of the major pathological processes underlying inflammatory pain, but there are few effective anti‐inflammatory drugs to alleviate such pain. The present study shows that minocycline, a widely used glial activation inhibitor, is effective in reducing neurogenic inflammation. Patch‐clamp recordings showed that small sized dorsal root ganglion (DRG) neurons were dramatically excited following intradermal capsaicin injection in the rat hind paw, evidenced by decreased rheobase and membrane threshold. Pretreatment with minocycline (30 mg/kg for 1 day, intraperitoneal injection) blocked the increased neuronal excitability. Western blot and immunostaining of DRG revealed the activation of satellite glial cells (SGCs) following capsaicin injection. The up‐regulation of glial fibrillary acidic protein (GFAP) was significantly inhibited by minocycline pre‐administration. Measurement of tumor necrosis factor α (TNF‐α) and its receptor, TNF‐α receptor 1 (TNFR1), showed that minocycline mainly blocked the up‐regulation of TNF‐α in SGCs and TNFR1s in neurons following capsaicin injection. The pivotal role of TNF‐α in neurogenic inflammation was further supported by the findings that incubation DRG with TNF‐α mimicked the increased excitability of DRG neurons induced by capsaicin injection, and that TNF‐α application enhanced cutaneous vasodilation in the hind paws induced by antidromic electrical stimulation of dorsal roots. Based on these results, we propose that minocycline is a potential therapeutic drug that can reduce neuronal excitability and neurogenic inflammation by working on SGCs to inhibit the expression of TNF‐α.     

Vascularization of the tumours affects the pharmacokinetics of bleomycin and the effectiveness of electrochemotherapy

Pre‐clinical and clinical data indicate differences in the responses of melanoma and carcinoma tumours to electrochemotherapy. The purpose of this study was to investigate the origin of this difference, whether it is due to the intrinsic difference in tumour cell susceptibility to the chemotherapeutic, or due to the tumour micro‐environment. For this purpose, we performed a pre‐clinical study in B16F1 melanoma and TS/A carcinoma tumours in mice, in which the antitumour effectiveness of electrochemotherapy with bleomycin, the intrinsic sensitivity of tumour cells in vitro, the pharmacokinetics of bleomycin in plasma and tumours, and the vascularization of tumours in vivo were evaluated. The results of the treatment show that carcinoma was significantly more responsive to electrochemotherapy than melanoma. This effect cannot be ascribed to the intrinsic sensitivity of these cells, as melanoma cells were more sensitive than carcinoma cells in vitro. The difference in responses could be ascribed to differences in the pharmacokinetics of bleomycin; at the time of electroporation in carcinomas, more bleomycin was accumulated. This effect could be due to differences in tumour vascularization, as carcinoma tumours had numerous well‐distributed, small blood vessels, while melanomas were less vascularized, exhibiting predominantly larger vessels. In conclusion, this study provides evidence on the importance of the tumour micro‐environment, particularly the tumour vasculature, in the responses of the tumours to bleomycin electrochemotherapy. Vasculature is important for the pharmacokinetics of bleomycin, influencing drug accumulation and drug distribution in tumours, and might be used as a predictive factor for the tumour response to electrochemotherapy.     

LSD1 inhibition: a therapeutic strategy in cancer?

Introduction: The role of epigenetic dysfunction in cancer is increasingly appreciated. This has raised the question as to whether enzymes that regulate the structure and function of chromatin might represent novel therapeutic targets. The histone demethylase LSD1 is one such candidate and novel, potent inhibitors are under development.

Areas covered: The literature on LSD1 (also known as KDM1A, AOF2, BHC110 or KIAA0601) was identified in Pubmed and is herein discussed. Areas covered include the structure and enzymatic activity of LSD1, its role in chromatin regulatory complexes, its functional roles in normal and malignant tissue, pharmacological inhibitors of its activity and their putative therapeutic roles.

Expert opinion: Pre-clinical data supporting a therapeutic role for LSD1 inhibitors are most encouraging in acute myeloid leukaemia, although optimal dosing strategies and beneficial combinations with other agents remain unclear. Studies making use of potent, selective LSD1 inhibitors active in the nanomolar range are required to establish therapeutic indications in other subtypes of haematological malignancy, and in solid tumours.     

Investigational drugs for neuroendocrine tumours

Background: Neuroendocrine tumours (NETs) are usually slow-growing neoplasms, which arise in the gastrointestinal tract, endocrine pancreas, lungs or thymus. The majority are malignant. The treatment of patients with metastatic disease consists of biotherapy with alpha-interferon and somatostatin analogues, various chemotherapy combinations or liver embolization. Objective: To review and discuss new treatments for patients with metastatic NETs. Method: Review of the published literature during the last 5 years on treatment of patients with NETs. Results/conclusion: Several new drugs with various mechanisms of action including cytotoxic drugs, tyrosine kinase receptor inhibitors and antiangiogenic drugs as well as radiolabelled substances have been introduced during recent years. Many of these compounds have shown promising results in patients with NETs.     

The use of human tumour cell lines in the discovery of new cancer chemotherapeutic drugs

Background: Human tumour cell lines have played a major role in anticancer drug discovery, but cell lines may model only some aspects of tumour behaviour in cancer patients. Growing evidence supports a theory that stem cells with self-renewing properties sustain tumours. Objective: This review considers the extent to which a deeper understanding of the origin and properties of tumour cell lines might lead to new strategies for anticancer drug discovery. Methods: Recent literature on normal and tumour stem cells is reviewed and placed in the context of a discussion on the derivation and properties of tumour cell lines. Results/conclusion: Early-passage cell lines may model the more rapidly proliferating cells in human tumours and, thus, retain some of the properties of tumour stem cells. The effects of anticancer drugs on cell lines should be considered not only with regards to the induction of apoptosis, but also to the induction of senescence or other pathways that lead to host immune and inflammatory responses.     

Preparation of fluorine‐18‐labelled fluoromisonidazole using two different synthesis methods

¹⁸F‐labelled fluoromisonidazole [1H‐1‐(3‐[¹⁸F]fluoro‐2‐hydroxypropyl)‐2‐nitroimida‐zole; ([¹⁸F]FMISO)] is used as an in vivo marker of hypoxic cells in tumours and ischaemic areas of the heart and the brain. The compound plays an important role in evaluating the oxygenation status in tumours during radiotherapy. In this paper, we report experiments carried out in our laboratory in synthesizing [¹⁸F]FMISO using two different methods. The first method (I) for the [¹⁸F]FMISO synthesis was the fluorination of (2R)‐(?)‐glycidyl tosylate to [¹⁸F]epifluorohydrin. The subsequent nucleophilic ring opening, achieved with 2‐nitroimidazole, leads to labelled FMISO. The second method (II) was the fluorination of the protected precursor 1‐(2′‐nitro‐1′‐imidazolyl)‐2‐O‐tetrahydropyranyl‐3‐O‐toluenesulphonyl‐propanediol, followed by a rapid removal of the protecting group. With the first method, the radiochemical yield was about 10% at the end of the synthesis (EOS), and the radiochemical purity was over 99%. The radiochemical yield in the second method was 21% (EOS) on an average, and the radiochemical purity was over 97%. When an automated commercial synthesis module was used with method II, slightly better and more reproducible yields were achieved. The improvement in the synthesis yield with the automated apparatus will be valuable when working with high activities, and therefore it is under further development. Copyright © 2003 John Wiley & Sons, Ltd.     

Uptake of 7,12-Dimethylbenz(a)anthracene and Benzo(a)pyrene in Melanin-Containing Tissues

Abstract: It is widely accepted that UV exposure is the main etiological factor for malignant melanoma. Epidemiologic studies, however, have indicated that also chemical carcinogens may be a risk factor for the disease. Polycyclic aromatic hydrocarbons such as 7,12-dimethylbenz(a)anthracene and benzo(a)pyrene represent an important class of carcinogenic chemicals. It is known that 7,12-dimethylbenz(a)anthracene can induce melanotic tumours in various animal species, and human melanocytes in culture have been found to be capable of metabolizing benzo(a)pyrene to its proximate carcinogen benzo(a)pyrene-7,8-diol. In the present study the disposition of ¹⁴C- and ³H-7,12-dimethylbenz(a)anthracene and ¹⁴C-benzo(a)pyrene was studied in pigmented and albino mice and Syrian golden hamsters by whole-body autoradiography. The results showed pronounced retention of label in the melanin-containing structures of the eyes and the hair follicles in the pigmented animals. The labelling of the corresponding structures in the albino animals was low. Additional experiments showed that 7,12-dimethylbenz(a)anthracene and benzo(a)pyrene as well as some of their metabolites are bound to melanin in vitro. The specific localization of the polycyclic aromatic hydrocarbons in pigmented tissues due to melanin affinity, combined with bioactivating capacity of melanocytes, suggest that these substances may play a role in the induction of malignant melanoma.     

Paediatric solid malignant tumours in Zimbabwe

This paper presents solid childhood tumours seen in Zimbabwe. There were equal number of boys and girls under the age of fifteen years presenting with malignant tumours. Different tumours however showed differences in the sex frequencies. The commonest tumour seen was the Wilm's tumour with lymphomas as the second commonest tumour. Burkitt's lymphoma was very rare as were tumours of the central nervous system.     

Pharmacotherapy for overactive bladder: minimally invasive treatment – botulinum toxins

Introduction: Considered by many a ‘revolution’ in the treatment of intractable overactive bladder (OAB) and with an increasing number of centers including it in their practice worldwide, botulinum neurotoxin A (BoNT/A) injected into the bladder wall is a treatment of significant potential. In anticipation of the results of multicenter, placebo-controlled, dose-ranging studies, this is a critical review of the available literature on the use of botulinum toxins in the treatment of either neurogenic or idiopathic OAB.

Areas covered: The review is based on the English-language literature published by Medline on the use of botulinum toxins in neurogenic or idiopathic detrusor overactivity/OAB since the seminal publication in 2000. The reader is exposed to the cumulative data as well as to a more critical insight on the clinical efficacy of single and repeat injections of the most widely used formulations, the injection techniques, including different doses, dilutions and injection sites, the mechanism of action, the side effects and the cost-effectiveness of the treatment.

Expert opinion: Despite the markedly heterogeneous methodologies, published studies suggest that BoNT/A is effective when a number of outcomes are considered, and is considered safe. As results of large registration studies are awaited, additional research on the optimization of clinical practice parameters such as benefit–risk ratio, injection technique, predictors of response and long-term safety, as well as on the mechanism of action and the cost-effectiveness of the treatment, would be welcome.     

氚标记强效镇痛剂N-[1-(β-羟基-β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺的制备以及与阿片受体的结合试验

本文报道以N-[1-(对-溴苯甲酰甲基)-3-甲基-4-哌啶基]-N-丙酰苯胺(Ⅲ)为前体,以PdO/BaSO₄作催化剂,用氚气进行卤—氚置换,氚化还原羰基的反应。反应产物经硅胶纸层析纯化后,用甲基橙比色法定量测定,得到N-{1-[β-羟基-β-氚-β-(对-氚苯基)乙基]-3-甲基-4-哌啶基}-N-丙酰苯胺(Ⅳ,[³H]F-7302),其比放射性为59 Ci/mM,放化纯度为98%。[³H]F-7302与小鼠脑内阿片受体的特异性结合在浓度为4.5×10^-9M时达到饱和,解离常数Kd=1.25×10^-9M,最大结合量B_max=93.08×10¹²M/g蛋白,其特异性结合与非特异性结合比值达10～15。     

Some aspects of metabolic activation of chemical carcinogens in relation to their organ specificity

The role of organ-specific, enzymic release of alkylating intermediates in determining which tissue develops a tumour in response to a given N-nitrosamine has been evaluated on the basis of published data on the carcinogenicity of 62 N-nitrosamines that induce tumours in specific tissues in rats. A good correlation was noted between the metabolic capacity for N-nitrosamine activation and the organ in which tumours are induced. A relationship was also noted between the localization of carcinogen activating enzymes in rat tissues and the site at which the tumour developed following administration of N-(acetoxy) methyl-N-methylnitrosamine. This compound was shown to be cleaved by soluble enzymes equally efficiently in various rat tissues, such as liver, kidney, spleen and small intestinal mucosa, to yield the alkylating and mutagenic intermediates which are presumably those also formed from the parent N,N-dimethylnitrosamine by microsomal enzymes. N-(acetoxy)methyl-N-methylnitrosamine causes tumours of the gastrointestinal tract, although the parent N,N-dimethylnitrosamine rarely affects this site in rats.The neurotropic carcinogen 3,3-dimethyl-1-phenyltriazene is known to undergo predominantly in the rodent liver oxidative N-mono-demethylation by microsomal enzymes to yield a carcinogenic, mutagenic, and alkylating intermediate, 3-methyl-1-phenyltriazene; however the parent compound produces extrahepatic tumours exclusively. To explain this alternative model of organ specificity, the half-life of 3-methyl-1-phenyltriazene was measured and found to be long enough to permit its distribution throughout the body. Furthermore, subcutaneous injection of 3-[C¹⁴-methyl]-1-phenyltriazene into rats yielded alkylated bases in nucleic acids of hepatic and extrahepatic tissues including brain, the major target organ of the parent compound 3,3-dimethyl-1-phenyltriazene. Eight hours after injection of 3-methyl-1-phenyltriazene the O ⁶ N ⁷-methylguanine ratio was found to be lowest in the liver and highest in the brain, indicating a low rate of O ⁶-methylguanine excision. Thus, for this carcinogen, the persistence of alkylated DNA bases may be a final determinant in tissue specific induction of tumours.The implications of these data for the use of in vitro metabolic activation systems in short-term tests for detecting potential carcinogens are discussed.Presented at the Symposium Influence of Metabolic Activations and Inactivations on Toxic Effects held at the 18th Spring Meeting of the Deutsche Pharmakologische Gesellschaft, Section Toxicology, D-6500 Mainz, March 15, 1977