Comparative clinical study of single and combination therapy of human lymphoblastoid interferon (HLBI) with 5-FU in the treatment of advanced renal cell carcinoma

A clinical trial using human lymphoblastoid interferon (HLBI) was done on patients with advanced renal cell carcinoma to compare the efficacy of monotherapy with that of combined administration with a 5-fluorouracil (FU) agent. A total of 24 patients with definitely diagnosed advanced renal cell carcinoma were enrolled in either of the HLBI treatments. Principally, the daily intramuscular injection of 3 million units of HLBI was done for 4 consecutive days and thereafter followed by twice of weekly injections. The combined agent used in the present study was 300 or 600 mg of 5-fluorouracil agent given orally. The efficacy of HLBI was evaluated according to direct assessment standard of chemotherapy to a solid tumor expelled by the committee of Japanese health and welfare ministry. Of 11 patients who received monotherapy, 3 had a partial response rate of 27.3 percent. While only one of 13 patients having received combined HLBI administration with oral 5-FU tablets showed a partial response with a response rate of 7.7 percent. A total of 4 patients partially responded to either HLBI treatment with a subsequent response of 16.7 percent. Partial response implied reduction of lung metastatic foci in 3 patients and primary lesion in one patient. There was observed untoward fever-up in all patients with HLBI injections which was relieved with acquired tachyphylaxis owing to repeated injections. Otherwise minimal adverse effects were temporary elevation of liver transaminase in 4 and leucopenia in 2 patients during the HLBI treatment both of which eventually returned to the normal level without discontinuation of HLBI therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Treatment of renal cell carcinoma with human lymphoblastoid interferon alpha and UFT in combination. A prospective multicenter trial

A cooperative study of combination of UFT (a compound of FT and Uracil) and human lymphoblastoid interferon (IFN-alpha) was conducted in the cases of metastatic renal cell cancer. IFN-alpha was administered over 3 times a week at a dose of 3 X 10(6) units in combination with UFT at a daily dose of 600 mg FT equivalent. Twenty-eight patients from 16 collaborating institutions were the subjects of the present study. The antitumor effects of the drugs were clinically evaluable in 25 cases according to the response criteria of Japan Society for Cancer Therapy. Complete responses and partial responses were observed in 3 and 2 cases, respectively, showing a response rate of 20 per cent. One complete responder had bone and liver metastases and has been alive for more than 2 years without any evidence of relapse. All of the other responders had lung metastasis. The survival durations of the other two complete responders were 716 days and 255 days. The two partial responders had been alive for more than 819 days and 471 days. The adverse effects of this combination therapy were minimal. Combination of a biological response modifier and a cancer chemotherapeutic agent seems to be a way to increase the treatment efficacy of renal cell cancer.     

Intratumoural and intraventricular human lymphoblastoid alpha interferon (HLBI) for treatment of glioblastoma multiforme

A series of ten patients with glioblastoma multiforme were treated with human lymphoblastoid alpha interferon (HLBI) as a single therapy after partial surgical resection (5 cases) or stereotactic biopsy (5 cases). Treatment consisted of intratumoural administration of HLBI (15 x 16(6) IU) every month (8 cases) or in the continuous intraventricular infusion of HLBI (1.8 x 10(6) IU daily) in 15-day cycles (2 cases) until rapid growing of the tumour and important neurological deterioration. The treatments were well tolerated. As judged from data from control groups, the patients demonstrated no improvement in mean survival time and follow-up CT-scan showed rapid progression of the tumour in all cases.     

Antitumor effects of human lymphoblastoid interferon on advanced renal cell carcinoma

Human lymphoblastoid interferon alpha was administered intramuscularly at a dose of 3 times 10(6) units per day to 25 patients with advanced renal cell carcinoma. Six patients (24.0 per cent) showed objective responses, including 2 with complete regression of tumors. Nine patients (37.5 per cent) showed disease stabilization, while the disease progressed in 9 others (37.5 per cent). All tumor responses (2 complete, 4 partial and 2 mixed responses) were seen in lung, skin and liver metastases in patients whose primary tumors had been removed. Mean time to response was 87 +/- 74 days (range 28 to 240 days) and mean duration of response was 6.5 +/- 6.4 months (range 1 to greater than 20 months). Human lymphoblastoid interferon alpha was a potential active antitumor agent in patients with advanced renal cell carcinoma.     

Metastatic potential of human renal cell carcinoma: experimental model using subrenal capsule implantation in athymic nude mice

Summary The aim of this study was to determine whether subrenal capsule (SRC) implantation is a suitable model for the study of the metastatic potential of our human renal cell carcinoma (HRCC) lines and to establish new sublines with enhanced metastatic ability. NMRI athymic nude mice 7–11 weeks old received SRC implantation of our HRCC lines RC43 and RC21. These lines were not metastatic when implanted s.c. Mice were killed after 4 or 8 weeks, or when moribund. With the RC43 cell line the success rate for implantation was 69%, with 89% of these showing metastases. The average volume of the implanted tumour fragments was 0.5 mm³ (range 0.28–0.7), the average volume at the primary site at the time of death was 9087 (9–32000) mm³. Metastases were found in lymph nodes, liver, spleen, peritoneum, psoas muscle, pancreas, diaphragm and skin. The average volume of the metastases was 4139 (0.5–9000) mm³. Growing cell lines were established in vivo and in vitro from one splenic, one peritoneal, one diaphragmatic, and one hepatic metastasis. These sublines have faster in vivo and slower in vitro growth rates than the parental lines. With the RC21 cell line the success rate for implantation was 56% and the metastatic rate 78%. The average volume of the implanted tumour was 0.8 mm³ (0.28–1.2), the average volume at the primary site at the time of death was 2685 mm³ (1.4–6534) and the average volume of metastases was 7.1 mm³ (0.5–37.5). Metastases were found in lymph nodes, lung and skin. No establishment was attempted for RC21 because of the small dimensions of these metastases. SRC implantation is thus considered a useful tool for the study of the metastatic ability of our cell lines RC43 and RC21. The establishment of new sublines with a faster growth rate and an enhanced metastatic ability will be useful for further studies on the metastatic process.     

Hyperthermia with simultaneous administration of interferon using established human renal carcinoma heterotransplanted in nude mice

Using human renal carcinoma heterotransplanted in nude mice, the effects of the combined use of hyperthermia and interferon (natural human interferon-alpha; IFN-alpha, and recombinant interferon-gamma; IFN-gamma) were examined. The hyperthermic device used was the Clini-Therm, Mark VII, 915 MHz, microwave. The administration of interferon was started immediately before hyperthermia and carried out on consecutive days. The combined use of hyperthermia and IFN was compared with hyperthermia and with IFN alone. The combined use of hyperthermia and IFN-alpha was shown to have significant anti-tumour effects compared with the former or latter alone. Of 10 nude mice (10 implanted tumours) used for the experiment, 5 showed complete disappearance of the implanted tumours and the others showed prolongation of survival. Combined treatment with IFN-gamma and hyperthermia showed no significant effect when compared with other treatment groups. Combined treatment with local hyperthermia and IFN-alpha may have some application to the clinical management of renal carcinoma.     

Preclinical chemotherapy on human head and neck cancer xenografts grown in athymic nude mice

This study was undertaken to investigate the potential role of xenografts established from human head and neck squamous cell carcinoma (HNSCC) in the selection of new anticancer agents for phase II clinical trials. Eight HNSCC tumor lines were established in NMRI nude mice. The tumor-bearing animals were then treated with drugs at the maximum tolerated dose level. Treatment with drugs known for their activity in 15%-30% of HNSCC patients [cisplatin (CDDP), bleomycin (BLEO), 5-fluorouracil (5-Fu), cyclophosphamide (CY), and doxorubicin (DOX)] caused strong responses in up to 38% and moderate responses in 50%-67% of the HNSCC tumor lines. Methotrexate (MTX), known to cause remissions in about 40% of HNSCC patients, was only minimally active in this model system. A clinically ineffective drug, amsacrine (m-AMSA), was included as a negative control and showed no or minimal activity in all four HNSCC lines tested. A number of experimental drugs that have promising preclinical activity were also tested. Brequinar sodium (Dup 785) and 10-ethyl, 10-deaza-aminopterin (10-EdAM) showed activity in three of five, and two of the four tested tumor lines respectively. N,N-dimethylformamide (DMF) and 5-aza-2'-deoxycytidine (5-aza-dCyd), agents with the capacity to induce differentiation in in vitro systems, showed moderate activity in 43% and 40%, and strong activity in 14% and 40% of the lines, respectively. Our results indicate that the nude mouse xenograft model may play a role in the screening of new drugs, and in particular, it could be of help in the selection of drugs to be tested in phase II HNSCC clinical trials.     

细胞因子对肾癌荷瘤裸鼠生长抑素的影响

为研究细胞因子对肾癌宿主体内生长抑素（ＳＳ）的影响及相互关系，探索肾癌治疗的更好方法，作者以４．４×１０６ｍｌＲＣＣ９４６１６人肾癌细胞注入裸鼠背部皮下，将荷瘤裸鼠随机分为ＴＮＦ、ＩＬ－２、ｒＩＦＮ、ＴＮＦ加ＩＬ－２、ＴＮＦ加ｒＩＦＮ及对照组。分别给药，实验结束时取血０．５～０．８ｍｌ，及瘤体、瘤旁和正常组织各１ｇ，放免法测定ＳＳ浓度。结果显示各细胞因子均可改变各组织中的ＳＳ浓度，以ＴＮＦ加ＩＬ－２组最明显（Ｐ＜０．０１）。作者认为，ＳＳ的分布受细胞因子的影响，这一影响可能是通过调节机体的免疫机制和对肿瘤的杀伤作用而产生的。研究提示将ＴＮＦ、ＩＬ－２、ＳＳ联合应用可能会对肾癌的生物治疗更有效     

Metastatic properties of the human prostatic cell line, PPC-1, in athymic nude mice

Limitation in the number of human prostatic cell lines has created a gap in knowledge regarding the in-vivo progression of this common cancer. The recently isolated primary prostatic carcinoma cell line, PPC-1, has been shown to be tumorigenic in athymic nude mice. These cells are now shown to form metastases to secondary sites in 10 of 12 animals in this initial study. Metastases were localized to lung and lymph nodes, and the tumor histology closely resembled that of the undifferentiated, rapidly dividing primary tumors. This is the first report describing the metastatic properties of a primary prostatic cancer cell line. PPC-1 cells are therefore likely to represent a good model system for the study of human prostate cancer progression.     

Heterotransplantation of human transitional cell carcinoma in athymic mice.

Human bladder tumors were obtained and transplanted into nude mice or other control animals. Tumor measurements, growth rate and selected histological studies were completed. No correlation between the growth of the tumor in the nude mouse and the clinical course of histologic tumor appearance in the host was detected. Metastases were not found. This feature has been noted generally to be uncommon in the nude mice model with some other human tumors. Despite careful technique tumor growth was achieved in only 40% of the appropriate experiments. The factors responsible for this variability and different growth rate in the nude mouse require further assessment before the results of other experimental treatments can be evaluated.     

Transplantable human prostatic carcinoma (PC-82) in athymic nude mice. II. Tumor growth and androgen receptors

Androgen receptor (AR) levels were measured in PC-82 tumor tissue grown in hormonally manipulated nude mice. In the nuclei of tumor tissue from intact male mice a relatively low concentration (mean 25 fmol/mg protein) of androgen receptors (ARn) was found, while no receptors for estrogens or progestins were detected. The total number of androgen receptors in the PC-82 tumor tissue (measured in the nuclei 1 h after injection of a single high dose of testosterone (T)) was found to be 100 fmol/mg protein. The antiandrogen cyproterone acetate, administered in combination with the high dose of T, significantly lowered the amount of ARn in the tumor tissue. In the nuclei of tumor tissue from intact tumor-bearing male mice with T-containing Silastic implants, a 4-times higher amount of tightly associated AR was found. In addition, an increased growth rate of the tumor was observed following T implantation. This finding suggests that the increased growth rate of the PC-82 tumor is associated with a continuous occupancy of AR in the nuclei of the tumor tissue. Castration of tumor-bearing male mice, which arrests the growth of this tumor, did not affect the concentration of ARn in the tissue compared to that of tissue in the intact control situation. In addition, the total amount of AR measured after T injection was not affected by castration. Therefore, the availability of a sufficient and steady level of T in the plasma and consequently the duration of the presence of AR in the nucleus of the PC-82 tumor tissue, rather than the total concentration of AR, appear to be the limiting factors in the modulation of hormonal responses in this androgen target tissue.     

The effect of radiation therapy and hyperthermia on a human prostatic carcinoma cell line grown in athymic nude mice

The effect of radiation and/or hyperthermia on a human prostatic carcinoma xenograft in athymic nude mice was investigated. A human prostate carcinoma subline (1-LN-PC-3-1A) was inoculated subcutaneously in the thigh of male athymic nude mice. When tumors reached a size of approximately 200 mm.3, they were treated with either radiation (X) or hyperthermia (H) alone, or in combination (X + H). In the combined treatment, hyperthermia was delivered immediately after radiation exposure. Comparison of the time required to reach twice the tumor volume observed at the time of treatment was used to define therapeutic impact on tumor growth. The combined treatment resulted in median tumor volume doubling time of 35.5 days, compared to 18 days and 25.5 days, respectively, for hyperthermia or radiation alone. Analysis of tumor doubling time using a proportional hazards regression indicates that under the conditions of this experiment, the effect of radiation and hyperthermia for 1-LN-PC-3-1A tumors is additive. The impact of this treatment regimen in the management of prostatic cancer requires further investigation.     

Local bone resorption induced by serially transplantable human renal cell carcinoma in nude mice

The high incidence of metastatic bone disease in urological cancer makes it necessary for clinicians to look for a valid experimental model to investigate the basic interactions between cancer cells and bone in order to improve the treatment. A new model of bone resorption was defined, namely the subcutaneous injection of tumor cell suspensions of serially transplanted renal cell carcinoma in nude mice after disruption of the periosteum of the calvaria. The tumor induced osteolysis associated with osteoclast proliferation with reactive bone formation. The X-p film from nude mice calvaria showed the same multiple osteolytic punched-out lesions as those of the patient's skull.     

Non-cross-resistant sequential combination chemotherapy consisting of cis-diammine-dichloroplatinum (II) mainly, based on synchronization theory, in human bladder cancer xenografts in athymic nude mice

We examined the chemotherapies with cis-diamminedichloroplatinum (II) (CDDP) alone and in combination, using the human bladder cancer xenografts (BT-8 and BT-11 strains) in athymic nude mice (BALB/C), to establish the most effective and useful method for urothelial cancer in clinical use. First, to assess the anti-tumor activities of single-drug and our devised VPM or CisCF combination chemotherapies, experiments were done using the BT-8 strain bladder cancer (transitional cell carcinoma and grade III). The schedule and dosage of each chemotherapy were as follows. Vincristine (VCR): 0.06 mg/kg, days 1-6, peplomycin (PEP): 0.9 mg/kg, days 1-6, methotrexate (MTX): 0.6 mg/kg, days 1-6, cytosine arabinoside (Ara-C): 3 mg/kg, days 1-6, 5-fluorouracil (5-FU): 30 mg/kg, days 1-6, adriamycin (ADM): 3 mg/kg, days 1-6, cyclophosphamide (CPM): 10 mg/kg, days 1-10, and CDDP: 2.5 mg/kg, days 1-6. These were for single-drug chemotherapies. The VPM combination consisted of VCR (0.06 mg/kg, days 1 and 4), PEP (0.3 mg/kg, days 1-6) and MTX (0.3 mg/kg, days 2, 3, 5 and 6), and the CisCF combination consisted of CDDP (2.5 mg/kg, days 1 and 4), Ara-C (3 mg/kg, days 1 and 4) and 5-FU (15 mg/kg, days 2, 3, 5 and 6). The control group was given normal saline of 0.1 ml/20 g body weight, intraperitoneally. All anti-cancer drugs were also given intraperitoneally. Secondly, to assess the anti-tumor activities of CDDP alone and various modes of combination chemotherapies with or without CDDP, the following experiments were done using the BT-11 strain bladder cancer (a mixed type of transitional cell carcinoma and squamous cell carcinoma). CDDP: 2.5 mg/kg, days 1-6. VPM X 2: VCR (0.04 mg/kg, days 1, 4, 8 and 11), PEP (0.2 mg/kg, days 1-4) and MTX (0.2 mg/kg, days 2, 3, 5, 6, 9, 10, 12 and 13). CisCF X 2: CDDP (2.5 mg/kg, days 1 and 8), Ara-C (3 mg/kg, days 1, 6, 8 and 13) and 5-FU (30 mg/kg, days 3, 4, 5, 10, 11 and 12). VPM-CisCF (I): VCR (0.04 mg/kg, days 1 and 4), PEP (0.2 mg/kg, days 1-7), MTX (0.2 mg/kg, days 2, 3, 5 and 6), CDDP (2.5 mg/kg, day 8), Ara-C (3 mg/kg, days 8 and 13), and 5-FU (30 mg/kg, days 10-12).(ABSTRACT TRUNCATED AT 400 WORDS)     

ACHN人肾癌裸鼠移植瘤模型的生物学特性及放射治疗观察

目的观察ACHN人肾癌裸鼠皮下移植瘤模型的生物学特性及其对放射线的敏感性。方法分别利用瘤细胞悬液接种法、瘤块包埋法获得ACHN人肾癌裸鼠移植瘤模型，观察移植瘤的生长情况、成瘤率、肝肺转移率及病理形态。ACHN皮下荷瘤鼠14只，随机分为空白对照组和放疗组，6MV X直线加速器对放疗组移植瘤局部单次照射12Gy，观察裸鼠的耐受性及肿瘤生长抑制情况；透射电镜观察瘤细胞超微结构变化。结果瘤块包埋法成瘤稳定，成瘤率92．5%，肝转移率43％，未见肺转移。裸鼠对12Gy射线局部照射耐受良好，放疗组移植瘤与空白对照组比较生长明显受抑制（P〈0．01）；放疗组瘤细胞凋亡现象明显。结论ACHN人肾癌裸鼠移植瘤模型可作为肾癌放疗实验研究的有效工具。     

The modulating effect of interferon alpha-2a on the antitumor activity of UFT against a human gastric carcinoma xenograft,SC-1-NU,in nude mice

The modulating effect of recombinant human interferon alpha-2a (IFN) on the antitumor activity of UFT, a mixed compound of tegafur and uracil at a molar ratio of 1:4, was investigated against SC-1-NU, a human gastric cancer xenograft serially transplanted in nude mice. IFN was administered subcutaneously at a dose of 60,000 IU/mouse daily for 14 days, and UFT was given at a dose of 15 mg/kg as tegafur daily, except on Sundays, for 3 weeks. The agents were administered either alone or simultaneously. Synergistic antitumor activity on SC-1-NU was produced by the combination of IFN and UFT without any increment of side effects, and the combination therapy also increased intratumoral thymidylate synthetase (TS) inhibition and the amount of 5-fluorouracil (5-FU) in the intratumoral RNA. Thus, IFN seems to modulate the antitumor activity of UFT against SC-1-NU through an inhibition of DNA synthesis and RNA distortion, and therefore this combination could be useful for clinical application.     

Clinical effect of UFT in advanced renal cell carcinoma

Single administration of 1-(2-tetrahydrofuryl)-5-fluorouracil (UFT) to patients with renal cell carcinoma with assessable lesions brought about 1 case each of complete response, partial response and no change, 3 cases of partial deterioration and the effective rate of 33.3%. As adverse effects, anorexia occurred in 1 of the 6 patients, but continual administration was possible by reducing the dose. The effective rate of UFT is high with few adverse effects, compared with the conventional chemotherapy. Therefore, UFT is considered to be an effective preparation for treating renal cell carcinoma.