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目的　观察电穿孔技术结合博莱霉素化疗对结肠癌裸鼠移植瘤的抗肿瘤效果 ,探讨其免疫效应机制 ,为其临床应用提供实验依据。方法　 2 0 0 2年 11月至 2 0 0 3年 6月 ,用人结肠癌Lovo细胞系建立结肠癌裸鼠移植瘤模型 ,随机分为电穿孔化疗组 (B E )、单纯化疗组 (B E - )、单纯电击组 (B -E )和阴性对照组 (B -E - ) ,动态观察肿瘤大小 ,7d后处死并取出皮下肿瘤称重 ,观察其组织学改变 ,并用LDH法检测小鼠脾NK、LAK杀伤活性。结果　B E 组移植瘤较其他各组明显缩小 (P <0 0 1) ;B E 组完全缓解 1例 ,部分缓解 7例 ,B -E 和B E -组内各有 1例部分缓解 ,而B -E -组中无一例有效 ,B E 组有效率与其余各组的差异有统计学意义 (P <0 0 1) ;组织学观察也显示B E 组的移植瘤内大片肿瘤细胞坏死、血管损伤和炎细胞浸润 ;各组小鼠的NK和LAK细胞的杀伤活性差异无显著意义 (P >0 0 5 )。结论　电穿孔化疗可显著增强结肠癌裸鼠移植瘤对化疗的敏感性和疗效 ,可能主要与T细胞介导的肿瘤特异性免疫机制有关 ,可成为结肠癌治疗的一种新方法。     

Potentiation of effects of anticancer agents by local electric pulses in murine bladder cancer

Electrochemotherapy is a novel cancer treatment in which electric pulses (EP) are used as a means of delivering anticancer agents to the cytoplasm of cancer cells (electroporation). The present study evaluates whether electrochemotherapy has in vitro and in vivo anticancer effects in murine bladder cancer. Using mouse bladder tumor cells (MBT-2 cells), in vitro electrochemotherapy was performed by applying EP to the cell suspension immediately after the addition of anticancer agents. The cytotoxicity of adriamycin (ADM), bleomycin (BLM) and cis-diamminedichloroplatinum(II) (CDDP) was determined by measuring succinate dehydrogenase (SD) activity in both electroporated and non-electroporated cells. In addition, intracellular concentrations of these anticancer agents were also measured. In the in vivo study, tumor-bearing C3H/He mice were treated with an intraperitoneal injection of anticancer agents followed by a local delivery of EP at the tumor site. Then, tumor growth rate (TGR) was determined and compared to that in the sham-treated control group, the EP-only group and the drug-only group. The in vitro study showed that, with electroporation, the cytotoxicity of BLM in electroporated cells was increased by as much as 95.7-fold compared to that of non-electroporated MBT-2 cells; CDDP showed only an increase of 1.8-fold and ADM showed no increase. After electroporation, the intracellular concentration of BLM, CDDP and ADM showed an increase of 120-, 1.7- and 0.8-fold, respectively. In electrochemotherapy for in vivo growing tumors, the potentiation of the antitumor effect was most prominent when combined with BLM, only slightly with CDDP, and totally absent with ADM. It is clear from in vitro and in vivo studies that, in a murine bladder tumor, the anticancer effect of BLM can be considerably potentiated by applying EP. Thus, BLM seems to be the most suitable anticancer agent for electrochemotherapy of bladder cancer. Received: 28 August 1999 / Accepted: 27 July 2000     

电穿孔化疗对结肠癌裸鼠移植瘤模型的作用研究

目的:观察电穿孔技术结合博莱霉素化疗对结肠癌裸鼠移植瘤的抗肿瘤效果,为本疗法的临床应用提供实验依据。方法:于裸鼠左前肢皮下接种人结肠癌LoVo单细胞悬液,3周后成功建立结肠癌裸鼠皮下移植瘤模型40只,随机将其分为电穿孔化疗(B E )组、单纯化疗(B E-)组、单纯电穿孔(B-E )组和阴性对照(B-E-)组,每组10只。动态观察肿瘤大小,治疗第7天处死小鼠并取出皮下肿瘤称重,。并观察其组织学改变。结果:B E 组裸鼠移植瘤体积较其他各组明显缩小(P<0.01),该组1只裸鼠的移植瘤呈完全缓解,部分缓解7只;B-E 和B E-组内各有1只部分缓解,而B-E-组中无一有效。B E 组有效率与其余各组的差别有统计学意义(P<0.01)。组织学观察也显示B E 组的移植瘤内大片肿瘤细胞坏死、血管损伤和炎细胞浸润。结论:电穿孔化疗可显著增强结肠癌裸鼠皮下移植瘤对化疗的敏感性,疗效明显,有可能成为结直肠癌治疗的一种新方法。     

Proglumide, a gastrin receptor antagonist, inhibits growth of colon cancer and enhances survival in mice.

Some tumors are responsive to hormone manipulation. Some gastric and colonic adenocarcinomas from both humans and animals have specific gastrin receptors. A transplantable mouse colon adenocarcinoma cell line (MC-26) contains gastrin receptors; growth of MC-26 colon cancer in vivo is stimulated by pentagastrin (PG). The purpose of this study was to determine whether a gastrin-receptor antagonist, proglumide (PGL), would inhibit growth of MC-26 colon cancer and prolong survival in tumor-bearing mice. Subcutaneous tumors were induced by injecting single-cell suspensions of MC-26 cells into 50 mice divided into 10/group. In Experiment 1, all mice received 1 X 10(5) tumor cells and treatment groups were divided as follows: Group A received intraperitoneal (IP) saline (0.2 ml tid beginning on day 1); B, IP, PGL (250 mg/kg tid) from day of tumor cell inoculation; and C, IP PGL (250 mg/kg tid) from day 7 after tumor implantation. In Experiment 2, mice were inoculated with half the number of tumor cells. Group I mice received saline and Group II received PGL in the same manner starting on day 1. Tumors were measured and all mice were sacrificed on day 23. In Experiment 1, mean tumor area in Group B (PGL-treated) was significantly smaller than Group A on days 11, 14, 17, and 21. Tumors of Group C were significantly smaller than controls on day 21. Survival of PGL-treated mice was significantly prolonged. In Experiment 2, mean tumor area, mean tumor weight, and tumor DNA and RNA content were significantly less in the PGL-treated group than control. It was concluded that growth of a gastrin-responsive colon cancer was inhibited and host survival was enhanced by treatment with a gastrin-receptor antagonist. Hormone manipulation may be a useful treatment for gastrointestinal cancers.     

Possible Involvement of Antitumor Immunity in the Eradication of Colon 26 Induced by Low-Voltage Electrochemotherapy with Bleomycin

Purpose: The antitumor efficiency of electrochemotherapy using chemotherapeutic agents and high-voltage electric pulse has been reported. This study was done to define the precise nature of the involvement of antitumor immunity in the regression of tumor nodules in electrochemotherapy, and to evaluate the effectiveness of using low-voltage electroporation. Methods: Balb/c mice and Balb/c nu/nu nude mice were inoculated subcutaneously with Colon 26 cells or Meth A cells. Electrochemotherapy using bleomycin and low-voltage electroporation (CUY21) was performed as a treatment against tumor nodules. Results: Colon 26 tumors were eradicated in the mice given an intratumor (i.t.) injection of 500 μg bleomycin followed by treatment with electric fields ranging from 50 to 150 V/cm, with complete response rates ranging from 80% to 100%. The mice rejected inoculations of rechallenged Colon 26 cells, but not Meth A cells. In the Balb/c nu/nu nude mice, complete regression of the tumor was not seen after electrochemotherapy under the same therapeutic conditions that resulted in almost complete cure in the Balb/c mice. Conclusion: Our results suggest that the generation of T-cell-dependent, tumor-specific protective immunity might be involved in the process of tumor nodule regression in low-voltage electrochemotherapy. Received: February 14, 2002 / Accepted: July 2, 2002 Reprint requests to: Y. Gunji     

电脉冲化疗治疗人前列腺癌裸鼠移植瘤

目的　探讨平阳霉素（ＰＹＭ） 与电脉冲（ＥＰ） 相结合的电脉冲化疗对人前列腺癌细胞系ＰＣ３ｍ 裸鼠皮下移植瘤的作用。方法　将左右侧颈背部荷有ＰＣ３ｍ 肿瘤的裸鼠随机分为５ 组：按左右不同分别给予如下治疗：（１）Ｐ－ Ｅ－ ｜Ｐ＋ Ｅ－ ,（２）Ｐ－ Ｅ－ ｜Ｐ－ Ｅ＋ ,（３）Ｐ－ Ｅ－ ,｜Ｐ＋ Ｅ＋ ,（４）Ｐ＋ Ｅ－｜Ｐ＋ Ｅ＋ ,（５）Ｐ－ Ｅ＋ ｜Ｐ＋ Ｅ＋ 。Ｐ－ Ｅ－ 代表未治疗,Ｐ＋ Ｅ－ 代表肿瘤内注射平阳霉素,Ｐ－ Ｅ＋ 代表单给电脉冲,Ｐ＋ Ｅ＋ 代表电脉冲化疗,即肿瘤内注射平阳霉素后给予电脉冲。结果　亚治疗量的平阳霉素肿瘤内注射后给予电脉冲,１００％ 有效,其中６２．５ ％ 部分缓解、３７．５％ 完全缓解,即Ｐ＋ Ｅ＋ 有效,而其他组合无效。结论　平阳霉素介导的电脉冲为前列腺肿瘤及其他肿瘤的局部治疗提供了新思路。     

Electrochemotherapy: aspects of preclinical development and early clinical experience

OBJECTIVE: To develop an optimized, reproducible system of electrochemotherapy, and to investigate its clinical application in patients with cutaneous or subcutaneous recurrences of inoperable or progressive disease recalcitrant to current anticancer treatments. BACKGROUND: Electrochemotherapy is the application of electric pulses to tumor tissue, rendering the cell membranes permeable to otherwise impermeant or poorly permeant anticancer drugs. This facilitates a potent local cytotoxic effect. STUDY DESIGN: The optimal parameters for electrical pulses and bleomycin concentration were obtained in vitro and then applied to tumors derived from 4 histologically distinct human cancer cell lines (7860, PC3, OE19, MCF-7) established in athymic nude mice. Comparison was made with tumors that received bleomycin alone, electric pulses alone, and untreated controls. The optimized electrochemotherapy was then applied to patients with cutaneous or subcutaneous tumors, of any histologic type, recurrent or metastatic and unresponsive to standard chemotherapy and/or radiotherapy regimens. Tumors were assessed at monthly intervals to determine response to the treatment. RESULTS: In vivo: Using the optimal parameters ascertained in vitro, all tumors treated by electrochemotherapy with bleomycin (n = 24) had significantly regressed (P < 0.001, all 4 lines) compared with control tumors (n = 72). Twelve tumors completely regressed (50%) following a single application, with 12 partial regressions (50%). Clinical: In 30 patients (111 tumors), none of the treated tumors progressed. Sixty percent of tumors (66 of 111) showed complete regression, 22% (24 of 111) partial response, and 18% (21 of 111) no change. Electrochemotherapy was more effective in smaller tumors (<3 cm), 71% (64 of 90) showing complete regression, 20% (18 of 90) partial response, and 9% (8 of 90) no change. CONCLUSIONS: Electrochemotherapy parameters optimized in vitro are applicable in vivo. This treatment is effective in athymic nude mice for all histologic types indicating a nonimmunologic mode of action. In clinical application, electrochemotherapy is an effective, safe, and reproducible therapy. Patients with cutaneous or subcutaneous tumors previously refractory to surgical intervention, systemic chemotherapy, and/or radiotherapy responded successfully irrespective of histologic type.     

电穿击化疗治疗异位移植裸小鼠人结直肠肿瘤肝转移

目的 :用电穿击化疗对异位移植裸小鼠人结直肠肿瘤肝转移模型进行治疗 ,探讨其疗效和机制。方法 :将 4 0只皮下人结肠癌LoVo细胞系肿瘤的裸鼠随机分成 1 0区组 ,每区组 4只 ,随后将每区组的小鼠分至电穿击化疗组、化疗组、电击组、阴性对照组 ,并给予相应的治疗。 1w后处死小鼠 ,观察瘤重及病理改变情况。结果 :电穿击化疗组小鼠的肿瘤显著减小 ,其中有一只小鼠的肿瘤完全消失 ,平均瘤重为 1 8.3mg ,与其余各组平均瘤重 (化疗组 36 .9mg、电击组 37.9mg、阴性对照组 4 2 .7mg)相比在统计学上差异有显著性 ,P<0 .0 1。光镜下可见电穿击化疗组的肿瘤组织有大量片状坏死、炎性细胞浸润、血管的扭曲及内皮的脱落和坏死 ,而化疗组和电击组则仅见少量炎性细胞的浸润和单个细胞的坏死。结论 :电穿击化疗可以显著增强肿瘤对化疗的敏感性 ,为人结直肠肿瘤肝转移的治疗提供了一种新的途径     

Antitumour effect of electrochemotherapy with bleomycin on human prostate cancer xenograft

OBJECTIVE

To investigate the antitumour effect of electroporation (EP), a drug delivery system that has been shown to be effective synergistically with antitumour drugs, with bleomycin on the growth of prostate cancer xenografts in nude mice.

MATERIALS AND METHODS

PC‐3 cells were implanted subcutaneously into nude mice. After determination of the optimal conditions of electric pulse voltage and bleomycin dose, tumour growth in mice treated with EP plus bleomycin was compared with that in mice receiving EP alone, bleomycin alone or no treatment. In all four groups, apoptosis in the tumours was assessed.

RESULTS

There was a significant reduction in tumour growth in mice that received EP with bleomycin. Apoptotic cells in tumours at 24 h after treatment with EP plus bleomycin showed a significant difference compared with the other three groups, but not at 12 h after treatment.

CONCLUSIONS

These results indicate the possibility that EP with bleomycin could be effective as an ablation therapy for prostate cancer, especially androgen‐independent cancer.     

Enhanced antitumor effects of bleomycin and moderate hyperthermia by additional use of ethanol

The combined effects of moderate local hyperthermia, bleomycin and ethanol were investigated with Lewis lung carcinoma tumors in female C57BL/6 mice. Different combinations of treatments were performed on days 4 and 7 after tumor implantation. Combined treatment of 41°C hyperthermia and bleomycin resulted in mild reductions of tumor growth. Hyperthermia plus bleomycin led to marked reduction in tumor growth under the condition of a 43°C temperature. The antitumor effects of 41°C hyperthermia combined with bleomycin were enhanced by the additional use of ethanol, and these effects were more remarkable than those of 43°C hyperthermia and bleomycin. A possible application of these findings to clinical therapy for advanced esophageal cancer was discussed.     

Gastrin stimulates growth of colon cancer

Gastrin is trophic for normal gastric and colonic mucosa. We examined the potential trophic effects of chronic gastrin administration on the growth of mouse colon adenocarcinoma (MC-26). Thirty-three mice bearing transplantable MC-26 colon cancers were treated with varying doses (125, 250, or 500 micrograms/kg/day) of pentagastrin. Significant increases in tumor weight and DNA content were observed. Fundic mucosal weight and DNA content in these mice showed a dose-related trophic response. The weight of control fundic mucosa was 10 mg and rose to 20, 45, and 65 mg with increasing doses of gastrin. The DNA content of control fundic mucosa was 155 micrograms and rose to 220, 340, and 480 micrograms as the dose of gastrin was increased. Pentagastrin stimulated growth of the MC-26 colon cancer, but the threshold for gastrin-stimulated tumor growth was different from that of normal mucosal growth. The hyperplastic response of the fundic mucosa was increased by increasing gastrin doses; whereas, colon cancer hyperplasia was maximal at the lowest dose tested (125 micrograms/kg/day) and did not increase further with increasing doses of hormone. Mice bearing gastrin-stimulated tumors died at a significantly greater rate than did mice with untreated tumors (80% of control mice and none of the treated mice were alive at day 55). The effects of gastrin treatment on the growth of MC-26 colon cancer persist after treatment is discontinued; mice with tumors that were treated with gastrin for either 7 or 14 days and in which the treatment was stopped were all dead by 35 or 28 days, respectively, after the end of treatment.     

Effects of electropermeabilization after the administration of anticancer drugs on transitional cell carcinoma

OBJECTIVE: To assess in vitro and in vivo the potential utility of electropermeabilization (EP) as an anticancer drug delivery system for the treatment of transitional cell carcinoma (TCC). MATERIALS AND METHODS: To analyse the effects of EP on the internalization of adriamycin and bleomycin by cells, aliquots of a suspension of YTS-1 carcinoma cells (derived from a human TCC line) were mixed with a solution of adriamycin or bleomycin and then exposed immediately to an electric field (1000 V/cm, 1 Hz, 100-micros square wave, eight pulses). After a 2-h incubation the concentration of each drug in the cells was measured by high-performance liquid chromatography (for adriamycin) and by bioassay (for bleomycin). The concentrations of drugs in the cells were compared with untreated cells. To analyse the effects of EP on cytotoxicity, the same treatments were applied to a suspension of cells plus adriamycin or bleomycin and then the cells incubated for 6 h with tritiated thymidine ([3H]-TdR), monitoring the incorporation of [3H]-TdR into the cells. Cells with no electrotreatment acted as controls. To assess the effects on tumours in vivo, YTS-1 cells were transplanted subcutaneously into nude mice; when the tumours had reached 7 mm in diameter, EP was applied (using electrical pulses as before, 10 min after the direct injection of bleomycin into the tumour). Tumours were then measured regularly and compared with sham-treated tumours, tumours treated with electric pulses alone, and tumours treated with bleomycin alone. Survival was also compared. RESULTS: There were no significant differences in the levels of adriamycin between cells with and with no EP, whereas there was a marked difference for bleomycin. Growth inhibition by adriamycin with and with no EP was similar, while the growth-inhibitory effects of bleomycin were almost doubled. There was a reduction in tumour size only in the group treated with bleomycin plus electric pulses and two of five tumours disappeared completely. Survival in this group was also significantly better than in the other groups. CONCLUSION: EP after administering bleomycin might be an effective treatment for TCC.     

Experimental studies on combined chemotherapy with hyperthermia and ethanol for advanced esophageal cancer. II. Effects of combined treatments on tumor growth in tumor-bearing mice

The combined effects of local hyperthermia, bleomycin and ethanol were investigated using Lewis lung carcinoma (3LL) in female C57BL/6 mice and FM3A tumors in female C3H/He mice. The combined treatments were performed on days 4 and 7 or on days 4, 7 and 10 after tumor implantation. Hyperthermia at 43 degrees C for 60 min or 15 mg/kg of bleomycin resulted in mild reductions of tumor growth, respectively, whereas hyperthermia at 41 degrees C for 60 min alone did not show antitumor effects. Synergistic effects were observed with 43 degrees C hyperthermia and bleomycin. Furthermore the effects were enhanced by the combined use of ethanol (10% ethanol, 0.05 ml, i.t.). The antitumor effects of combined treatments of 41 degrees C hyperthermia and bleomycin were not so remarkable as those of 43 degrees C hyperthermia and bleomycin. In the combination of 41 degrees C hyperthermia, bleomycin and ethanol, marked increase of antitumor effects was observed particularly in 3LL tumor. A possible application of these findings to clinical therapy for advanced esophageal cancer was discussed.     

Immunological evaluation of splenectomy in tumor-bearing mice

The effect of splenectomy upon neoplastic outgrowth was examined after inoculation of methylcholanthrene-induced C3H/He murine tumors. Three days or 20 days after tumor inoculation, splenectomy resulted in significant retardation of tumor growth when compared with sham operation, while splenectomy 6, 9, 15 days after tumor inoculation did not alter the tumor outgrowth. These results suggest that spleen might have immunologically negative element in early or late stage of tumor burden. In fact, spleen cells from mice bearing MCA-F tumors for 3 days or 30 days nonspecifically facilitated the tumor outgrowth in Winn assay. The non-specific tumor-enhancing cells were radioresistant (700 rads), capable of phagocytizing carbonyl-iron and adherent to plastic dish suggesting those were tumor enhancing macrophages. On the other hand, spleen cells from tumor-bearing mice for 9 to 15 days specifically reduced the tumor growth in Winn assay, and those cytotoxic cells were radio-sensitive (700 rads) T cell population.     

Insulin-like growth factor-binding protein 3 inhibits growth of experimental colocarcinoma

BACKGROUND: We have previously shown that an important cell growth regulatory protein, insulin-like growth factor-binding protein 3 (IGFBP-3) is depleted in peripheral blood after open--but not laparoscopic--surgery. We have also demonstrated that IGFBP-3 induces apoptosis of human colon cancer cells in vitro. We report here the effect of IGFBP-3 on the growth of colonic epithelial cells in vivo. METHODS: Two tumor models were used: chemically induced carcinogenesis with azoxymethane (AOM) and inoculation of syngeneic colon cancer cells. In AOM-induced carcinogenesis, wild type (WT) and IGFBP-3 transgenic (IGFBP-3-TG) CD1 mice were injected with AOM and the number of aberrant crypt foci (ACF) in the colon studied. In the syngeneic model, BALB/c mice were inoculated with CT26 cells. The control group received saline, while the test group was administered IGFBP-3 weekly. Tumor weight was assessed 2.5 weeks after establishment. RESULTS: The number of aberrant crypt foci was significantly lower in IGFBP-3 transgenic mice (1.3 +/- 1.1) compared to WT controls (6.8 +/- 6.0) (P < .001). Further, CT26 tumors were significantly smaller in BALB/c mice that received IGFBP-3 (0.364 +/- 0.165 g) than in WT controls (0.742 +/- 0.261 g) (P < .01). CONCLUSIONS: IGFBP-3 inhibits the development of colonic tumors in experimental models and may hold promise as an adjuvant therapy for patients with neoplasms.     

Enhanced antitumor effects of bleomycin and moderate hyperthermia by additional use of ethanol

The combined effects of moderate local hyperthermia, bleomycin and ethanol were investigated with Lewis lung carcinoma tumors in female C57BL/6 mice. Different combinations of treatments were performed on days 4 and 7 after tumor implantation. Combined treatment of 41 degrees C hyperthermia and bleomycin resulted in mild reductions of tumor growth. Hyperthermia plus bleomycin led to marked reduction in tumor growth under the condition of a 43 degrees C temperature. The antitumor effects of 41 degrees C hyperthermia combined with bleomycin were enhanced by the additional use of ethanol, and these effects were more remarkable than those of 43 degrees C hyperthermia and bleomycin. A possible application of these findings to clinical therapy for advanced esophageal cancer was discussed.     

Synergistic Effect of Interstitial Laser Coagulation and Doxorubicin in a Murine Tumor Recurrence Model of Solitary Colorectal Liver Metastasis

Background Interstitial laser coagulation (ILC) is gaining acceptance for treatment of unresectable colorectal liver metastases. However, local recurrence rates are still high. To overcome this problem, we investigated the potential of additional systemic therapy after ILC in a murine model. Methods Single C26 colon carcinoma nodules (∼1 mm³) expressing firefly luciferase were implanted in the left liver lobe of 32 BALB/c mice. Seven days after implantation, tumors were treated with either ILC alone (neodymium–yttrium aluminum garnet; 6 W/cm; 800 J/cm) or ILC followed by 1 mg/kg of doxorubicin intravenously. Controls received either doxorubicin alone or sham treatment. Tumor load was measured by in vivo bioluminescent imaging. Results Solitary colorectal liver metastases developed over 7 days after tumor implantation in the liver. Extrahepatic disease was not observed. The ILC dose was set to ablate the liver metastases with recurrent tumor growth in 9 of 16 mice after 7 days. After ILC plus doxorubicin, complete tumor destruction occurred without recurrence (0 of 14). Sham treatment or treatment with doxorubicin alone showed an exponential increase in tumor load. Conclusions A murine tumor recurrence model after local ablative treatment of solitary liver metastasis was developed. The combination of ILC and doxorubicin had a strong synergistic effect that led to complete tumor remission in all animals treated.     

A new experimental trial using repeated heating every 24 hours for local hyperthermic therapy with bleomycinin vivo

This report presents the effect of repeated heating every 24 hrs using bleomycin (BLM) which, although seemingly contrary to the usual agreement that hyperthermia should be carried out with a long interval due to thermotolerance, holds many possibilities. FM3A cells on the foot pad of C3H mouse were immersed in a heated water bath at 43 and 44°C for 30 min. The effect of repeated heating was appreciated by an improved growth curve and 50 day survival compared to mice which received heating twice with a 96-hr interval. Repeated heating every 24 hrs 5 times with BLM suppressed tumor growth significantly as compared to heating twice with a 96-hr interval without BLM. The longest survival time was obtained by the repeated heating with BLM among all protocols. There is therefore a good possibility that more effective results could be obtained clinically by repeated heating over a short period.     

A new experimental trial using repeated heating every 24 hours for local hyperthermic therapy with bleomycin in vivo.

This report presents the effect of repeated heating every 24 hrs using bleomycin (BLM) which, although seemingly contrary to the usual agreement that hyperthermia should be carried out with a long interval due to thermotolerance, holds many possibilities. FM3A cells on the foot pad of C3H mouse were immersed in a heated water bath at 43 and 44 degrees C for 30 min. The effect of repeated heating was appreciated by an improved growth curve and 50 day survival compared to mice which received heating twice with a 96-hr interval. Repeated heating every 24 hrs 5 times with BLM suppressed tumor growth significantly as compared to heating twice with a 96-hr interval without BLM. The longest survival time was obtained by the repeated heating with BLM among all protocols. There is therefore a good possibility that more effective results could be obtained clinically by repeated heating over a short period.     

The role of the spleen in tumor bearing host: II. The influence of splenectomy in mice

The effect of splenectomy on neoplastic outgrowth was examined prior to and after implantation of methylcholanthrene-induced C₃H/He murine tumors. Splenectomy performed 12 days before tumor inoculation did not affect the tumor outgrowth, however, both splenectomy and sham operation performed shortly before tumor inoculation resulted in significant tumor facilitation compared with the non-operated group, suggesting that this accelerated tumor was not related to the presence or absence of splenic tissue, but rather to systemically-induced immunosuppression. While splenectomy performed 6, 9, 12 days after tumor inoculation did not alter the tumor growth, splenectomy performed early (3 days) or late stage (20 days) after tumor cell challenge revealed a retarded neoplastic outgrowth, compared with the sham operated group. These results suggest that splenectomy in very early and late stages of tumor-bearing host may be effective for tumor treatment.