To choose the optimal chemotherapy regimens, we have employed a new chemosensitivity testing method, the collagen gel droplet embedded culture drug sensitivity test (CDDST) for patients with non-small cell lung cancer (NSCLC). This method requires fewer cancer cells(1 x 10(5) cells in 2 specimens biopsied by bronchoscopy) than conventional chemosensitivity tests and can be also used to assess cases of malignant effusion. Correlations between the in vitro and in vivo responses were: true positive ratio, 75.0% (21/28 patients); true negative ratio 85.0% (17/20 patients); and accuracy 79.2%. The median survival time (MST) of patients (n = 11) with unresectable NSCLC who were given optimal chemotherapy based on the results of the CDDST was 15.8 months and the MST of those (n = 16) who did not receive a sensitive agent was 5.6 months. There was a significant difference between these two groups (p = 0.0048, log-rank test). These results suggest that the CDDST is an effective method for chemosensitivity testing in unresectable NSCLC.

Various types of drug delivery system (DDS) for antitumor drugs have been developed to reduce severe systemic toxicities and to enhance antitumor effects by improving their pharmacokinetics. In this paper, outlines are first given of the concept and design of DDS, focusing on polymeric antitumor drugs (macromolecular prodrugs) and then describing the superior DDS effects shown in preclinical studies of DE-310, a DDS optimized for the camptothecin analogue DX-8951. Clinical trials of DE-310 are now ongoing in the USA and Europe.

Nausea and vomiting induced by chemotherapy have an impact on cancer patients' quality of life (QOL). The Functional Living Index-Emesis (FLIE), which is designed to assess the change in QOL from the influence of nausea and vomiting is rarely used in Japan, regardless of its utility, because it is written in English. We investigated the use by cancer patients with the main object of designing a reliable and valid Japanese version of the FLIE. We also verified the validity of a Japanese translation and improved part to design a highly precise Japanese version FLIE. Consequently, we found a correlation between the FLIE Japanese version and the QOL questionnaire Quality of Life Assessment of Cancer Patients Receiving Chemotherapy (QOL-ACPRC), which was the external standard. Furthermore, we improved the questionnaire to raise the rate of patient response, and improve reliability and validity. We think that this FLIE Japanese version will become useful in assessing the change in patient QOL due to the influence of nausea and vomiting.

Before and after launch of 5-HT3, antagonist, necessary dose and duration of chemotherapy were compared between the patients who were confirmed to have undergone chemotherapy before the launch of 5-HT3 antagonist (retrospective group) and the ones currently using ondansetron (OND) for chemotherapy-induced emesis (prospective group). Clinical usefulness of OND was evaluated through survey on quality of life (QOL) to patients and questionnaires to physicians, nurses & patients. Necessary dose of chemotherapy was evaluated by investigating actual dose of cisplatin (CDDP). As the result, necessary dose of CDDP was confirmed to be different between retrospective and prospective groups. The influence on the actual CDDP dose was observed with or without use of G-CSF or by recommended dose of CDDP, while no influence by 5-HT3 antagonist was observed. For necessary duration of chemotherapy, significant difference was not observed between retrospective or prospective groups. On the other hand, actual CDDP dose or necessary duration of chemotherapy were confirmed to be greatly affected by chemotherapy-induced adverse events such as blood disorder (e.g. bone marrow suppression) or renal disorder, rather than chemotherapy-induced emesis. As the result of QOL survey to patients and other questionnaires to medical staff & patients, the fact of chemotherapy-induced emesis to lower the patient's QOL as well as the importance of emetic control was confirmed. It was also confirmed that the workload of nurses or other medical staff has lessened since the launch of 5-HT3 antagonists.

The activity and toxicity of a weekly infusion of low-dose paclitaxel was studied. Twelve patients with metastatic or advanced breast cancer received paclitaxel (80 mg/m2 over 1 h) every week. Administration was continued for 6 weeks with two weeks rest until disease progression or limiting toxicity. Dexamethasone 20 mg, diphenhydramine 50 mg, and ranitidine 50 mg were given prior to each dose of paclitaxel. Six patients had received prior standard CMF therapy, and four patients had received CMF and docetaxel therapy. Two patients had not received prior therapy. The overall response rate was 58% with 17% complete responses and 42% partial responses. Responses were observed in both patients without prior therapy, and in five of 10 (50%) with prior therapy. Grade 3/4 neutropenia occurred in one patient; febrile neutropenia was not observed. There was no neuropathy or hypersensitivity. Weekly paclitaxel is active and well tolerated in patients with metastatic or advanced breast cancer. This schedule allows a high cumulative dose of paclitaxel without major myelo- or neurotoxicity. This weekly regimen deserves further exploration.

We treated 12 patients with metastatic breast cancer with weekly paclitaxel therapy. Paclitaxel was administrated by 1 hour infusion at a dose of 80 mg/m2 after short premedication every week on an outpatient basis. Administration was continued for 3 weeks followed by 1 week rest. All patients had received prior metastatic chemotherapy, and prior anthracycline therapy was done in 66.7% of the patients. Partial responses were observed in 66.7% of the patients and progressive disease in 33.3%. The response rate was 66.7%. Responses were observed in 62.5% of the patients with prior anthracycline therapy. Grade 3/4 leukopenia and neutropenia occurred in 25% of the patients, respectively, and no grade 3/4 peripheral neuropathy was observed. Dyspnea occurred in 25% of the patients and was grade 3 in 16.7%. Dyspnea is thought to be one of the adverse events requiring caution with weekly paclitaxel administration. Weekly paclitaxel therapy is effective and well tolerated in patients with metastatic breast cancer.

To examine apoptosis as a measure of chemosensitivity to anti-cancer drugs in gynecological cancer xenografted into nude mice.

To evaluate the antitumor efficacy against metastatic breast cancer of fluoropyrimidines alone and combined with other chemotherapeutic agents, we developed a murine model of breast cancer metastatic to the lung by orthotopically implanting MDA-MB-435S breast tumors into mice. MDA tumor cells greatly metastasized to lung tissue only after the orthotopically implanted tumors were surgically removed. Measurement of the expression of enzymes involved in 5-FU metabolism showed significantly higher activity of dihydropyrimidine dehydrogenase (DPD) and lower activity of thymidylate synthase (TS) in the MDA metastases than in the orthotopically implanted tumors. Based on the enzymatic properties of metastatic tumors, the minimum toxic doses of UFT (17.5 mg/kg/day) as a DPD-inhibitory fluoropyrimidine (DIF), and of 5'-DFUR (120 mg/kg/day) as a non-DIF, were orally administered to mice with pulmonary metastasis of the breast tumor. The results showed that UFT significantly inhibited the growth of pulmonary metastases of the breast tumors, but 5'-DFUR did not. UFT seemed to inhibit the growth of the pulmonary metastases of the breast tumors in combination with paclitaxel (50 mg/kg) more than in combination with 5'-DFUR, although the antitumor efficacy of neither combination was significantly different from that of paclitaxel alone. These results suggest that combination of DIF with other chemotherapeutic drugs, such as taxanes, is required to attain high antimetastatic and antitumor efficacy against breast tumor metastases, based on the molecular characteristics of the metastatic tumors.

We investigated the antitumor vasculogenesis and antitumor activity of gamma-hydroxybutyric acid (GHB), a metabolite of UFT. In a mouse dorsal air sac (DAS) assay, UFT demonstrated a wide spectrum of anti-tumor vasculogenesis except for AZ-521 tumor. Although the expression of vascular endothelial growth factor (VEGF) was detected in almost all tumor cell lines used in the DAS assays, expression of basic fibroblast growth factor (bFGF) was only detected in the AZ-521 tumor. GHB inhibited the chemotactic migration and morphological changes of human umbilical vein endothelial cells (HUVECs) induced by VEGF at IC50 values of 2.8 and 0.31 microM respectively. In addition to these in vitro assays, GHB blocked tumor growth of MC-5, a human breast cancer, in a xenograft model at inhibition rate of 37%. Moreover, GHB showed an additive effect in combination with 5-FU in this model. These results indicate that the anti-tumor vasculogenesis activity of GHB is involved in part in the antitumor effect of UFT.

Since the emesis induced by cytotoxic drugs is intractable, and is a possible determinant of a patient's QOL during chemotherapy, the control of this adverse event is essential to complete a course of cancer chemotherapy. The anti-emetic effects of a 5-HT3 antagonist, ondansetron hydrochloride (OND), was evaluated during a course of CDDP-containing chemotherapy. Forty-eight patients with gynecologic carcinoma, respiratory malignancy, or urological cancer were followed throughout their treatment courses. For acute emesis, prophylactic OND was given intravenously before CDDP administration, and OND tablets were used for 4 days from the day following CDDP administration as a measure against delayed emesis. The efficacy of OND gradually decreased for the acute emesis (1st course: 73.8%, 2nd course: 62.8% and 3rd course: 56.7%). The efficacy, however, did not decrease against the delayed emesis. Of patients with a good response, "effective" or "highly effective", in the previous treatment course, over 80% could again obtain a good response in the next treatment course. Adverse events of this anti-emetic treatment were not observed except for mild leukocytosis in one case, and this unexplainable effect abated without any specific treatments. In conclusion, the anti-emetic effects of OND sufficiently prevented the emetogenic action of CDDP throughout the treatment course, with a special importance for successful control in the first treatment course. The additional use of corticosteroid might enhance the effects of OND for female patients.

To evaluate the feasibility and efficacy of a biweekly schedule of paclitaxel in advanced or recurrent breast cancer, 18 patients were enrolled in this pilot study. Paclitaxel of 120 mg/m2 was administered over 3 hours, and cycles were repeated every two weeks until disease progression or toxicity precluded further treatment. Patients received a median of 10 infusions with actual dose intensity of 55.9 mg/m2/wk, and median time to progression was 4.8 months. The overall response rate was 33.3%, and one patient achieved stable disease for at least 6 months. The responders included patients who received prior anthracycline and/or docetaxel treatment, and the response rate was consistent regardless of metastatic sites. Myelosuppression was the most common toxicity, and a few patients needed G-CSF support, treatment delay or dose reduction because of grade 3 or 4 neutropenia or leukopenia. Although one patient withdrew from this study because of grade 3 sensory disturbance, this regimen was generally well tolerated. A biweekly schedule of paclitaxel seems to be feasible and effective in patients with advanced or recurrent breast cancer.

A 72-year-old female had undergone mastectomy at the age of 67 for right breast cancer (T2a, n1 alpha, positive for ER). In the surgery the pectoralis muscle was preserved. For adjuvant therapy, 20 mg/day of tamoxifen was orally administered for 5 years. Six years after surgery, relapse was detected in the right major pectoralis muscle. Irradiation at this site and oral administration of 120 mg/day of toremifene citrate were started. The patient had a medical history of diabetes, and the control of her blood sugar was poor. About 2 months after oral administration of toremifene citrate was started, flares with blebs and swelling were observed in the right lower leg, suggesting acute phlebothrombosis of the right lower limb. The symptoms were ameliorated by intravenous administration of heparin and an antibiotic. In administering a high dose of toremifene citrate to patients with complications, careful follow-up is needed.

What should be the standard treatment for taxane-refractory metastatic breast cancer remains controversial. In this paper, a case in which the 5'-DFUR + CPA + THP therapy was effective for paclitaxel-refractory metastatic breast cancer is reported. A 41-year-old female received pectoral muscle preserved mastectomy under diagnosis of the left breast cancer in May 1996. In June, 1999, a coin lesion of 2.2 cm diameter was found in the left middle lung field with chest X-ray. Paclitaxel 210 mg/m2 (once for three weeks, 8 cycles in total) resulted in marked improvement. The regimen of paclitaxel 70 mg/m2 (medication consecutive once-weekly for three weeks, and withdrawal for next week; 1 cycle) was carried out continuously with the patient ambulatory. Because resistance to the treatment appeared at the time the total dose reached 2,700 mg, 5'-DFUR + CPA + THP therapy (THP 30 mg/m2 (i.v.) x day 1, CPA 77 mg/m2 (p.o.) x 14 days, 5'-DFUR 460 mg/m2 (p.o.) x 14 days; 3 weeks with 1 cycle) was carried out, and definite improvement in the lung findings were observed. 5'-DFUR + CPA + THP therapy may be of use as a second-line therapy in paclitaxel-refractory recurrent breast cancer.

An 82-year old man received total androgen blockade therapy (bilateral orchiectomy and 375 mg/day flutamide) for the treatment of stage C prostate cancer. Serum PSA levels were undetectable for 13 months and thereafter increased gradually. We administered estramustine phosphate sodium (EPS) instead of flutamide under the diagnosis of hormone refractory prostate cancer. EPS therapy was discontinued after 9 months because serum PSA levels increased again. Then, the patient complained of bilateral breast nodules and pain. Bilateral mammectomies were performed due to bilateral breast cancers which had been diagnosed by aspiration biopsies and radiographic examinations, but he died four months after the operations. Final pathological diagnosis was ductal adenocarcinoma of the breasts. Immunohistochemical study revealed expressions of PSA in the breast cancers. We diagnosed double cancers of the prostate and the breast because of the different expression patterns of progesterone receptor between them. We review the literatures and discuss the differential diagnosis of prostate cancer and PSA-producing breast cancer.