Intraperitoneal saline-injected MR imaging through an implanted catheter-port system (saline-MRI) was conducted in 7 patients with ovarian tumor after surgical removal of the primary tumor. Two types of T2 weighted coronal images of the abdomen were obtained after saline injection through the implanted catheter-port system. One uses long TE (about 1000 msec) with fat-saturation and thick slices (100 mm thickness) to depict the injected saline alone. The other uses medium TE (about 100 msec) without fat-saturation and thin slices (10 mm thickness) to depict both intraperitoneal saline and abdominal structures. Saline sequentially fills the Douglas pouch, paracolic gutter, Morison's pouch and subphrenic space in most patients. The relation between injected saline and abdominal structures was seen well on T2-weighted images using medium TE. Adhesions of the peritoneum were well demonstrated. In one patient, a catheter perforation to the bowel loop was diagnosed, because the small bowel loop was immediately filled with injected saline. Saline-MRI can be used to depict intraperitoneal drug distribution during intraperitoneal chemotherapy and can diagnose complications related to intraperitoneal chemotherapy.

The results of in vitro tests against solid tumors have been generally influenced by the mixing in of fibroblasts, and so have SDI tests. We demonstrated that the influence of fibroblasts can be excluded by performing the SDI test on an agar layer, thus significantly inhibiting the growth of fibroblasts in the liquid top layer. In the agar SDI test, SDS is used to dissolve formazan; however, this lowers the sensitivity to some extent. We added additional DMSO to SDS and to raise the sensitivity.

A late phase II clinical trial of amrubicin hydrochloride, a novel synthetic anthracycline derivative anticancer agent, was conducted at 14 institutions nationwide, in patients with non-Hodgkin's lymphoma. In this multi-center collaborative study, doxorubicin hydrochloride was replaced by amrubicin hydrochloride in CHOP therapy, a standard regimen for non-Hodgkin's lymphoma consisting of cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate and prednisolone. A total of 39 patients were enrolled in this study between January 1996 and March 1998. Among them, 37 patients were eligible for this study. The study drugs were administered to patients with non-Hodgkin's lymphoma according to the following schedule: amrubicin hydrochloride (100 mg/m2, body surface area), cyclophosphamide (750 mg/m2) and vincristine sulfate (1.4 mg/m2, a maximal dose of 2.0 mg/body) were administered intravenously on day one, while prednisolone (60 mg/m2/day) was administered orally on days 1 to 5. This cycle of treatment was repeated every three weeks in principle. The efficacy and safety were assessed for 37 eligible patients. The combined rate for CR + CRu was 70.3% (26/37) and the overall response rate (CR + CRu + PR) was 86.5% (32/37). demonstrating that amrubicin hydrochloride was very effective in the treatment of non-Hodgkin's lymphoma. The most frequent adverse reactions that occurred during the study were myelosuppressions: leukopenia and neutropenia, 100% (37/37); and decreases in hemoglobin levels, 81.1% (30/37). Thrombocytopenia, elevations of serum GOT and GPT levels, anorexia, nausea/vomitting, fever, stomatitis and alopecia were also observed. Although leukopenia and neutropenia of grade 3 or higher were noted in 89.2% (33/37) and 94.6% (35/37), respectively, they were controllable by administrations of G-CSF or solely by follow-up observations. One patient developed intestinal paralysis (grade 4) and another developed hematemesis. In conclusion, these results indicate that amrubicin hydrochloride is an effective agent as a component of combination chemotherapy for non-Hodgkin's lymphoma.

An early phase II multi-center collaborative study of amrubicin hydrochloride, a novel synthetic anthracycline derivative anticancer agent, was conducted for malignant lymphoma at 12 institutions nationwide. A total of 41 patients were enrolled in this study between January 1988 and October 1990. Of these, 36 patients, six patients with Hodgkin's disease (HD) and 30 patients with non-Hodgkin's lymphoma (NHL), were eligible for the study. The starting dose of amrubicin hydrochloride was 100 mg/m2 (body surface area) and it was administered once every three weeks, in principle. The efficacy was assessed for 34 patients, excluding two patients: one who has not been followed up adequately and the other violated the dosing schedule (once per week). The overall response rates (CR + PR) were 50.0% (3/6) for HD and 42.9% (12/28) for NHL. Furthermore, a relatively high response rate was noted in 8 (36.4%) of 22 NHL patients who had been treated with other anthracycline derivatives prior to the trial. The safety of amrubicin hydrochloride was assessed for 36 eligible patients. Leukopenia (grade 3 or higher) and thrombocytopenia were noted in 21 patients (58.3%) and 10 patients (27.8%), respectively. Anorexia, nausea/vomiting, fever, alopecia, decrease in hemoglobin and elevations of GOT and GPT levels were observed with a relatively high frequency. Other than myelosuppression, the following adverse reactions (grade 3 or higher) occurred during the course of the trial: diarrhea (two patients), alopecia (two patients), stomatitis (one patient), anorexia (one patient), nausea/vomiting (one patient) and fever (one patient). In conclusion, these results indicate that amrubicin hydrochloride is effective in the treatment of patients with malignant lymphoma.

We developed a new dosage formulation, methotrexate bound to activated carbon particles (MTX-CH), and used it to reduce tumors via its long-acting effect at the administration sites. MTX-CH was injected locally into tumors on the back of BALB/c mice, 30 mg/mouse, as MTX and compared with mice treated with MTX aqueous solution, saline solution, activated carbon particles (CH-40) and non-treated mice. The MTX concentration at the administration sites was higher in the MTX-CH group than in the MTX aqueous solution group. A marked effect on the control of tumor growth by MTX-CH was noted after repeated administration (every 3 days, total 4 times) throughout the observation period. Although tumor size was not reduced, necrosis was microscopically observed around the site of MTX-CH administration. For the reasons mentioned above, MTX-CH is superior to MTX aqueous solution in terms of long-acting effect at the administration sites and the control of tumor growth.

The purpose of this study was to perform a simple percutaneous transfemoral implantation of a portcatheter access system using a new catheter coating for hepatic artery chemotherapy infusion, and to evaluate the complications of transfemoral infusion port implantation. The methods of treatment for complications were also studied. The port-catheter system was percutaneously implanted via femoral artery access in 180 patients with malignant liver tumors. Blood flow redistribution was performed using embolization coils. An unfixed 5 Fr catheter was placed in a hepatic artery, and connected to a port implanted subcutaneously below the level of the inguinal ligament. The success rate of implantation was 99%. Complications after placement were observed as follows: port system obstruction (9.6%); dislocation of the catheter tip (8.4%); drug toxicity (4.5%); and infection (3.4%). Notable is the avoidance of cerebral infarcts. In 3 of 17 patients with port obstruction, recanalization of the port was achieved. In 11 of 15 patients with catheter dislocation, replacement of the catheter-port system was successful. In 5 patients with hepatic artery occlusion, the replacement of a microcatheter-port access system was achieved, and hepatic artery chemotherapy infusion was resumed. This percutaneous transfemoral implantation of a catheter-port access system would seem to be a very simple and useful method for many clinical doctors, and it may improve the quality of life in patients with an unresectable malignant liver tumor.

We devised a fibrin clot (FC) using an ultraviolet (UV)-crosslinking method. To evaluate the in vivo chemotherapeutic effects for cancer chemotherapy with our novel drug delivery system, the anticancer agent cis-platinum (CDDP) was impregnated into each FC and this "FC-UV-CDDP" was intraperitoneally (i.p.) administered to each ascitic hepatoma AH-130 in cancer-bearing rats. Other groups of AH-130 bearing rats, i.p. injected with CDDP or non-treated, served as the controls. We recorded the survival period of each animal and autopsied it at the time of death. All the animals treated with "FC-UV-CDDP" survived for more than 5 weeks and had no retention of ascites. Furthermore, all the surviving rats underwent a challenge with AH-130 cells. Two of 3 repeatedly challenged rats revealed no evidence of recurrence of the cancer and survived for more than 3 months. The control rats died of cachexia with a massive ascites within 2 weeks. Thus, our newly devised "FC-UV-CDDP" system favorably functioned in an experimental cancer model. These data suggested that this oncolytic effect was attributed to the possibility of inducing immune responses against AH-130 as well as to a sustained release of CDDP from FC.

We studied the pharmacokinetics of the intraperitoneal administration of CPT-11 for four patients with peritoneal metastasis (2 gastric cancer cases, 2 colon cancer cases). CPT-11 was administrated in a dose of 40-60 mg and the intraperitoneal and serum levels of CPT-11, SN-38 and SN-38 glucuronized (SN-38 Glu) were measured periodically. Intraperitoneal therapy with CPT-11 was effective for the control of malignant ascites. No serious side effects were observed. The levels of CPT-11, SN-38 were no different 30 min afterwards the administration of CPT-11 either intraperitoneally or intravenously. The high concentration of CPT-11 was achieved with intraperitoneal therapy and a small fraction of CPT-11 changed into SN-38 in the abdominal cavity.

The anti-emetic effect and safety in patients receiving ondansetron hydrochloride (OND group) and ondansetron and dexamethasone (DEX group) concurrently in cases of acute and delayed onset emesis induced by a single high dose of cisplatin, given as a chemotherapy to gynecological cancer patients, were comparatively studied. The study subjects were 139 gynecological cancer patients. The OND group received 4 mg of ondansetron via slow intravenous injection on Day 1, 30 minutes prior to cisplatin, and for Days 2 to 5, the subjects orally received 4 mg ondansetron tablet each day. The DEX group received the same dose regimen of ondansetron as the OND group for Days 1-5, but in addition the subjects received dexamethasone injection in doses of 8 mg twice daily on Day 1 and 4 mg (1 mg QID) daily for Days 2-5. An anti-emetic effect against acute nausea and vomiting was achieved in 47.9% of the OND group and in a higher rate of 84.2% of the DEX group. Significantly better efficacy was seen in the DEX group also in the complete suppression rate of nausea and vomiting and the improvement of food intake. The group also achieved better efficacy in delayed onset of emesis. Adverse reactions were observed in 2 cases (2 reports of headache) in the OND group and 5 cases (2 reports of hiccups, 2 headache, 2 diarrhea, one constipation, one hot facial flushes and one elevation of gamma-GTP) in the DEX group; however, since the symptoms were all mild, we did not consider there was any problem in safety. We conclude from the above findings that concurrent administration of ondansetron hydrochloride and dexamethasone is a clinically useful treatment for acute and delayed onset emesis induced by a single high dose of cisplatin given to gynecological cancer patients.

The purpose of this study was to evaluate the efficacy and toxicity of weekly vinorelbine (VNB) in patients with metastatic breast cancer previously treated with both adriamycin (ADM) and docetaxel (TXT). VNB was administered weekly at the dose 20 mg/m2 by i.v. infusion over 20 minutes followed by flushing the vein with 100 ml of normal saline. From June 1999 to August 2000, ten patients were enrolled in this study. Patient characteristics were that the cumulative doses (median) of previous ADM and TXT were 300 mg (range, 120-880 mg), 560 mg (range, 120-960 mg) respectively. The median number of metastatic sites was four, with poor performance status (ECOG 1-2: 40%, 3-4: 60%). The median cycles of weekly VNB were seven (range: 2-12). Two of 10 assessable patients obtained partial response, with an overall response rate of 20%. The main toxicity (NCI grade 4) was leukopenia in 10% of 10 patients. Phlebitis (grade 2) was observed in 4 of 10 patients (40%). VNB is an active agent against metastatic breast cancer pretreated with both ADM and TXT, possessing no severe toxicities.

A late phase II clinical study of S-1, a novel oral antitumor agent of fluorinated pyrimidines, in patients with advanced/recurrent head and neck cancer was conducted in 25 institutions across Japan as a multi-institutional cooperative study from August 1995 to March 1998. Out of 59 eligible patients, the objective responses were 4 complete responses (CR) and 13 partial responses (PR). The response rate was 28.8% (17/59, 95% CI: 17.8-42.1%). The response rate in previously treated patients was 28.3% (15/53), whereas that in treatment naive patients was 33.3% (2/6). The response rate in patients with prior chemotherapy was 26.7% (12/45). Major adverse reactions of grade 2 or more were anemia (25.4%, 15/59), leucopenia (22.0%, 13/59), neutropenia (25.4%, 15/59), thrombocytopenia (3.4%, 2/59), anorexia (6.8%, 4/59), nausea/vomiting (1.7%, 1/59), stomatitis (1.7%, 1/59), skin symptoms including eruptions or desquamation (5.1%, 3/59), and malaise (1.7%, 1/59). Grade 4 anemia was observed in one case; however, this returned to the normal level after the termination of drug administration and the blood transfusion. Therefore, this event was confirmed to be reversible. Based on these results, we conclude that S-1 is an active agent for the treatment of advanced/recurrent head and neck cancer.

Cisplatin shows effectiveness for various solid cancers and often plays a role as the key drug in combination chemotherapy. The most common method of cisplatin administration is bolus intra-venous injection. However, other administration methods are tried in order to reinforce the effect, and also to reduce the side effects. Generally, renal damage is more prominent with bolus injection. In contrast, bone marrow suppression is more severe with intermittent administration. Although there is no clear evidence about the anti-tumor effects, a dramatic local effect is sometimes observed by intra-arterial chemotherapy. By intraperitoneal chemotherapy, while a systemic effect is observed in addition to local effects, due consideration of the systemic side effects is also needed. These protocols are used in many institutes, but the efficacy is not yet proven by comparison trials. In future, randomized prospective studies should be performed to test the usefulness of the regimens.

Anthracyclines have been in clinical practice since the 1960s and represent one of the most commonly used classes of anticancer drugs. Doxorubicin (adriamycin) is one of the first anthracyclines in clinical use, has a broad anti-tumor spectrum, and has been used against hematopoietic malignancies such as lymphoma, myeloma and leukemia, and solid tumors such as breast cancer, ovarian cancer and sarcomas. There are two chemotherapeutic regimens containing doxorubicin that have been established as the state of the art therapy against malignant lymphomas. One is ABVD therapy for Hodgkin's lymphoma, and the other is CHOP therapy for aggressive non-Hodgkin's lymphoma (NHL). In these regimens as well as the regimen for breast cancer, doxorubicin is delivered by bolus intravenous infusion for 30 minutes to one hour. The use of continuous infusion schedules of doxorubicin for 72 to 96 hours has been reported to reduce the incidence of cardiac toxicity somewhat, providing a pharmacokinetic basis for the hypothesis that high peak concentrations are associated with an increased incidence of cardiotoxicity. VAD regimen for myeloma, and EPOCH regimen for relapsed aggressive NHL have been reported and used. However, this approach is not widespread because of concern over compromising antitumor efficacy, unpredictable toxicities, and logistical issues. Continuous infusion schedules of doxorubicin might be reevaluated for the clinical benefit especially for patients with breast cancer treated by trastuzumab and doxorubicin, because trastuzumab was reported to enhance cardiac toxicity.

To give optimal treatment to the patients with early lung cancer, we are trying to establish two new techniques to select the patients of poor prognosis and sensitive to the chemotherapy. To pick up the patients of poor prognosis nevertheless the early stage of their lung cancer, we are developing a new method to detect cancer cells floating in the peripheral blood flow with RT-PCR using cancer specific mRNA. To choose optimal chemotherapy regimens, we have established a new chemosensitivity testing (collagen gel droplet embedded culture drug sensitivity test: CDDST) for non-small cell lung cancer (NSCLC). Median survival time (MST) of the patients (n = 11) with unresectable NSCLC, who were given optimal chemotherapy according to CDDST, was 15.8 months and MST of those (n = 16) who did not have any sensitive agents according to CDDST was 5.6 months. There was significant difference between these two groups (p = 0.0048; logrank).

The pathogenesis of pulmonary fibrosis (PF) induced by bleomycin and its derivative, peplomycin (PEP), is insufficiently understood. To prevent PF and to administer PEP safely, we examined the influence of PEP on pulmonary function in 135 patients who underwent concomitant chemo (PEP + 5-FU)-radio (60Co) therapy and pulmonary function tests. In the inductive therapy, 5 mg of PEP was intramuscularly injected three times a week and a total of 41.6 +/- 14.3 mg was administered. Of the patients, 98 received oral azelastine hydrochloride (AZH, 4 mg/day) during the inductive therapy with the aim of prophylaxis of PF. The oxygen partial pressure in arterial blood (PaO2) only slightly decreased from 84.2 +/- 12.1 mmHg before treatment to 82.8 +/- 12.5 mmHg after treatment, while, carbon oxide diffusion (%DLco) decreased after treatment in most patients (p < 0.001, by paired t test) with mean values before treatment of 106.3 +/- 24.5% and after treatment 99.5 +/- 24.9%. The decrease of %DLco was associated with the dose of PEP until about 40 mg but further decreases of %DLco were not prominent. In the patients who underwent oral AZH, the decrease of %DLco weaker than that in patients without AZH: the decrease rates of %DLco in the former and latter were 4.3 +/- 9.4% and 14.1 +/- 15.9%, respectively. From the chest X-ray examination, mild PF was suspected in three patients but no advancement of PF or clinical symptoms were observed. From these results, it was concluded first that %DLco is more useful than PaO2 as the predisposing risk factor for PF, second that the decrease of %DLco depends on the dose of PEP until about 40 mg, third that AZH is expected to inhibit PEP-induced PF, and fourth that a small dose (20-40 mg) of PEP can be administered without inducing PF if care is exercised as to the patient's age, general condition and the value of %DLco in the use of PEP.

Acute myeloid leukemia (AML) has been treated with combination chemotherapy, hematopoietic stem cell transplantation (HSCT) and differentiation induction therapy. Intensive induction and consolidation therapy including high dose cytarabine (HDAC) is a widely used combination in chemotherapy in the USA and European countries. In Japan, the efficacy of HDAC needs to be evaluated under a good clinical trial. Stem cell source for HSCT has been expanded, and the number of peripheral blood stem cell transplantations is greater than that of bone marrow transplantation, especially for auto-transplantation. Despite some randomized clinical trials, we still do not know whether HSCT provides longer survival than chemotherapy for patients with AML when performed during their first remission. Differentiation therapy for acute promyelocytic leukemia (APL) using ATRA showed clear success in the treatment for AML. APL is stratified with its specific karyotype and morphology, and this stratification leads to the improvement of overall survival of patients with APL. Several clinical study groups in the world have studied prognostic factors and it has been shown that the chromosomal abnormality of AML cells is closely related to the response to the chemotherapy. The stratification of AML using these prognostic factors is incorporated in some clinical trials to determine whether this approach actually leads to better survival for patients with AML.

Cisplatin and its analogues have been most frequently used for treatment of human cancer including ovarian cancer. Most advanced ovarian cancer which was fatal before introduction of cisplatin have become to be treated for cure by combination chemotherapy containing cisplatin and its analogues. Thus, combination chemotherapy containing cisplatin and carboplatin have become a standard chemotherapy for treatment of ovarian cancer. Initially, platinum-based combination chemotherapy is associated with a 60-70% clinical response rate. However, the overall 5-year survival rate for advanced ovarian cancer patients is still around 20-30%. This low survival rate is due to the fact that some primary tumors and most recurrent tumors develop drug resistance that leads to treatment failure. Thus, overcoming drug resistance is the key to successful treatment of ovarian cancer. The mechanism of cisplatin-resistance in ovarian cancer is multifactorial, and accumulation of multiple genetic changes may lead to the drug-resistant phenotype. In this review, we report several genetic factors conferring cisplatin-resistance which have been elucidated in our laboratory.