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Experimental chemotherapy with 5-fluorouracil (5-FU; 60 mg/kg), 1-hexylcarbamoyl-5-fluorouracil (HCFU; 70 mg/kg), 3-(3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl)-1-ethoxym ethyl-5- fluorouracil (BOF-A2; 30 mg/kg) and UFT (20 mg/kg as tegafur with uracil at a molar ratio of 1:4) was performed using human gastric (H-111) and colon (Co-4) carcinoma strains in nude mice. 5-FU was administered ip with a q4d x 3 schedule and the other agents were given po daily for three weeks. Concentrations of 5-FU in the serum and the tumor were assessed by gas chromatography-mass fragmentography, two hours or 12 days (5-FU) after the last treatment, and thymidylate synthetase (TS) was assayed according to the method of Spears et al. using the same schedule. The antitumor activity of the agents was assessed in terms of the actual tumor weight at the end of the experiment. HCFU was effective against both strains and 5-FU was effective against Co-4, although the other agents were ineffective against either strain. Statistically significant correlations were found between the serum and tumor concentrations of 5-FU and antitumor activity. Statistically significant correlations were also observed between the antitumor activity and TS inhibition rate (TSIR) and the activity of free thymidylate synthetase (TSfree), with higher TSIR and lower TSfree resulting in higher antitumor activity. Therefore, TSIR and TSfree were thought to be promising indicators for predicting the antitumor activity of fluoropyrimidines.

Although brainstem infarction is known to cause cardiopulmonary arrest, there are only a few reported cases. We experienced a patient who was brought into our emergency department with cardiopulmonary arrest. After successful resuscitation, she remained comatose, her eyes being fixed in the middle position with no light reflex. She was quadriplegic, but showed occasional right-sided myoclonic involuntary movement. Brain computed tomography performed on the fourth hospital day revealed a diffuse low-density area in the left temporo-occipital lobe. Secondary brainstem infarction due to cerebral hypoperfusion or hypoxemia was ruled out, as other causes of cardiopulmonary arrest were not found. We considered that her cardiopulmonary arrest was caused by brainstem infarction. Cardiopulmonary arrest due to brainstem infarction may be overlooked because of diagnostic difficulty.

The antitumor activity and pharmacokinetics of (7R, 8S, 10S)-10-((3-deamino- 3-(4-morpholino)-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-8- ethyl- 7,8,9,10-tetrahydro-1,6,7,8,11-pentahydroxy-5,12-naphthacenedione hydrochloride (KRN8602) were evaluated using five human breast carcinoma xenografts in nude mice. The maximum non-toxic dose of KRN8602 was 2 mg/kg by q4d x 3 intraperitoneal and peroral administration. KRN8602 showed significant antitumor activity against MX-1, which is less sensitive to adriamycin, with the chemotherapeutic indices of 13.0 for po administration and 9.5 for ip injection. Although KRN8602 also inhibited the growth of T-61 significantly, the antitumor activity of this agent against the other three breast carcinoma xenografts was limited. To elucidate this discrepancy, pharmacokinetic analysis and MTT assay were conducted using the KRN8602-sensitive MX-1 and KRN8602-insensitive R-27. While no differences were observed in the area under the curve and the peak concentration of KRN8602 for each tumor, a difference in the sensitivity of the tumor strains was obvious in MTT assay. The efficacy of this agent seemed to depend on the sensitivity of each type of tumor cell rather than the concentration of agent in tumor tissues. If it were possible to select patients with sensitive tumor cells to this agent by the MTT assay, the phase II trial might be completed within a short period by reducing the number of studied patients.

The levels of epidermal growth factor (EGF) receptors were investigated in surgically resected tumors of various origins including esophagus (n = 33), lung (n = 14), pancreas (n = 9), colorectum (n = 10), breast (n = 23) and stomach (n = 8). The 125I-EGF binding capacities of squamous cell carcinomas of esophagus and lung were exceptionally higher than those of the other cancer tissues. Immunohistochemical staining with an anti-EGF receptor monoclonal antibody detected EGF receptors in the basal cells and parabasal cells of normal esophageal epithelium and in all the cancer cells of squamous cell carcinoma tissues of esophagus and lung. DNA replicating cells were examined by the bromodeoxyuridine staining method and it was found that the basal cells and parabasal cells of normal epithelium and peripheral cells of cancer pearls are proliferating. Contrary to this, a tumor antigen TA-4, known as a specific marker for squamous carcinoma, was detected in the differentiated cancer cells and in middle-layer squamous cells. These results strongly suggest that the increase in EGF receptor levels may be associated with the development of human squamous cell cancers of esophagus and lung. Thus, measurement of EGF receptor expression in tumor tissues has diagnostic value and should prove useful for the development of new therapies.

The MTT assay reported by Mosmann is a rapid and convenient colorimetric assay for cellular growth and survival in vitro. In this paper, the MTT assay was modified as a chemosensitivity test, and its potential was investigated. Using 10 human tumor xenografts in athymic nude mice, the predictability of in vitro antitumor effects of drugs using the MTT assay was compared with that using the clonogenic assay. The MTT assay showed excellent reproducibility, and the predictable rate in this assay was 86.7%, with 100% true-positive and 77.8% true-negative rates, almost equivalent to the 90.0% predictable rate of the clonogenic assay. This method also has several advantages with respect to rapidity, quantitation, management of many samples, and cell number required for the assay. Application of this assay to chemosensitivity testing seems to be valuable and useful.

To elucidate the mode of action of busramustine (KM2210), 17 beta- and alpha-busramustine, estradiol and chlorambucil were used for experimental chemo- and endocrino-therapy against hormone-dependent (T-61) and independent (MX-1) human breast carcinomas serially transplanted into BALB/cA female nude mice. Busramustine was administered po daily for 3 weeks at doses of 12.5-300 mg/kg for the beta-isomer and 25-300 mg/kg for the alpha-isomer. Five to 50 mg of estradiol per kg was administered im once, and 3 to 6 mg of chlorambucil per kg was administered po daily for 3 weeks. All of the compounds were effective against estrogen receptor-positive T-61 with a clear dose-response relationship, while estrogen receptor-negative MX-1 was sensitive to all of the agents except estradiol. Since the alpha-isomer of busramustine was effective against both tumor lines, the mode of action of 17 beta-busramustine may not be related to estrogenic action by estradiol released from the maternal compound. However, 17 beta-busramustine generated the estrogen receptor system of T-61 tumor and resulted in the endometrial hyperplasia of tumor-bearing nude mice, suggesting that this compound also has estrogenic action on transplanted human breast carcinoma and tumor-bearing host mice, besides non-estrogenic antitumor activity on human breast carcinoma xenografts.

Lung cancer tissues from 68 patients were examined for epidermal growth factor (EGF) receptor levels and EGF receptor gene copy numbers. Histologic cell types of these lung cancer tissues included squamous-cell carcinoma (n = 30), adenocarcinoma (n = 28), large-cell carcinoma (n = 4), and small-cell carcinoma (n = 6). Tissues of squamous-cell carcinoma exhibited exceptionally high 125I-EGF binding activity, and those of small-cell carcinoma showed no EGF binding activity. Southern blot hybridization analysis revealed EGF receptor gene amplification in the squamous-cell carcinomas with high EGF binding activity. The EGF receptor levels in squamous-cell carcinomas and adenocarcinomas were compared with their pathological staging grouping and pathological findings, including degree of differentiation, diameter of tumor, and lymph node metastasis. However, unlike previous reports on breast and bladder cancers, there was no obvious correlation between these pathological characteristics and the EGF receptor levels of lung cancer.

The prognostic value of epidermal growth factor (EGF) receptor level was studied in 32 patients with esophageal squamous cell carcinoma. The EGF receptor levels of tumors were measured by iodine 125 (125I)-EGF binding assay, and the patients subsequently were divided into two groups: a group with high EGF binding capacities (greater than or equal to 2.5% of input), and a group with low EGF binding capacities (less than 2.5% of input). The cumulative survival rates for the two groups were calculated by the Kaplan-Meier method. The generalized Wilcoxon test indicated that the survival rate of the high EGF binding group was significantly lower than that of the low EGF binding group (P less than 0.05). In tumors from two patients with the highest EGF receptor levels, EGF receptor gene amplification was observed. These patients developed mediastinal lymph node metastasis and died 4 and 11 months after surgery, respectively. These results suggest that elevated EGF receptor level is a significant prognostic indicator for esophageal squamous cell carcinoma.

EGF receptor-hyperproducing cells of squamous carcinoma origin were inoculated s.c. into the bilatero-abdominal regions of athymic mice and a mini-osmotic pump containing EGF was implanted on teh back. After 2 weeks the tumors formed from 5 different cell lines in the presence of EGF weighed 3 to 6 times more than those formed in the absence of EGF. The cells recovered from these tumors maintained their original characteristics such as the amplified EGF receptor gene, high numbers of EGF receptors and a sensitivity to EGF-mediated inhibition of growth in vitro. These results suggest that EGF plays an important role in promoting growth of squamous-cell carcinoma in vivo.

EGF receptor levels were investigated in esophageal squamous-cell carcinoma tissues from 31 patients. Twenty-two (71%) of these cancer tissues exhibited significantly higher 125I-EGF binding activity than normal mucosa in the adjacent non-cancerous tissues. These EGF receptor levels were then compared on the basis of pathological findings including lymph-node metastasis, depth of invasion, differentiation type, vascular invasion, infiltration and location of the lesion. Unlike previous reports on breast and bladder cancers, our study showed no obvious correlation between these pathological characteristics and the EGF receptor levels in esophageal carcinomas. Immunohistochemical staining with the anti-EGF receptor monoclonal antibody detected EGF receptors in squamous cells of the cancer tissues as well as in the basal cells of nearby normal epithelium. Since the basal cells have proliferative potential in the esophagus, the increase in EGF receptor levels in these cells may possibly be associated with the development of human esophageal squamous-cell cancer.

The plasma levels of immunoglobulins IgA, IgG and IgM have been measured in 35 British, 44 Hawaiian-Japanese and 37 Japanese healthy adult women. Previous investigations showed that the mean levels of all three immunoglobulins were higher in Japanese than in British normal women. The present study finds that Hawaiian-Japanese women have "Japanese" levels of IgA, "British" levels of IgM and are intermediate for IgG. Thus, plasma IgM concentrations correlate with breast cancer incidence rates in the three racial groups and the reduced amounts of plasma IgM found in Japanese patients with breast cancer support this association.