Immunotherapy of murine transitional cell carcinoma

A series of 6 controlled experiments in C3H/He mice were performed to evaluate nonspecific immunotherapeutic regimens with a transplantable murine bladder tumor (MBT2). Immunotherapeutic agents studied included live Bacillus Calmette-Guerin (BCG) preparations in varying doses and strains (Tice, Pasteur, and Glaxo), Re mutant glycolipid (ReG) from Salmonella typhimurium, BCG cell wall skeletons (CWS), CWS plus B4 glycolipid fraction of ReG, and Keyhole-Limpet Hemocyanin (KLH). Animals received an intradermal MBT2 inoculation and were then randomized to treatment and control (saline treated) groups. Immunotherapy was administered intralesionally 1 day after tumor transplantation. Tumors were excised by amputation at a volume of 400 mm. and animals were later rechallenged with tumor inocula, again treated, and followed for tumor incidence growth rate and survival. No antitumor affect was observed with ReG, CWS or CWS plus B4. KLH immunotherapy did result in measurable antitumor effect. Consistent and statistically significant (p less than 0.01) antitumor responses as measured by prolonged survival and decreased growth rate were observed with Tice and Pasteur strains of BCG in doses ranging from 5 X 10(5) to 1 X 10(7) colony forming units per animal. Doses in excess of 10(7) units were found to decrease antitumor response. Glaxo strain BCG had no beneficial effect when used in the maximal dose (10(6) colony forming units) that could be administered. In animals immunized with intermediate doses of live Tice or Pasteur strain BCG in the study, effective long term immunity to transitional cell carcinoma was observed. Although many new immunotherapeutic agents have been advocated in other tumor models, to date we have found Tice and Pasteur strains of live BCG to be the most effective agents in the treatment of transitional cell carcinoma.     

Doxorubicin chemotherapy in advanced transitional cell carcinoma

During the past year 25 patients with advanced transitional cell carcinoma were treated with intravenous doxorubicin hydrochloride (Adriamycin), 60 to 75 mg. per square meter of body surface area, every three weeks. Among the 19 evaluable patients, one partial objective remission lasting five months was observed. All 7 patients with bone pain had symptomatic relief and 12 patients had significant subjective improvement lasting an average of six-and-a-half months. Side effects were minimal and consisted of alopecia, mild leukopenia, and mild stomatitis; no significant cardiotoxicity was observed. Doxorubicin hydrochloride appears to have important antitumor activity in advanced urothelial tumors. Controlled clinical trials with this agent alone and in combined drug regimens are needed.     

In vitro study of the effect of hyperthermia on normal bladder cell line and on five different transitional cell carcinoma cell lines.

Intraluminal hyperthermia is potentially useful in the management of superficial bladder cancer. The potential inhibitory effect of hyperthermia on various human bladder cancer cell lines, normal human bladder cells and the murine MBT-2 bladder cancer cell line has been studied in vitro. These cell lines were exposed for one hour to 43 +/- 0.5C and compared to controls. Cell survival was assessed comparing the cell growth curve and colony formation. The human transitional cell carcinoma (TCC) cell lines vary in their sensitivity to heat. MGH-U1 was the most heat sensitive cell line. The human A-1698, CUB-2, UM-UC-3 and the murine MBT-2 lines were heat insensitive. We conclude that the cytocidal effect of hyperthermia in bladder transitional cell carcinoma is variable. Further experiments using the combination of hyperthermia and intravesical anticancer agents are in progress.     

Prostatic occurrence of transitional cell carcinoma after intravesical chemotherapy

Thirteen patients with Stage Tis, Ta, or T1 transitional cell carcinoma (TCC) of the bladder treated by transurethral resections and intravesical chemotherapy developed TCC of the prostate. Among the 13 cases, cytology specimens were obtained from 10 at the time prostatic disease was diagnosed; 9 demonstrated TCC. One was treated successfully by transurethral resection of a Ta lesion involving the prostatic urethra only. One of 2 patients declining radical surgery is alive with residual disease at twenty-four months, and the other died of progressive disease at nineteen months. Of the 10 patients who underwent radical cystoprostatectomy, 7 are alive with no evidence of disease eight to forty-two months postoperatively, with 2 of these 7 having received 4 courses of systemic methotrexate, vincristine, Adriamycin, and cisplatinum (MVAC) for metastatic disease. Two of the 10 died of metastatic disease six and thirteen months postoperatively, and one frail patient died of surgical complications. When treating patients with intravesical chemotherapy for superficial TCC, biopsy of the prostate should be done during follow-up examinations, especially in the presence of cytologic or palpable prostatic abnormalities.     

表浅性膀胱癌灌注化疗的个体化研究

目的 :探讨对表浅性膀胱癌制定个体化膀胱灌注化疗方案的临床意义。方法 :对 48例表浅性膀胱癌标本行原代细胞培养及药物敏感试验 (药敏 ) ,患者随机分为两组 ,一组用丝裂霉素C(MMC)灌注 ,另一组根据药敏结果 ,选择敏感的化疗药物 ,平均随访时间 1 2个月。结果 :各化疗药物的平均抑瘤率 ,原发组分别为吡柔比星 (THP) 50 .0 %、阿霉素 (ADM ) 53 .1 % ,MMC 56 .2 %、米托蒽醌 (MH) 4 7.0 % ,复发组为THP 38.0 %、ADM43 .8% ,MMC 43 .8%、MH 31 .0 % ,组内各化疗药物抑瘤率差异无显著性意义 ,而原发组抑瘤率显著高于复发组 (P <0 .0 5) ;MMC灌注组无瘤率为 58.3 % ,药敏组无瘤率为 79.1 % ,差异有显著性意义 (P <0 .0 5)。结论 :应根据药敏结果 ,选择相对敏感的化疗药物 ,制订个体化膀胱灌注化疗方案 ,以提高疗效 ,减少肿瘤复发率     

The effect of chloroquine and hyperthermia on murine neuroblastoma

A number of reports suggest that hyperthermia is an effective adjunctive treatment modality in management of neural crest tumors. Recent studies have demonstrated a synergistic effect of induced hyperthermia when coupled with chloroquine in an in vitro model. This study examines the effect of chloroquine and hyperthermia in an in vivo murine neuroblastoma model. Forty-seven Ajax white mice (weighing 20 to 30 g) received a subaxillary tumor burden (C-1300 murine neuroblastoma) per trochar (1.25 x 10(6) cells). The tumor was then incubated for 9 days. Mice were then divided into four groups: group 1, controls (n = 15); group 2, hyperthermia (n = 12); group 3, chloroquine (n = 10); and group 4, chloroquine with hyperthermia (n = 10). Hyperthermia was induced with 40 to 69 mW/cm2 at 2,450 MHz microwave radiation for 4 minutes to achieve a temperature of 41.5 degrees C for 10 of 14 treatment days. Chloroquine was administered intraperitoneally at a dose of 40 mg/kg body weight for 10 of 14 treatment days. Mice were weighed and tumor size was determined daily. Animals were killed on day 21 and postmortem examination was performed, with tumors graded histologically. Animal weight, tumor weight, and tumor size were similar for all groups (P greater than .05). Mortality was 6% in group 1, 25% in group 2, 50% in group 3, and 40% in group 4 (P less than .05). Rate of tumor metastases was also statistically different from controls: group 1, 0%; group 2, 60%; group 3, 90%; and group 4, 90% (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Treatment of murine transitional cell carcinoma with intralesional interleukin 2 and murine interferon gamma

The antitumor effect of intralesionally administered recombinant interleukin-2, alone or in combination with recombinant interferon gamma was studied in murine transitional cell carcinoma, MBT2. In the initial prophylactic model treatment was started at day one at the site of tumor inoculation. Maximal and significant reduction in tumor volume occurred in groups receiving 4,000 units of recombinant interleukin 2 and 10(7) colony forming units Bacillus Calmette Guerin (p less than 0.00001 vs saline control). In the same experiment, a reduction in tumor incidence and increase in survival occurred in groups receiving 4,000 units of recombinant interleukin 2, 1,000 units of recombinant interleukin 2 plus 2,000 units of recombinant interferon gamma, as well as 10(7) colony forming units Bacillus Calmette Guerin relative to saline control (p less than 0.005). The dose-response effect of recombinant interleukin 2 alone was also tested in a model of an established transitional cell carcinoma. Intralesional injection treatments were initiated after tumors were palpable. Reduction in tumor volume was observed in the group receiving 8,000 units of recombinant interleukin 2 (p = 0.01 vs saline control), but no significant advantage in survival was noted.     

Intraperitoneal chemotherapy for the prevention of transitional cell carcinoma implantation

PURPOSE: Tumor spillage from bladder perforation during transurethral resection of a bladder tumor or during cystectomy risks seeding the peritoneum with TCC. Current therapy is irrigation with sterile water with an unknown extent of clinical benefit. Intraperitoneal chemotherapy for other human cancers has demonstrable benefit but to our knowledge it has never been investigated for TCC. We investigated whether intraperitoneal chemotherapy can prevent TCC implantation in a murine model of tumor spillage and whether water irrigation is beneficial. MATERIALS AND METHODS: Laparotomy was performed in 28 Fischer 344 rats (National Cancer Institute, Frederick, Maryland) to instill 1 x 10 AY-27 TCC cells. Mitomycin (10 mg/m) was instilled in 9 rats and saline was used in the control group. A third group underwent lavage with sterile water. At sacrifice after 2 weeks tumors were measured in mm and weighed. A followup experiment of 4-week survival used 5 mg/m mitomycin and added a fourth group treated with water lavage plus mitomycin. RESULTS: All 9 rats in the saline control group had gross tumors at the laparotomy site as well as gross carcinomatosis. The 10 water lavage rats also demonstrated gross tumors but of smaller size (p = 0.02). All rats treated with mitomycin had no gross or microscopic evidence of tumor growth anywhere in the peritoneum. In experiment 2 none of the rats treated with lower dose mitomycin had gross or microscopic tumors regardless of water lavage. CONCLUSIONS: Intraperitoneal chemotherapy prevents TCC implantation in a murine model of tumor spillage. Water lavage decreases the tumor burden but it cannot effectively sterilize the peritoneum of tumor.     

Keyhole-limpet haemacyanin and immune ribonucleic acid immunotherapy of murine transitional cell carcinoma

Summary Transitional cell carcinoma is known to be an immunogenic tumour. This immunogenicity has been the basis of a search for effective immunotherapeutic agents and for the evaluation in this study of two additional agents, keyholelimpet haemacyanin (KLH) and immune ribonucleic acid (RNA) extract. The results in this animal model showed KLH to be a potent non-specific stimulant of the immune response which caused both a reduction in tumour growth and a prolongation of animal survival (p=0.01). No anti-tumour effects were observed with either local or systemic RNA.     

Keyhole-Limpet Haemocyanin (KLH) immunotherapy of murine transitional cell carcinoma

Urolithiasis - The antigenicity of transitional cell carcinoma of the bladder has stimulated the search for effective immunotherapeutic agents in the treatment of this disease. Non-specific...     

Histopathologic changes of transitional cell carcinoma of bladder after M-VAC chemotherapy

Over the past several years, we have utilized methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) as definitive, neoadjuvant, and adjuvant therapy for various stages of transitional cell carcinoma with reduced toxicities. Currently, there is little information concerning the histopathologic changes after M-VAC therapy. We report on the histopathologic changes of bladder transitional cell carcinoma following M-VAC chemotherapy in our protocol for treatment of bladder cancer. The main histopathologic findings after M-VAC therapy are squamous metaplasia, necrosis, fibrosis, and persistent transitional cell carcinoma. In 2 cases, there were persistent adenocarcinoma and squamous cell carcinoma. The importance of these observations in terms of diagnostic and therapeutic implications is reviewed.     

In vitro culture and chemotherapy sensitivity testing of human transitional cell carcinoma

In vitro chemotherapy sensitivity testing for transitional cell carcinoma and other urologic malignancies is an exciting research tool of great future promise. It is not yet an established clinical test of proved value for patients with genitourinary malignancies.     

Preliminary European results of local microwave hyperthermia and chemotherapy treatment in intermediate or high risk superficial transitional cell carcinoma of the bladder

INTRODUCTION: Superficial bladder cancer can be treated by transurethral resection (TUR) and adjuvant intravesical therapy. Intravesical bacillus Calmette-Guérin (BCG) has been proven to be more efficacious with respect to recurrence prevention than intravesical chemotherapy, although at the cost of more severe side effects. There is a need for a new treatment modality with higher efficacy and less toxicity. The subject of this study is the efficacy of local microwave hyperthermia and chemotherapy treatment in intermediate or high risk superficial transitional cell carcinoma (TCC) of the bladder. PATIENTS AND METHODS: Ninety eligible patients received adjuvant treatment with a combination of mitomycin-C (MMC) and local microwave hyperthermia. All patients had multiple or recurrent Ta or T1 TCC of the bladder and were classified as intermediate or high risk according to EAU criteria. In total, 41 patients were BCG failures. The treatment regimen included 6 to 8 weekly sessions followed by 4 to 6 monthly sessions. Follow-up consisted of video-cystoscopy and urine cytology every 3 months. All patients were observed for 2 years. RESULTS: Kaplan-Meier analyses of the total group (N = 90) indicated that 1 year after treatment only 14.3% (SE 4.5%) of all patients experienced a recurrence. After 2 years of follow-up the risk of recurrence was 24.6% (SE 5.9%). No progression in stage and grade was observed. CONCLUSION: Microwave induced hyperthermia combined with MMC has promising value in intermediate or high risk superficial bladder cancer patients compared to literature data of BCG and/or intravesical chemotherapy, particularly where other treatments, i.e. BCG, have failed.     

小鼠CD154真核表达质粒的构建及其对膀胱癌细胞体内成瘤性的影响

目的 构建小鼠CD154真核表达质粒，观察其转染膀胱癌细胞后对癌细胞体内成瘤性的影响。方法 逆转录-聚合酶链反应（RT-PCR）法扩增T739小鼠CD154 cDNA，重组到pcD-NA3．1／Zeo（＋）构成重组质粒。经阳离子脂质体转染小鼠膀胱移行细胞癌细胞BTT739，将转染后的细胞接种T739小鼠，观察肿瘤在体内的生长情况。结果 RT-PCR产物进行凝胶电泳可见0．8kb处的目的基因条带，序列测定结果正确；CD154重组质粒转染BTT739细胞后能够在肿瘤细胞内表达；转染CD154的肿瘤细胞在小鼠体内不能成瘤。结论 成功构建小鼠CD154真核表达质粒，将其转染肿瘤细胞后能抑制肿瘤细胞的体内成瘤性。     

Long-term survival under maintenance gemcitabine chemotherapy for metastatic transitional cell carcinoma

We report a case of a 74-year-old patient who received 41 courses of maintenance therapy with gemcitabine over a length of 28 months for metastatic transitional cell carcinoma. One year earlier the patient had received three cycles of adjuvant cisplatin-based combination chemotherapy after nephro-ureterectomy for a locally advanced urothelial cancer of the right renal pelvis. This case demonstrates a paradigm shift in the palliative treatment of advanced urothelial cancer, with the implementation of more tolerable agents such as gemcitabine. Even elderly patients with impaired renal function may benefit in terms of tumor reduction and survival from systemic chemotherapy, which may be applied over a prolonged period of time.     

The effect of hyperthermia on human prostatic carcinoma cell lines: evaluation in vitro

The effect of hyperthermia on established human prostate carcinoma cell lines (PC-3, DU-145) and related sublines (1-LN, 125-1L) was investigated in vitro. Cells were exposed to heat treatment at 43C or 37C for varying time intervals, (one hr or two hrs) and cell survival was evaluated by the colony formation assay and by measurement of cellular growth rate. While one hr exposure at 43C did show a mean inhibition of colony formation, ranging from 29 to 41%, a statistically significant increase in inhibition rate (p less than 0.001) was observed at two hr exposure, ranging from 57 to 92%. This study is a report of the cytotoxic effect of hyperthermia on established human prostatic tumor cell lines. These in vitro results indicate that hyperthermia may become a potentially useful form of adjunctive therapy for local control of prostatic cancer. However, the temperature and exposure time may have an important impact on cell kill when this new modality for cancer treatment is proposed for a clinical trial.     

热疗联合化疗与单纯化疗治疗非小细胞肺癌的疗效比较

目的：探讨热疗联合化疗治疗非小细胞肺癌（non—small cell lung carcinoma，NSCLC）的疗效。方法：2003年9月～2006年11月我院对52例NSCLC进行微波热疗联合NP方案化疗联合治疗（热疗联合化疗组），3个周期后评价疗效；并与2006年1～11月16例NSCLC单纯化疗（单纯化疗组）进行对比。结果：热疗联合化疗组近期疗效明显好于单纯化疗组，热疗联合化疗组总有效率（RR）为65．4％（34／52），显著高于单纯化疗组总有效率37．5％（6／16）（Z=-2．419．P=0．016）；热疗联合化疗组结束后疼痛明显改善，单纯化疗组无镇痛作用，差异具有高度统计意义（Z=-6．486，P=0．000）；2组的不良反应主要表现为恶心、粒细胞减少、血小板降低和肝功能异常，差异无显著性（P〉0．05）。结论：热疗联合化疗治疗NSCLC疗效优于单纯化疗治疗NSCLC。     

Phagocytic and natural killer cytotoxic responses of murine transitional cell carcinoma to postsurgical immunochemotherapy

Postsurgical immunochemotherapy with Corynebacterium parvum (CP) and cis-diamminedichloroplatinum (II) (CDDP) was evaluated in mice with transitional cell carcinoma (MBT-2). C3H/He mice were transplanted subcutaneously in the hind limb with 5 x 10(5) tumor cells. Ten to 14 days later when the tumor reached a diameter of five to seven mm., it was surgically removed. Mice were then randomized into four groups to receive a total of three treatments on days 1, 3 and 5 after surgery: 1) saline (control group); 2) CP, 250 micrograms. into the surgical site; 3) CDDP, 5 micrograms./gm. body weight intraperitoneally; and 4) combined CP and CDDP. Recurrence of tumor occurred in 70%, 52%, 55% and 28% of mice receiving surgery only, CP, CDDP, and combined CP and CDDP respectively. In the second part of the experiment, phagocytic activity using chemiluminescence assay and natural killer (NK) activity using chromium-51 release assay were determined with cells from the peritoneum, spleen and inguinal lymph nodes. CP or CDDP alone enhanced the phagocytic and NK activity. The most significant enhancement was obtained with cells from the inguinal lymph nodes of mice receiving combined CP and CDDP, the group with the lowest tumor recurrence. These results suggest that combination of CP and CDDP may be useful in control of postsurgical recurrence of bladder cancer.