Experimental studies on the combined effects of alpha and gamma interferons against human tumor xenografts transplanted into nude mice

The antitumor activities, resulting from the combined treatment of leukocyte interferon (IFN-alpha), with recombinant human immune interferon (IFN-gamma), against human tumor xenografts in nude mice, were studied. Nine human tumor xenografts, (7 from gastric carcinoma, 1 from gallbladder carcinoma and 1 from breast carcinoma), were serially transplanted into nude mice for the purpose of this experiment. Each human tumor xenograft was inoculated subcutaneously into BALB/c nu/nu nude mice and treatment was started after the estimated tumor had reached 100-300 mg. IFN was administered intramuscularly at a schedule of qd X 14. Treatment with either IFN-alpha or IFN-gamma alone, did not produce any antitumor effect against the various human tumor xenografts, however the combination of IFN-alpha with IFN-gamma resulted in achieving significant antitumor effects against the various human tumors. Inhibition of tumor growth was observed in 7 of the 9 tumors (77.8 per cent), and regression of the tumor was noted in 5 of the 9 tumors (55.6 per cent).     

Experimental studies on the combined effects of alpha and gamma interferons against human tumor xenografts transplanted into nude mice

The antitumor activities, resulting from the combined treatment of leukocyte interferon (IFN-α), with recombinant human immune interferon (IFN-γ), against human tumor xenografts in nude mice, were studied. Nine human tumor xenografts, (7 from gastric carcinoma, 1 from gallbladder carcinoma and 1 from breast carcinoma), were serially transplanted into nude mice for the purpose of this experiment. Each human tumor xenograft was inoculated subcutaneously into BALB/c nu/nu nude mice and treatment was started after the estimated tumor had reached 100–300 mg. IFN was administered intramuscularly at a schedule of qd×14. Treatment with either IFN-α or IFN-γ alone, did not produce any antitumor effect against the various human tumor xenografts, however the combination of IFN-α with IFN-γ resulted in achieving significant antitumor effects against the various human tumors. Inhibition of tumor growth was observed in 7 of the 9 tumors (77.8 per cent), and regression of the tumor was noted in 5 of the 9 tumors (55.6 per cent).     

Anti-interleukin-6 monoclonal antibody induces regression of human prostate cancer xenografts in nude mice

BACKGROUND: Despite clinical associations and in vitro data suggesting that autocrine interleukin-6 (IL-6) production contributes to prostate cancer progression or chemotherapy resistance, there have been no reports that explore the role of IL-6 on prostate tumors in vivo. In the present study, we investigated the effect of IL-6 inhibition on the growth of human prostate cancer xenografts in nude mice. METHODS: To determine if autocrine IL-6 production contributes to prostate cancer growth and chemotherapy resistance in vivo, xenografts of a human prostate cancer cell line that produces IL-6 (PC-3) were established in nude mice. The mice were randomly divided into four treatment groups: (1) saline (vehicle control) + murine IgG (isotype control); (2) etoposide + murine IgG; (3) saline + anti-IL-6 monoclonal antibody; and (4) etoposide + anti-IL-6 monoclonal antibody. Tumors were measured twice weekly during a 4-week treatment period. At the conclusion of the study, all mice were sacrificed, and in addition to final volume, tumors were evaluated for the degree of apoptosis by TUNEL analysis. RESULTS: Anti-IL-6 Ab (with saline or etoposide) induced tumor apoptosis and regression ( approximately 60% compared to initial tumor size). Etoposide alone did not induce tumor regression or apoptosis in this animal model, and there was no synergy between anti-IL-6 Ab and etoposide. CONCLUSIONS: These studies suggest that IL-6 contributes to prostate cancer growth in vivo, and that targeting IL-6 may contribute to prostate cancer therapy.     

Anti‐PSMA immunotoxin as novel treatment for prostate cancer? High and specific antitumor activity on human prostate xenograft tumors in SCID mice

BACKGROUND: Expression of the prostate specific membrane antigen (PSMA) is highly restricted to prostate epithelial cells. Therefore, toxin-based immunotherapy against this antigen may represent an alternative therapeutic option for prostate cancer. For these purposes, the effects of the recombinant anti-PSMA immunotoxin A5-PE40 on prostate tumor growth were investigated in vitro and in vivo. METHODS: The in vitro binding and cytotoxicity of A5-PE40 were tested on the PSMA-expressing prostate cancer cell line C4-2 and on the PSMA-negative cell line DU145 by flow cytometry and WST assays. The binding of the immunotoxin to SCID mouse xenografts and to various mouse organs was examined by Western blot analysis. In vivo, the antitumor activity of the immunotoxin was tested by injecting A5-PE40 in mice bearing C4-2 or DU145 xenografts. RESULTS: In vitro, a specific binding of A5-PE40 to C4-2 cells could be shown with a concentration-dependent cytotoxicity (IC(50) value=220 pM). In the next step, a specific binding of the immunotoxin to C4-2 xenografts could be demonstrated. In contrast, no binding on mouse organs expressing high homologous mouse PSMA was found. The treatment of mice with C4-2 tumors caused a significant inhibition of tumor growth in vivo, whereas DU145 xenografts remained totally unaffected. CONCLUSIONS: A5-PE40 represents a recombinant anti-PSMA immunotoxin with potent antitumor activity in mice bearing human prostate cancer xenograft tumors. Therefore, A5-PE40 could be a promising candidate for therapeutic applications in patients with prostate cancer.     

Treatment with soybean-derived Bowman Birk inhibitor increases serum prostate-specific antigen concentration while suppressing growth of human prostate cancer xenografts in nude mice.

BACKGROUND: Bowman Birk inhibitor (BBI) is an anticarcinogenic serine protease inhibitor that may inhibit the protease activity of prostate-specific antigen (PSA) and the growth of human prostate cancer xenografts in nude mice. METHODS: Human prostate cancer xenografts were established by implanting LNCaP cells into the prostate glands of NCRNU-M athymic nude mice. The animals with established tumors were maintained on a control diet or diets supplemented with 1% BBI or 1%, 2%, or 3% BBI concentrate (BBIC) for 6 weeks. The serum PSA concentrations were determined before and after the BBI or BBIC treatment period. The final tumor loads were determined at autopsy. RESULTS: Treatment with BBI or BBIC decreased the final tumor load and increased the tumor doubling time and PSA density in the nude mice bearing human prostate cancer xenografts. CONCLUSIONS: BBI and/or BBIC could be useful for prostate cancer treatment.     

Monoclonal antibodies in human renal cell carcinoma and their use in radioimmune localization and therapy of tumor xenografts

A series of monoclonal antibodies (Mabs) to human renal cell carcinoma (RCC) material was developed. Two Mabs (D5D and A6H) that showed especially restrictive reactivities were radiolabeled with iodine 131 and tested in nude mice bearing human tumor xenografts for their ability to specifically localize RCC. Extensive studies of tissue radioactive uptake indicated that these Mabs could specifically localize RCC tumors with some mice achieving high tumor:blood ratios ranging from 15 to 60. Scintigraphic scanning revealed specific and consistent detection of RCC xenografts. Finally, preliminary results indicate that larger intravenous doses of radiolabeled RCC Mabs were effective as radioimmune therapy in inhibiting RCC xenograft growth. Mabs can be produced that are highly restrictive to human RCC and may be useful clinically for radioimmunoscintigraphy or therapy.     

Antitumor effects of recombinant human tumor necrosis factor against human tumor xenografts transplanted into nude mice

Antitumor activities of recombinant human tumor necrosis factor (rH-TNF) against human tumor xenografts in nude mice were studied. Thirteen human tumor xenografts serially transplanted into nude mice were used for experiments; five gastric, two breast, two gallbladder, one colon and one esophageal carcinoma, one liposarcoma and one squamous carcinoma of the neck. They were inoculated into the subcutaneous tissue of BALB/c nu/nu nude mice and the treatment was started when the estimated tumor weight reached 100-300 mg. rH-TNF was administered intratumorally at schedule of qd X 5 or q3d X 5. rH-TNF showed a marked antitumor activity against various human tumors. The hemorrhagic necrosis was observed in all types of the human tumor xenografts (100 per cent), and the complete regression of the tumor was noted in 4 of 11 tumors (36.4 per cent). On the contrary, intraperitoneal rH-TNF exhibited little antitumor effect. The additive effect in the combination of TNF and Mitomycin C was observed against two Mitomycin C resistant gastric tumors.     

携带人内皮抑素基因的增殖型腺病毒AdTPHre-hE对胰腺癌的体内实验研究

目的通过建立裸鼠胰腺癌肿瘤模型,在体内实验中进一步证实携带人内皮抑素基因的增殖型腺病毒AdTPHre-hE的抗肿瘤作用.方法建立AsPC-1胰腺癌细胞BALB/c裸鼠皮下移植瘤模型,在瘤体内注射AdTPHre-hE治疗,观察肿瘤生长.ELISA法检测裸鼠血清中人内皮抑素浓度,肿瘤组织行Hexon单克隆抗体免疫组化染色及微血管免疫组化染色.结果AdTPHre-hE抑制肿瘤生长的作用显著强于Ad-hE(P＜0.01)和对照组(P＜0.01).随着治疗时间的延长,裸鼠血清中内皮抑素表达量不断增加,明显高于Ad-hE组(P＜0.01)和对照组(P＜0.01).病毒Hexon免疫组化染色显示,AdTPHre-hE治疗组移植瘤内可见片状或弥漫性分布的阳性染色,AdTPHre-hE治疗组瘤组织中微血管密度为16.3±4.3明显少于Ad-hE组的33.8±6.2(P＜0.01)和对照组的36.8±4.6(P＜0.01).结论增殖型腺病毒AdTPHre-hE介导人内皮抑素的表达,具有明显抑制肿瘤细胞生长的作用.     

Effect of oxygen tension on the antitumor activity of mitomycin C assayed by human tumor clonogenic assay

The effects of oxygen tensions on the antitumor activity of mitomycin-C (MMC) were surveyed using the human tumor clonogenic assay technique. Six human tumor xenografts (4 gastric cancers, and 2 colon cancers) were used in this study. Tumor cells were continuously exposed to MMC during the experimental period at various oxygen tensions, such as 2 per cent, which is considered to be hypoxic oxygen tension, 5 per cent which is considered as the physiological oxygen tension, and 20 per cent which is the conventional in vitro culture condition. The antitumor activities of MMC on the 6 human tumor xenografts increased when the oxygen tension was lowered from 20 per cent to 5 per cent. However, no further increases of the antitumor activities of MMC were observed by lowering the oxygen tension from 5 to 2 per cent. Additionally, the in vitro antitumor activities of MMC at various oxygen tensions were compared with the in vivo chemosensitivities evaluated in nude mice. In five of the 6 human tumor xenografts, in vitro chemosensitivities assayed at 2 or 5 per cent oxygen tension were concordant with in vivo chemosensitivities, although in vitro chemosensitivities assayed at 20 per cent were concordant with in vivo chemosensitivities in 3 of the 6 tested tumors.     

Antitumor effects of recombinant human tumor necrosis factor against human tumor xenografts transplanted into nude mice

Antitumor activities of recombinant human tumor necrosis factor (rH-TNF) against human tumor xenografts in nude mice were studied. Thirteen human tumor xenografts serially transplanted into nude mice were used for experiments; five gastric, two breast, two gallbladder, one colon and one esophageal carcinoma, one liposarcoma and one squamous carcinoma of the neck. They were inoculated into the subcutaneous tissue of BALB/c nu/nu nude mice and the treatment was started when the estimated tumor weight reached 100–300 mg. rH-TNF was administered intratumorally at schedule of qd×5 or q3d×5. rH-TNF showed a marked antitumor activity against various human tumors. The hemorrhagic necrosis was observed in all types of the human tumor xenografts (100 per cent), and the complete regression of the tumor was noted in 4 of 11 tumors (36.4 per cent). On the contray, intraperitoneal rH-TNF exhibited little antitumor effect. The additive effect in the combination of TNF and Mitomycin C was observed against two Mitomycin C resistant gastric tumors.     

抗人IgG抗体与丝裂霉素联合应用治疗膀胱癌的实验研究

目的 探讨抗人IgG抗体和丝裂霉素(MMC)联合应用对人膀胱癌细胞株的抑制作用及机制.方法 抗人IgG抗体和MMC单独或联合作用于人膀胱癌T24细胞,噻唑盐(MTT)法检测细胞生长抑制率,流式细胞仪检测T24细胞的凋亡率,蛋白质印迹法检测半胱氨酸天冬氨酸蛋白酶3(Caspase-3)和PARP的表达.采用T24细胞裸鼠移植瘤模型进行抗人IgG抗体和MMC的体内抗瘤实验.结果 单独应用抗人IgG抗体和MMC对T24细胞生长抑制率分别为(25.02±6.71)%和(32.31±6.46)%,而二者联用的抑制率达(73.66±5.81)%.PBS、25mg/L羊IgG、25mg/L羊抗人IgG抗体、2mg/L MMC、2mg/L MMCIk 25mg/L羊IgG和2mg/L MMC加25mg/L羊抗人IgG抗体处理T24细胞72 h后细胞凋亡率分别为1.7%、2.3%、20.7%、22.4%、28.3%和53.8%.羊抗人IgG抗体、MMC、MMC加羊IgG和MMC加羊抗人IgG抗体处理T24细胞72 h后出现17 000的Caspase-3和85 000的PARP剪切片断.体内实验显示羊IgG组、羊抗人IgG抗体组、MMC组、MMC加羊抗人IgG抗体组抑瘤率分别为2.31%、12.73%,36.81%和50.51%.HE切片观察见生理盐水组和羊IgG组移植瘤细胞基本无凋亡和坏死,羊抗人IgG抗体组肿瘤细胞凋亡和坏死增多,MMC组和MMC加羊抗人IgG抗体组则见大量肿瘤细胞凋亡和坏死.结论 抗人IgG抗体和MMC联合应用对膀胱癌具有体内外双重抗瘤作用,其抗瘤机制可能与诱导肿瘤细胞凋亡有关.     

Differential sensitivity of renal cell carcinoma xenografts towards therapy with interferon-alpha,interferon-gamma,tumor necrosis factor and their combinations

Summary Whereas cytokine therapy has proven efficacy in the treatment of metastatic renal cell carcinoma (RCC), many questions regarding the use of these drugs remain unanswered. In the present study we evaluated the antiproliferation effects of human recombinant alphainterferon (IFN), gamma-interferon and tumor necrosis factor-alpha (TNF) on eight human RCC xenografts. In particular, the importance of the administration route, dosage and tumor load was investigated. Response to the cytokines differed widely amongst the different tumors. Of three tested routes of administration (i.v., i.p. and s.c. peritumoral), only the s.c. peritumoral route was effective against tumor growth. After 6 weeks of therapy consisting of 150 or 1,500 units IFN/g given s.c. peritumorally three times a week or 30,000 units TNF/g given five times a week, alpha-IFN treatment resulted in 2%–100% growth inhibition; gamma-IFN, in 7%–80%; and TNF, in 35%–75% as compared with the untreated control. Growth of five of eight tumor lines could be inhibited completely by combinations of IFN and TNF, whereby the tumor dimensions at the beginning of therapy were decisive for the results. In some cases IFNs had optimal doses; however, the antitumor effects of TNF were always dose-dependent. Our studies indicate that the doses at which the optimal direct effects of cytokines are measured are critically dependent on the tumor treated. Although direct effects are only one part of the mode of action of cytokines, our results indicate that dosage of cytokines may need individualisation.     

Effect of tyrosine kinase inhibitor treatment of renal cell carcinoma on the accumulation of carbonic anhydrase IX‐specific chimeric monoclonal antibody cG250

What’s known on the subject? and What does the study add? TKI combined with chemotherapy has shown significant synergistic activity in glioma, colon‐, and breast carcinoma, possibly through improved delivery of therapeutic molecules through vascular normalization and reduced tumour interstitial fluid pressure. Whether this can be achieved with larger molecules such as antibodies is unclear. Possibly, a narrow time window exists in which lowered interstitial fluid pressures precedes tumour vasculature destruction during which enhanced antibody uptake and synergy might be achieved. Here we show that careful timing will be necessary because the TKI‐induced tumour‐vessel destruction is swift and prevents adequate antibody accumulation.

OBJECTIVE

To investigate the effect of three different tyrosine kinase inhibitors (TKIs) on the biodistribution of chimeric monoclonal antibody (mAb) cG250, which identifies carbonic anhydrase IX (CAIX), in nude mice bearing human renal cell carcinoma (RCC) xenografts. TKIs represent the best, but still suboptimal treatment for metastatic RCC (mRCC) and combined therapy or sequential therapy might be beneficial. CAIX is abundantly over expressed in RCC and clinical trials have shown abundant and specific tumour accumulation of cG250. Combining a TKI with mAb cG250, involved in a different effector mechanism, might lead to improved tumour responses and survival in patients with mRCC.

MATERIALS AND METHODS

Nude mice bearing human RCC xenografts were treated orally with 0.75 mg/day sunitinib, 1 mg/day vandetanib, 1 mg/day sorafenib or vehicle control for 7 or 14 days. At 7 days, mice were injected i.v. with 185 kBq/5 µg ¹²⁵I‐cG250. Mice were killed at predetermined days and cG250 biodistribution was determined. Tumours were analysed by immunohistochemistry for the presence of endothelial cells, laminin, smooth muscle actin, CAIX expression and uptake of mAb cG250.

RESULTS

While on TKI treatment, tumour uptake of cG250 decreased dramatically, tumour growth was slightly inhibited and vascular density decreased considerably as judged by various markers. When treatment was stopped at 7 days, there was robust neovascularization, mainly at the tumour periphery. Consequently, cG250 uptake also recovered, albeit cG250 uptake appeared to be restricted to the tumour periphery where vigorous neovascularization was visible.

CONCLUSIONS

Simultaneous administration of a TKI and mAb cG250 severely compromised mAb accumulation. However, shortly after discontinuation of TKI treatment mAb accumulation was restored. Combined treatment strategies with TKI and mAb should be carefully designed.     

Human renal cell carcinoma in the six day subrenal capsule assay

The applicability of the subrenal capsule assay (SRCA) as a method for chemosensitivity testing of human renal cell carcinoma (RCC) was assessed. Tissue fragments of about one mm3. in size, obtained from patients who had undergone nephrectomy because of renal cell carcinoma (RCC), were implanted in preirradiated mice. The change of the size of the implanted tissue as well as the histology of the tissue were determined six days later. Untreated control tumors were used to determine the evaluability of the individual assays using criteria based on 1) tumor growth (an increase in tumor size or a decrease not exceeding 0.05 mm.) and 2) tumor histology (presence of carcinoma cells in at least 70% of the tissues). The first criterion was fulfilled in 20/24 (83%) of the renal tumors; tumor histology was satisfactory in 9/24 (38%) of the tumors. Taken together, only 9/24 assays were considered to be evaluable. Discrepancies between measurement and histologic appearance were also found for individual tumors and for treated tumors. Due to the lack of correlation between measurement and histology change in tumor size therefore cannot be considered a reliable parameter for assessing viability or drug activity.     

表达白细胞介素-18的溶瘤腺病毒对裸鼠肾癌移植瘤的治疗作用

目的 观察表达IL-18的溶瘤腺病毒(ZD55-IL18)对裸鼠肾癌移植瘤生长及血管形成的抑制作用.方法 荷肾癌裸鼠随机分4组,每组8只.瘤体内注射ZD55-IL18、溶瘤腺病毒ZD55-EGFP、表达IL-18的增殖缺陷腺病毒Ad-IL18及PBS,每次注射病毒7×108PFU/只,连续注射3 d.注射后第7天,每组处死3只取肿瘤组织,免疫组织化学检测肿瘤E1A、IL-18、CD34、VEGF表达及凋亡.第50天时处死动物测量肿瘤体积.结果 ZD55-IL18、ZD55-EGFP、Ad-IL18及生理盐水处理组肿瘤体积(mm3)分别为:299.7±52.9、536.8±90.3、570.3±99.0、766.1±145.8,ZD55-IL18与各组之间差异有统计学意义(P<0.01).Ad-IL18处理组肿瘤无E1A蛋白表达,ZD55-IL18处理组有大量E1A蛋白表达,表明病毒复制.ZD55-IL18处理组肿瘤IL-18表达及凋亡细胞阳性率均显著高于Ad-IL18处理组.ZD55-IL18处理组肿瘤CD34、VEGF表达均显著低于Ad-IL18处理组.结论 表达IL-18的溶瘤腺病毒ZD55-IL18比增殖缺陷腺病毒Ad-IL18具有更强的抑制肾癌生长及血管形成作用.     

Antitumor activities of KW-2152, a new isoquinon agent,against human tumor xenografts transplanted into nude mice

The antitumor activities of KW-2152, a new isoquinon derivative, were examined in thirteen human tumor xenografts, transplanted into nude mice. KW-2152 was administered intravenously at a schedule of q4d×3, in daily doses of 7.3 mg/kg and 3.6 mg/kg, and q2d×6 with a daily dosis of 7.3 mg/kg, respectively. KW-2152 displayed significant antitumor activities against the human tumor xenografts in 3 out of 13 strains (23.1 per cent) at the schedule of q4d×3, with a daily dose of 7.3 mg/kg. Depending on the schedule of administration, tumor activity was observed in 8 out of 13 strains (61.5 per cent) at a schedule of q2d×6, with a daily dose of 7.3 mg/kg. SH-2 and SH-9 gastric tumors were sensitive to KW-2152 and growth was completely inhibited with the schedule of q4d×3, and a daily dose of 7.3 mg/kg. Thus, KW-2152 seems to have a wide antitumor spectrum, and the possible antitumor effects for clinical use, warrant attention.     

Interleukin-12 delivered by biodegradable microspheres promotes the antitumor activity of human peripheral blood lymphocytes in a human head and neck tumor xenograft/SCID mouse model

BACKGROUND: The role of cytokines in tumor regression is now well established. The major limitation for the clinical use of cytokines is the lack of a simple and effective protocol for the local and sustained delivery of cytokines to the tumor milieu. This study reports suppression of human head and neck squamous cell carcinoma (HNSCC) by human peripheral blood lymphocytes (HuPBL) following local, sustained delivery of interleukin-12 (IL-12) to tumors with biodegradable microspheres in a human/SCID mouse chimeric model. Materials and Methods Nondisrupted biopsy pieces (120 mg) of primary HNSCC were implanted s.c. into severe combined immunodeficient (SCID) mice and were expanded by serial passage in mice. Tumors were then titrated with different doses of allogeneic HuPBL by coengraftment of tumor pieces and HuPBL into the subcutis of SCID mice to determine whether the HuPBL possessed antitumor activity (the SCID/Winn model). The lymphocyte subsets that were responsible for the suppression of tumor engraftment were identified by selective depletion of the CD4+, CD8+, and CD56+ cells from the HuPBL prior to engraftment into mice. Attempts were then made to augment the antitumor activity of the HuPBL either by repeated intralesional bolus injections of recombinant human IL-12 (0.5 microg x 10 doses) or with a single dose of IL-12-loaded microspheres ( approximately 1.65 microg IL-12/mg microspheres, 2 mg microspheres/mouse). RESULTS: Successful engraftment of HNSCC was observed in 12 of 19 different patient samples. Normal histological architecture of tumor was maintained up to four serial passages in the SCID mice. After the first tumor engraftment, but not in subsequent passages, human immunoglobulin produced by plasma cells present in the tumor infiltrating lymphocyte population was detected in the mouse sera. Allogeneic human PBL displayed antitumor cytotoxic activity in a cell dose-dependent fashion when coengrafted with the tumors passaged in SCID mice. Lymphocyte subset depletion studies established that tumor suppression was dependent on both the CD8+ T lymphocytes and the CD56+ natural killer cells. Treatment of tumors with a single intralesional injection of IL-12-loaded microspheres was highly effective, resulting in the complete suppression of tumor engraftment in 50% of the mice. In contrast, treatment of tumors with repeated bolus IL-12 injections suppressed tumor engraftment only transiently and did not result in complete tumor rejection in any of the mice. CONCLUSION: The coengraftment of HNSCC and allogeneic lymphocytes into SCID mice provides a viable model with which to evaluate immunotherapeutic strategies for human cancer. The use of biodegradable microspheres for local sustained delivery of cytokines to augment lymphocyte mediated antitumor immunity within the tumor microenvironment provides a safer and simpler alternative to current cytokine immunotherapy protocols.     

A new serially transplantable human prostatic cancer (HONDA) in nude mice

A new serially transplantable human prostatic cancer (HONDA) in nude mice was established from a patient with metastatic prostate carcinoma. The tumor grows well in male nude mice. Doubling time of the tumor weight at passage #13 was 9.5 +/- 0.87 days (mean +/- SD). The tumor retains the original histological features of adenocarcinoma even after 6 years of continuous passage. High levels of human prostatic acid phosphatase were detected by radioimmunoassay in sera from the tumor-bearing mice. The tumor cells contain human prostate specific antigen. Electron microscopy showed particles resembling type A retroviruses in cisterns of endoplasmic reticulum, and particles resembling type C retroviruses in the intercellular space of the tumor cells. The tumor grew well in female mice treated with testosterone, but not in untreated female mice or castrated male mice.     

Antitumor activity of the polyamine analog N(1), N(11)-diethylnorspermine against human prostate carcinoma cells

BACKGROUND: Recent studies indicate that N-terminally bis-ethylated-polyamine analogs have significant antitumor activity in several human solid-tumor models. In this study, the in vitro and in vivo antitumor potential of the polyamine analog N(1), N(11)-diethylnorspermine (DENSpm) in human prostate carcinoma cells was examined. METHODS: The antiproliferative and biochemical effects of DENSpm were tested in four human prostate cancer cell lines, i.e., PC-3, TSU-pr1, DU-145, and JCA-1. The in vivo antitumor potential was explored in two groups of nude mice bearing small or more developed xenografts of the DU-145 cell line. The mice were treated with 40 mg/kg DENSpm, three times per day for two cycles of 6 days, on days 1-6 and 8-13. RESULTS: In vitro studies showed that all four tested human prostate carcinoma cell lines were sensitive to DENSpm in micromolar concentrations. In tumor-bearing mice, DENSpm clearly prevented tumor growth in both size groups, which became significant after day 17. Treatment with DENSpm evoked intracellular accumulation of the analog and various regulatory responses, e.g., downregulation of the polyamine biosynthesis, the induction of the catabolic enzyme spermidine/spermine N(1)-acetyltransferase (SSAT), and the depletion or decrease of natural polyamines. The cellular sensitivity to growth inhibition by DENSpm only correlated with the degree of ODC inhibition and SSAT induction. CONCLUSIONS: DENSpm has sustained inhibitory effects on the growth of human prostate carcinoma cells in vitro as well in vivo. This polyamine analog may provide a new tool in the chemotherapy of prostate cancers with various phenotypes.     

Increase in incidental renal cell carcinoma in the northern part of the Netherlands

OBJECTIVES: Evaluating in a retrospective survey the incidence of incidental and symptomatic renal cell carcinoma (RCC) between 1977 and 1994 in the northern part of the Netherlands and the mode of their detection. PATIENTS AND METHODS: Retrospectively, 173 patients surgically treated for RCC were divided into two groups according to the period of detection, 1977-1987 (n = 87) and 1987-1994 (n = 86). Because of the increase in abdominal ultrasound in 1987, this year was used as the cutoff date. In both periods the patients were grouped according to whether the tumor was found incidentally or whether the tumor was suspected. The mode of detection was recorded together with the tumor stage at presentation and survival. RESULTS: The incidental detection rate was 33% (29/87) in the 1977-1987 group and 49% (42/86) in the 1987-1994 group, showing a significant difference (p = 0.038). In the 1977-1987 group incidental tumors were detected with ultrasound in 83% and symptomatic tumors with ultrasound in 36%. Of the cases in the 1987-1994 group this percentage was 91 and 43%, respectively. Disease-free survival rates after a mean follow-up of 10 years were 63% in the incidental RCC group and 37% in the symptomatic RCC group (p = 0.0159). CONCLUSIONS: There is an increase in incidental tumors in this part of the Netherlands with ultrasound as the mode of detection. The disease-free survival is significantly better in the incidental tumor group.