Potentiation of the tumor cytotoxicity of melphalan by vasodilating drugs

Previous studies have shown that several vasoactive drugs can selectively reduce blood flow and increase hypoxia in experimental tumor systems. Our studies with one such agent, the vasodilator hydralazine, have clearly demonstrated that it can increase the tumor cytotoxicity of drugs which are known to be more toxic under hypoxic conditions. We have now extended our investigations to determine whether such selective reductions in tumor blood flow induced by hydralazine can increase the tumor cytotoxicity of other classes of cancer chemotherapeutic drugs. Our initial studies have involved the alkylating agent melphalan. Administration of hydralazine (5 mg/kg IP) at various times before or after melphalan results in increased tumor cytotoxicity in the Lewis lung carcinoma. An enhancement factor of between 2 and 3 was obtained in this tumor system. Similar results are observed if the vasodilator cadralazine is used. In contrast to the enhancement of the tumor cytotoxicity of melphalan by hydralazine, systemic toxicity is only increased by a factor of 1.2. Therefore, therapeutic gain may accrue from the use of vasodilating agents in combination with melphalan. Studies using spheroids to establish the mechanism responsible for the enhanced tumor cytotoxicity indicate that both hypoxia and pH can influence melphalan toxicity.     

pH distribution in human tumors

The effectiveness of hyperthermia in tumor therapy may depend on a lower extracellular pH of tumor compared to that of normal tissue. A technique for measuring extracellular pH in human tumors has been devised to test the usefulness of this parameter as prognostic indicator of tumor hyperthermia response. In a preliminary study 50 of 53 pH readings from 14 human tumors (both heated and unheated) were below normal physiological pH. Tumor pH values ranged between 5.55-7.69 (average for unheated tumors 6.81 +/- 0.09, SEM, only one determination was above 7.40). Although there was considerable heterogeneity of pH within tumors, the accuracy and drift of the 21 gauge needle electrode were not a problem. Fifteen minutes were required for pH stabilization after insertion of an 18 gauge open-ended catheter, and less than 5 min for equilibration after electrode insertion into the catheter. A saline wheal was used for anesthesia to preclude modification of pH by anesthetics. Central portions of tumors were no more acidic than peripheral regions, but large tumors tended to be more acidic than small tumors. The pH of several tumors of various sizes and histologies was also determined immediately before subsequent treatment sessions. These measurements were made by reinsertion of catheters in approximately the same locations at each session. The trend appeared to be that pH increased with the number of treatment sessions. Measurements of pH were made in four patients immediately prior to and at the termination of a heating session (same locations since catheter remained in place during heating sessions). Three of the four tumors showed increased pH readings of 0.25-0.54 units during heating. However, none of the four tumors achieved temperatures exceeding 42 degrees C. The pH measurement technique developed provides a safe and relatively easy method for determining extracellular pH in human tumors. There appears to be a correlation of pH values with tumor size, treatment session, and possibly blood flow.     

Clinical effects induced by intratumoral administration of anti-cancerous drugs in skin malignant tumors

Many drugs are applied in local treatment for skin malignant tumors. These drugs are living-BCG, OK-432, MY-1, WPG, interferon preparation (alpha, beta and gamma), TNF, IL-2, peplomycin, bleomycin and others. Some of them already have completed clinical trials and others are under clinical observation. In local administration of these drugs, skin lesions (malignant melanoma, CTL-mainly mycosis fungoides, carcinoma in situ and others) show good improvement. The effects were more observed in the tumors with diameters of 1 cm or less and appeared 3 to 10 injections in most cases. As complications, there are fever, general fatigue, vomiting, anorexia, leucopenia and others. Among them, the fever was most observed immediately after injections without any more severe complications. It may be concluded that treatment by intratumoral administration is useful for skin malignant tumors.     

The chronic administration of drugs that inhibit the regulation of intracellular pH: in vitro and anti-tumour effects.

Mean values of extracellular pH (pHe) in tumours tend to be about 0.5 pH units lower than in normal tissues, whereas values of intracellular pH (pHi) in tumours and normal tissues are similar. Previous studies have shown that drugs that acidify cells at lower pHe such as nigericin, used alone or with agents that inhibit the regulation of pHi, have toxicity to cultured cells at pHe < 6.5 in short-term exposure; these agents also lead to modest anti-tumour effects in mice when given acutely. To evaluate the long-term effects of these drugs at levels of pHe that might occur commonly in tumours, we exposed cells for up to 72h at pHe 6.8 or 7.2 in vitro. Nigericin (0.033 microM) caused time-dependent cell killing of murine KHT and EMT-6 cells at pHe 6.8 (but not at pHe 7.2) with a surviving fraction approximately 5 x 10(-3) after 72 h exposure. Cell killing was increased in the presence of 4,4-diisothiocyanstilbene 2,2-disulphonic acid (DIDS), an inhibitor of Na+-dependent HCO3-/CI- exchange, and to a lesser extent in the presence of 5-(N-ethyl-N-isopropyl) amiloride (EIPA), an inhibitor of Na+/H+ exchange. Cell killing was exquisitely sensitive to the level of pHe. Osmotic pumps were used to obtain a 72 h continuous infusion of nigericin in mice; this led to dose-dependent killing of cells in KHT tumours with surviving fraction of approximately 0.1 at maximum tolerated doses. Hydralazine, which may cause tumour hypoxia and lower pHi as well as pHe, caused cytotoxity when given alone by chronic infusion, and enhanced the cytotoxicity due to nigericin. The addition of DIDS and/or EIPA (using two pumps) further enhanced anti-tumour toxicity, with a surviving fraction of approximately 0.002 at tolerated doses of the four drugs used to treat KHT tumours. The experiments demonstrate the activity of drugs that inhibit the regulation of pHi against murine tumours when delivered by chronic infusion.     

IFT80蛋白对肿瘤影响的研究

  目的  探讨IFT80（intraflagellar transport 80）蛋白在骨癌、肺癌、胰腺癌、胃癌、小肠癌、前列腺癌、乳腺癌和卵巢癌组织的表达分布情况与癌细胞增殖中的作用。  方法  免疫组织化学研究IFT80的表达,免疫荧光和细胞培养研究抑制IFT80后对癌细胞增殖的影响和纤毛之间的关系。  结果  1）IFT80在胃癌和肺癌组织中高表达,乳腺癌和小肠癌组织中中等表达,骨癌和卵巢癌组织中少量表达,前列腺癌和胰腺癌组织中几乎不表达;2）抑制IFT80后发现肺癌细胞增殖加快,纤毛减少变短;3）高分化,Ⅱ A期胃癌和正常胃组织中IFT80蛋白大量表达,而在低分化晚期,几乎不表达,在其他不同分化的胃癌中不同程度表达。  结论  在不同癌组织中IFT80分布情况不一致。IFT80分布在细胞纤毛上,通过其表达的减少来调节纤毛的数量和长短参与癌细胞的增殖,故在严重癌组织中含量最低。      

pH effects on the cellular uptake of four photosensitizing drugs evaluated for use in photodynamic therapy of cancer

The difference in extracellular pH in malignant as compared to normal healthy tissues has been proposed to contribute to selective uptake of photosensitizers in tumors. Hematoporphyrin IX (HpIX), disulfonated meso-tetraphenylporphine (TPPS(2a)), meso-tetra(3-hydroxyphenyl)porphine (mTHPP) and meso-tetra(3-hydroxyphenyl)chlorin (mTHPC) were chosen to examine the pH dependence of their cellular drug uptake. The study was performed in the pH range 6.5-8.0 and showed that significantly higher amounts of the drug are taken up by T-47D cells at low pH values only in the case of HpIX. The pH value of the incubation medium did not influence the cellular uptake of mTHPP, mTHPC and TPPS(2a) significantly. The present work indicates that tumor selectivity of dyes, which get more lipophilic with decreasing pH value, may be related to the low extracellular pH value.     

The potential of immunomodulatory drugs in the treatment of solid tumors

Lenalidomide (REVLIMID?) CC-5013 (Celgene, NJ, USA) is approved, in both the USA and Europe, in combination with dexamethasone for the treatment of multiple myeloma patients who have received at least one prior therapy, and is rapidly being accepted worldwide for this condition. Lenalidomide is also approved in the USA and Canada for use in transfusion-dependent anemia in patients with low- and intermediate-1-risk myelodysplastic syndromes associated with del (5q) abnormality with or without additional abnormalities. Lenalidomide is an IMiD? immunomodulatory compound, incorporating structural modification of the drug thalidomide, which is active against a wide variety of autoimmune Th-2-dependent disorders, including erythema nodosum of leprosy, leishmaniasis, as well as severe ulcerative disorders such as Behcet's syndrome. Unfortunately, long-term use of thalidomide is limited, particularly by neurotoxicity. To date, results suggest that lenalidomide is more active than thalidomide and does not cause the neurotoxicity seen with thalidomide. Lenalidomide has multiple properties, including anti-inflammatory, antiangiogenic and costimulatory effects, as well as being able to inhibit T-regulatory cells, all of which are properties deemed desirable for anticancer activity. This article covers the evidence that lenalidomide may have a major role in the treatment and control of many cancer types other than del (5q) myelodysplastic syndrome and multiple myeloma.     

The relationship between intracellular and extracellular pH in spontaneous canine tumors.

Recently, it has been suggested that the cellular uptake of chemotherapeutic drugs may be dependent on the pH gradient between the intracellular (pHi) and extracellular (pHe) compartments. It has been demonstrated in murine tumor models that the extracellular environment is acidic, relative to the intracellular environment, thus favoring preferential accumulation of drugs that are weak acids into cells. However, concomitant measurements of pHi and pHe in spontaneous tumors have not been reported, so it is not certain how well the murine results translate to the clinical scenario. In this study, both types of measurements were performed in dogs with spontaneous malignant soft tissue tumors. On average, pHe was more acidic than pHi, with maintenance of a more physiologically balanced intracellular tumor environment. However, the magnitude of the gradient varied widely, and individual tumors had both positive and negative pH gradients (pHi - pHe). These data suggest that the magnitude and direction of the pH gradient may need to be measured for individual patient tumors and/or that manipulation of pHe may be required if exploitation of the pH gradient is to be achieved for tumor-selective augmentation of intracellular drug delivery.     

The histological types and the effects of radiation on tumors

The effects of radiation on tumors should be divided into radiosensitivity and radioresponsiveness. The local effects of radiation are not always consistent with curability. Though local control is one requirement to attain cure, the primary factor that affects long-term survival is the natural history of the tumor. The effects of irradiation can not be predicted only by determining the histological type of tumor. However, the natural history of the tumor can be understood by careful observation of the stroma in the tumor and condition of the host. As the result, radiocurability can be predicted to some extent.     

Lumican在肿瘤中表达及作用的相关研究进展

Lumican属于富含亮氨酸重复序列的小分子蛋白聚糖家族（small leucine-rich repeat proteoglycans,SLRPs）。近年来许多研究表明Lumican参与调节细胞稳态以及细胞功能。且Lumican基因的表达也与多种恶性肿瘤有关,但Lumican在肿瘤中的表达及其作用仍不是很明确。本文简述Lumican的结构、功能,重点描述Lumican在不同肿瘤中的表达情况、作用及作用机制,并对Lumican的诊断意义和深层研究进行了展望。     

The effects of dexamethasone on transcapillary transport in experimental brain tumors: II. Canine brain tumors

Summary We studied the effect of dexamethasone on transcapillary transport in ten Avian Sarcoma Virus (ASV)-induced canine brain tumors, before and one week after administration of dexamethasone, 2.5 mg/kg/day. A computed tomographic (CT) method was used to measure regional values of K₁ (blood-to-tissue transfer constant), k₂ (tissue-to-blood efflux constant), and V_p (tissue plasma vascular space) of meglumine iothalamate (Conray-60^TM); the values were reconstructed for each 0.8 × 0.8 x 5 mm volume element of the CT data. For all tumors considered together, there was a decrease in the whole tumor K₁ value of meglumine iothalamate from 26 ± 2.2 (SE) before dexamethasone to 24 ± 2.9 l/g/min after dexamethasone. V_p decreased from 7.2 ± 0.7 to 6.7 ± 0.9 ml/100 g, and the size of the tumor extracellular space (V_e) decreased from 0.30 to 0.26 ml/g. These changes were not statistically significant. However, when each tumor was used as its own control, k₁ significantly decreased after dexamethasone in four tumors, significantly increased in two and was unchanged in four. These results suggest that decreased blood-to-tissue transport may be one mechanism underlying resolution of tumor associated cerebral edema in some brain tumors and that the effects of dexamethasone on blood-to-tissue transport in brain tumors are variable from one tumor to the next. Decreased permeability may not be the sole mechanism by which dexamethasone reduces tumor-associated cerebral edema.     

艾迪注射液对消化道肿瘤患者肿瘤标志物的影响

目的 探讨艾迪注射液对消化道肿瘤康复期患者肿瘤标志物CEA、CA199及生活质量的影响.方法 比较消化道肿瘤康复期患者使用艾迪注射液前后CEA、CA199检测值及生活质量评分(EORTC QLQ-C30)的变化.结果 疗程前CEA为(4.23±0.57)ng/L,CA199(22.65±5.43)ng/ml; 疗程后C...     

微小RNAs对胸腺上皮细胞肿瘤的影响及研究进展

胸腺作为机体重要免疫器官,参与机体多种免疫功能。胸腺瘤和胸腺癌是来源于胸腺上皮细胞的肿瘤,在我国前纵隔肿瘤中较为常见。微小RNA（microRNAs,miRNAs）是一类内源性非编码小分子单链RNA,长度约为22个氨基酸,参与转录后基因表达调控过程。近年来miRNAs的研究已成为各学科的研究热点,针对miRNAs的新型诊断方法与治疗手段不断在国内外学术期刊上报道。胸腺上皮细胞肿瘤由于常伴有副肿瘤综合征,使其在临床症状表现及治疗方面复杂多样,通过miRNAs与胸腺上皮细胞肿瘤的研究,有望从根源上找出胸腺肿瘤多样性的原因并找到有效治疗手段。本文对近几年miRNAs与胸腺上皮细胞肿瘤的研究进行文献复习,探讨miRNAs对胸腺上皮细胞肿瘤的影响及研究进展,并作一综述。     

ATP 结合转运蛋白 C4与肿瘤及化疗药物的研究进展

ATP 结合转运蛋白 C4（ABCC4,MRP4）对于转运生理性、内源性或者外源性物质起重要作用。ABCC4基因在多种实体肿瘤和血液系统肿瘤中表达增高,并影响转移复发等过程。并且 ABCC4可降低多种化疗药物的细胞内浓度,下调细胞对化疗药物的敏感性,导致患者预后不良。     

多种药物对肝癌细胞端粒酶活性的影响

目的：观察几种在肝部职常用的药物对肝癌细胞ＳＭＭＣ－７７２１端粒酶活性的影响,进一步探讨它们的抗癌作用机制。方法：利用化疗药物顺铂,丝裂霉素Ｃ、阿霉素、５－氟尿嘧啶、干扰素、全反式维甲酸、叠氮胸苷处理肝癌细胞,然后使用ＴＲＡＰ方法观察处理的前后端粒酶活性的变化,同时利用流式细胞术观察细胞周期和凋广。结果：化疗药物顺铂和丝裂霉素Ｃ对肝癌细胞端粒酶活性有抑制作用,流式细胞术检测表明当端粒酶活性受到抑制