Pharmacokinetics of FT-207 rectum suppository in squamous cell carcinoma of the uterine cervix. (I) Pharmacokinetics in single administration at a dose of 1 gram

In order to use FT-207 rectum suppository for a long-term maintenance chemotherapy of squamous cell carcinoma of the uterine cervix, we examined its pharmacokinetics by single administration at a dose of 1 g employing chemical assay. The results were as follows: 1. The blood level of FT-207 showed its peak of 30 mcg/ml at 2 hours after administration, of which half-time was 9 hours. Inter-individual differences were few in changes in the curve. 2. The blood level of 5-FU showed two peaks, 0.25 mcg/ml at 4 hours and 0.017 mcg/ml at 36 hours after administration. There were large inter-individual differences in its alteration. 3. At the time of operation, both FT-207 and 5-FU showed low concentrations in blood. 4. The level of 5-FU in cervical focus was 0.068 mcg/g which was the highest among those in all genital organs, and 2.7 times higher than the level of 5-FU in blood. 5. There was a significantly positive correlation at r = 0.174 (p less than 0.1) between the level of 5-FU in the focus of cervical cancer and the level of FT-207 in blood.     

Serum concentration of 5-FU and tegafur (FT-207) after administration of tegafur (FT-207) suppository with the colostomy

Tegafur (FT-207) suppositories were administered at a rate of 750 mg via the artificial anus (ST Group) following surgery of rectal cancer. Comparative studies were conducted of changes in blood concentrations of 5-FU and tegafur at the time of initial administration and following one week of continuous use for the low-anterior resection cases (LA Group) and the rectal administration cases (RE Group). FT-207 concentration at initial administration was low in the ST group compared to those for both LA and RE groups which received anal administration of the drug, but only little changes were noted. Blood concentration one hour after administration was 11.1 micrograms/ml, elevated to 14.3 micrograms/ml at two hours, and remained at 10 micrograms/ml and above for six hours following administration. The ST group 5-FU concentrations at two, four and six hours after administration were significantly lower than those in the RE group but the changes were little. Blood concentrations were 0.015 microgram/ml at one hour after administration, 0.017 micrograms/ml at two hours and maintained virtually the same level thereafter. An effective concentration of 0.012 microgram/ml was maintained even at ten hours following administration. After one week of administration of the suppositories, the ST group showed the lowest concentration among three groups, but it was approximately double compared to the initial concentration; FT-207 showed nearly the same concentration in the LA group and 5-FU blood concentration was 0.025 microgram/ml at one hour after administration, reached to a maximum of 0.030 microgram/ml at two hours and maintained 0.020 microgram/ml and higher at ten hours. 5-FU concentration in the LA and RE groups after one week of continuous administration showed a dual-peaked pattern. No patient with an abnormal artificial anus was involved in this study. The artificial anus is thought to be an adequate and effective administration route of FT-207 suppositories.     

宫颈鳞状细胞癌患者血清鳞状细胞癌抗原变化的临床意义

目的　研究子宫颈鳞状细胞癌患者血清中鳞状细胞癌抗原水平与病理分级、临床分期及对治疗反应之间的关系。方法　利用雅培公司提供的 IMX全自动快速粒子酶免疫分析系统 ,对 2 5例正常献血员和 83例经病理学诊断的宫颈鳞状细胞癌患者 ,进行了血清中鳞状细胞癌抗原血清检测并分析其与病理分级、临床分期之间关系。其中 80例患者放射治疗前后血清鳞状细胞癌抗原水平变化情况进行了自身比较。结果　中晚期宫颈鳞状细胞癌患者血清鳞状细胞癌抗原水平与病理分级、临床分期之间无相关性。放射治疗前后患者血清鳞状细胞癌抗原水平有明显变化。结论　对子宫颈鳞状细胞癌患者 ,在治疗前后检测血清鳞状细胞癌抗原水平 ,可以作为对放射治疗疗效判断的参考指标之一。     

子宫颈鳞癌IA1期30例临床分析

背景与目的：宫颈鳞癌IA1期术前诊断和处理仍有争议,本研究旨在探讨IA1期宫颈鳞癌诊断和处理的恰当方式。方法：回顾分析我院1992～2001年收治的30例宫颈鳞癌IA1期患者的临床和病理资料。结果：30例患者中7例既无症状又无明显体征(23．3％)。23例行细胞学检查,阳性率为86.9％(20／23);23例行阴道镜检查,准确率为78．2％(18／23);10例行宫颈管刮取术,4例阳性。30例患者中22例行广泛或次广泛全子宫切除术(73．3％),6例行全子宫切除术,2例行宫颈冷刀锥切术;28例子宫切除标本宫旁组织均未受侵,阴道残端均无癌残留,其中8例行盆腔淋巴结清扫术,平均切除淋巴结22枚,均为阴性,两例锥切标本切缘干净;术前诊断与最后诊断符合率为56．7％(17／30)。术后中位随访时间34个月(17～111个月),均无复发。结论：IA1期宫颈鳞癌术前阴道镜检查及宫颈多点活检诊断准确率低;冷刀锥切可提高诊断准确率,同时又可作为要求保留生育功能的IA1期宫颈鳞癌患者的治疗方式。     

Muscle metastasis of squamous cell carcinoma of the uterine cervix]

Muscular metatasis are rare, their number is probably underestimate. The authors report a case of a patient treated, in 1993, for a squamous cell carcinoma of the uterine cervix. Five years later, the patient developed a metatasis to muscular psoas. She underwent combined surgical excision and adjuvant radiation therapy. The patient is alive and well 30 months after diagnosis of the metastasis.     

Evaluation of preoperative administration of N1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) suppository in surgical adjuvant chemotherapy for large bowel cancer

A prospective randomized study was performed for 72 patients with large bowel cancer, and 36 cases each of rectal cancer and colonic cancer, who had received curative resection respectively. The regimen consisted of two adjuvant chemotherapies: group A, postoperative administration of FT-207 suppository; group B; preoperative and postoperative administration of the same suppository. A follow-up study was then done. The results revealed the 5-year survival rate to be 65.1% for group A and 72.4% for group, B respectively. With rectal cancer, 5-year survival was 57.8% for group A and 70.5% for group B respectively. In colonic cancer the figures were 70.8% for group A and 75.0% for group B. Thus, there was no significant difference but a somewhat higher survival rate was observed in the preoperative plus postoperative administration group. Comparison of in the prognosis two groups classified according to the degree of nodal metastasis and invasion revealed good results in group B. The above-mentioned facts suggest that pre- and post-operative administration of FT-207 suppositories as adjuvant chemotherapy for colorectal cancer is superior to postoperative use alone.     

Combination therapy of renal cell carcinoma with interferon-alpha and UFT (or FT-207)

Human lymphoblastoid interferon (IFN-alpha MOR-22; OIF) was administered to forty-two patients suffering from renal cell carcinoma. Twenty-six patients with metastatic lesions or primary tumor were treated in a clinical trial with either MOR-22 alone or combination of MOR-22 and UFT (or FT-207). The efficacy was assessed in ten of twenty patients who had received MOR-22 alone for more than eight weeks, but objective response was not observed. The efficacy was done in eight of fourteen patients with MOR-22 and UFT (or FT-207) in combination. Complete response was achieved in one, and partial response in two, with an objective response rate of 37.5%. But the difference was no statistically significant in the survival rate of each therapy. In evaluable twenty patients with MOR-22 prophylactically, there was only one case who had occurred lung metastases with a refractory rate of 8.3%. Forty-one patients were examined for side effects to drugs. The main side effects were fever, anorexia, general fatigue, hematologic toxicities, and hepatic dysfunction in both therapy. These side effects occurred with more increased frequency in combination therapy of UFT (or FT-207) compared to MOR-22 alone.     

Increased expression of DNA methyltransferase 1 (DNMT1) protein in uterine cervix squamous cell carcinoma and its precursor lesion

Aberrant DNA methylation has been shown to play important roles during multistage carcinogenesis in various human organs. The aim of this study was to evaluate the significance of DNA methyltransferase 1 (DNMT1) protein expression during cervical carcinogenesis. We carried out an immunohistochemical examination for DNMT1 in 34 samples of histologically normal squamous epithelium, 36 samples of low-grade cervical intraepithelial neoplasia (CIN), 61 samples of higher-grade CIN and 30 samples of squamous cell carcinoma of the uterine cervix. The DNMT1 protein expression score, reflecting the intensity and incidence of DNMT1 nuclear immunoreactivity, was increased even in low-grade CIN (P<0.0001) in comparison with histologically normal squamous epithelium and was further increased in higher-grade CIN (P<0.0001 compared to low-grade CIN). The DNMT1 protein expression score remained at a plateau in microinvasive carcinoma (Stage IA, P=0.0690 compared to higher-grade CIN) and then decreased with cancer invasion (Stage IB or more, P=0.0176 compared to Stage IA), whereas the proliferating cell nuclear antigen (PCNA) labeling index did not decrease with cancer invasion (P=0.8259 between Stage IA and Stage IB or more). Thus, the DNMT1 protein expression score and the PCNA labeling index were not mutually correlated in squamous cell carcinoma of the uterine cervix (P=0.2304). These data suggest that progressively increasing expression of DNMT1 protein is not entirely a secondary result of increased cell proliferative activity, but is associated with an early step of multistage cervical carcinogenesis.     

Detection of squamous cell carcinoma antigen in normal squamous epithelia and in squamous cell carcinomas of the uterine cervix

Squamous cell carcinoma (SCC) antigen is a subfraction of tumor antigen TA-4 isolated from a cervical squamous cell carcinoma. The specificity of SCC antigen and the factors influencing its release into serum were evaluated. Antigen concentrations were measured in 157 tissue extracts and in 188 sera of patients with nonmalignant or malignant gynecologic diseases. A commercial radioimmunoassay based on polyclonal antibodies (Abbott Laboratories, North Chicago) was used. Cytosol concentrations were significantly higher (P less than 0.005) in normal squamous epithelia (means = 6040 ng/mg cell protein [CP]) and in squamous cell carcinomas (means = 2483 ng/mg CP) of the exocervix than those in normal columnar epithelia and in adenocarcinomas of the endocervix, endometrium, ovary, and breast (means = 1-508 ng/mg CP). Despite the high antigen concentrations in normal squamous epithelia, elevated serum levels (greater than 2.5 ng/ml) were almost exclusively found in patients with cervical squamous cell carcinomas. The sensitivity of SCC antigen as a marker for primary carcinomas was 61%, increasing from 29% in Stage I to 89% in Stage IV. The positivity rate was higher in women with well-differentiated (78%) and moderately differentiated carcinomas (67%) than in those with poorly differentiated tumors (38%). The results show that SCC antigen is not tumor specific. The release into serum is independent of local tissue content, but is apparently influenced by the infiltrative growth, the mass, and the degree of histologic differentiation of the tumor.     

Age as a prognostic factor in patients with squamous cell carcinoma of the uterine cervix

Correlations between age and several prognostic factors, such as histologic cell type, depth of invasion, intravascular invasion, and lymph node metastases (LNM), were analyzed in squamous cell carcinoma of the cervix (SCC). A total of 380 patients with Stage IB or more advanced SCC underwent radical hysterectomy at the authors' institution from 1971 to 1987. The cases were divided into four age groups: 30 to 39 years, 40 to 49 years, 50 to 59 years, and 60 to 69 years. The depth of invasion was classified in four categories according to pathologic examination of surgical specimens. The only significant factor was the frequency of LNM with deeper invasion, which was less in the 60-to-69-year age group than in the younger age groups. The 5-year survival rates of the patients with LNM also were higher in the 60-to-69-year group. Thus, age 60 or older can be considered a prognostic factor correlating to LNM in squamous cell carcinoma of the cervix.     

Phase II study of mitomycin-C, vincristine, and bleomycin in advanced squamous cell carcinoma of the uterine cervix.

Utilizing the stathmokinetic principle of timed vincristine and bleomycin, we combined these two agents with Mitomycin-C. The dose schedule included vincristine 0.5 mg/m2 intravenously (i.v.) geginning on day 1 and repeated twice weekly for 12 weeks; each injection was followed in 6-12 hours by bleomycin 6 mg/m2 for 12 weeks. Mitomycin-C was administered as a 20 mg/m2 bolus beginning on day 2 and repeated at 6-week intervals. Thirty patients were entered into this study, 27 were fully available for response. Thirteen patients (48%) met criteria of response (greater than 50% reduction in volume of measurable tumor). Significant myelosuppression resulted from this therapy. Median leukopenia nadir was 3.8 X 10(3) cells/mm3 and median thrombocytopenia nadir was 116 X 10(3) cells/mm3. Additional toxic reactions included anemia, lassitude, anorexia, peripheral neuropath fever, and skin rash. Despite significant, but manageable, toxicity, this combination appears to represent an improvement in the chemotherapy of a traditionaly refractory solid tumor.     

ICRF-159 (razoxane) in patients with advanced squamous cell carcinoma of the uterine cervix. For the Gynecologic Oncology Group

Thirty-one patients with advanced squamous cell carcinoma of the cervix were entered onto this phase II study evaluating the efficacy of ICRF-159 (razoxane). Three of these patients were excluded; one had no tumor, one had a second primary, and one received no therapy. ICRF-159 was administered orally at a dose of 2.5 g/m2 weekly until progression, unacceptable toxicity, or death. Adverse effects were primarily hematologic in nature. Twenty-three of the 28 patients exhibited leukopenia which in ten instances was severe (below 2000/mm3). Seven cases had thrombocytopenia (one case below 50,000/mm3). Other toxicity, including fever and anorexia, was mild to moderate. There was tumor response in five (18%) patients (one CR, four PRs) ranging from 1 to 5 months. Fifteen patients with stable disease and eight with progressive disease had a median survival duration of 3.8+ and 3.5+ months, respectively. ICRF-159 showed limited activity in this patient population. However, it might be considered for combination with other low myelosuppressive agents.     

Effect of FT-207 on bladder cancer in rats induced by BBN. II: The effect of oral administration of FT-207 during oncogenesis of bladder cancer

The effect of Tegafur (FT-207) by oral administration on the development of urinary bladder tumors in Wistar strain male rats induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) was studied. Urinary bladder tumors were induced in 18 of 20 rats (90.0%) when rats were given 0.05% BBN in the drinking water for 8 weeks and then given water without BBN for 12 weeks. When FT-207 100mg/kg B. W./day was given in their diet after treatment with 0.05% BBN for 8 weeks, tumors developed in the urinary bladder with low incidence (9 of 16 rats: 56.3%). Hematotoxicity was not observed in all animals treated with FT-207. These results shows that FT-207 also inhibited the development of urinary bladder tumors treated with BBN in rats by oral administration, which were similar those our previous results showed by intraperitoneal administration of FT-207.     

Clinical significance of mucin staining in keratinizing-type squamous cell carcinoma of the uterine cervix

Tumor tissue from 57 cases of keratinizing-type squamous cell carcinoma of the uterine cervix that had been stored in the archives of Osaka City University Hospital between May 1986 and October 1994 were stained with periodic acid-Schiff (PAS) reagent following amylase and alcian blue to identify the presence of intracellular mucin and to assess the value and significance of demonstrating the presence of mucin. Nineteen specimens (33.3%) stained positive for mucin with alcian blue or PAS following diastase. The results of mucin staining were not significant in terms of survival by Kaplan-Meier's analysis.     

Plasma proteomic analysis of patients with squamous cell carcinoma of the uterine cervix

Objective

To compare plasma protein expression between patients with squamous cell carcinoma (SCC) of the cervix and normal controls.

Methods

Plasma samples from patients with benign gynecological disease (normal cervix, n=6) and cervical cancer (SCC, n=6) were subjected to plasma proteomic analysis using two dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization mass spectroscopy (MALDI-MS). Western blotting and immunoturbidimetric assay were performed to validate the results of 2-DE.

Results

Eight proteins showed differential expression between controls and SCC patients; six (ceruloplasmin, complement C3, afamin precursor, alpha-1-B-glycoprotein, transferrin, alpha-fibrinogen precursor) were up-regulated, while two (chain A, crystal structure of antithrombin and apolipoprotein A-IV precursor) were down-regulated in the plasma of SCC patients. Western blotting analysis revealed significant elevation of ceruloplasmin, complement C3, afamin, and alpha-1-B-glycoprotein in the plasma of SCC patients in comparison to controls. Immunoturbidimetric assay of a larger group confirmed the results of 2-DE and Western blotting, and showed that ceruloplasmin and complement C3 were significantly elevated in the plasma of SCC patients in comparison with controls and patients with carcinoma in situ (CIS) of the uterine cervix.

Conclusion

Plasma protein expression determined using 2-DE and MALDI-MS will give a chance to identify tumor-specific biomarkers for SCC of the cervix.