Quantitative lymph node burden as a 'very-high-risk' factor identifying head and neck cancer patients benefiting from postoperative chemoradiation.

Background: Adjuvant chemoradiation (CRT) is standard for head and neck squamous cell carcinoma (HNSCC) patients with positive margins or extranodal extension (ENE) following surgery. However, emerging evidence suggests the number of positive lymph nodes (LNs) is the dominant determinant of survival in non-oropharyngeal HNSCC and thus may better identify those benefiting from treatment intensification. Patients and methods: Patients from the National Cancer Database diagnosed with non-oropharyngeal HNSCC (oral cavity, larynx, hypopharynx) between 2004 and 2014 and undergoing surgical resection, neck dissection, and postoperative radiotherapy (RT) were included. Multivariable regression with first-order interaction terms was used to model the interaction between postoperative CRT and continuous number of positive LNs with respect to overall survival. Results: In total, 7144 patients met inclusion criteria. In multivariable analysis, increasing number of positive LNs was associated with both increasing mortality (P < 0.001) and increasing benefit from postoperative CRT versus RT alone (interaction P < 0.001). While there was no benefit from postoperative CRT in patients with 0-2 LN+ [hazard ratio (HR) 0.96, 95% confidence interval (CI) 0.86-1.07, P = 0.47], increased benefit was seen in those with 3-5 LN+ (HR 0.84, 95% CI 0.70-1.00, P = 0.05) and those with ≥6 LN+ (HR 0.65, 95% CI 0.51-0.82, P < 0.001) in multivariable models. By contrast, margin status and ENE did not reliably identify patients benefitting from postoperative CRT based on statistical tests of interaction. Even in patients with ENE, positive margins, or both, only those with ≥6 LN+ had improved survival with postoperative CRT. Conclusion: Increasing metastatic nodal burden was associated with increased benefit from CRT compared with RT alone, surpassing conventional high-risk factors in identifying patients benefiting from CRT. Stratification by metastatic LN number may characterize a very-high-risk patient cohort best suited for treatment intensification.

Phase I/IIa trial of the mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) administered orally in patients with refractory or advanced malignancies and sarcoma.

BACKGROUND: Ridaforolimus is an inhibitor of mTOR with evidence of antitumor activity in an I.V. formulation. This multicenter, open-label, 3 + 3 design nonrandomized, dose-escalation, phase I/IIa trial was conducted to determine the safety, pharmacokinetic (PK) and pharmacodynamic parameters, maximum tolerated dose, and antitumor activity of oral ridaforolimus. PATIENTS AND METHODS: Patients with metastatic or unresectable solid tumors refractory to therapy were eligible. Seven different continuous and intermittent dosing regimens were examined. RESULTS: One hundred and forty-seven patients were enrolled in this study among which 85 were patients with sarcoma. Stomatitis was the most common DLT observed. The dosing regimen, 40 mg QD × 5 days/week, provided the best combination of cumulative dose, dose density, and cumulative exposure, and was the recommended dosing regimen for subsequent clinical development. PK was nonlinear, with less than proportional increases in day-1 blood AUC0-∞ and Cmax, particularly with doses >40 mg. The terminal half-life estimate of ridaforolimus (QD × 5 40 mg) was 42.0 h, and the mean half-life ∼30-60 h. The clinical benefit rate, (complete response, partial response, or stable disease for ≥4 months was 24.5% for all patients and 27.1% for patients with sarcoma. CONCLUSION: Oral ridaforolimus had an acceptable safety profile and exhibited antitumor activity in patients with sarcoma and other malignancies. ClinicalTrials.gov Identifier NCT00112372.

Local surgical treatment with curative intent in rectal cancer.

The surgical treatment of rectal cancer includes radical resection techniques and local excision procedures. Radical resection techniques are still the golden standard in the management of rectal cancer, but the increased postoperative morbidity and mortality led to the idea that less traumatizing procedures of local excision may have the same oncologic results, in selected cases. Yet, the significantly higher local recurrence rate after local excision in comparison to radical resection has been certified by most studies; that points out the need of clearly defined guidelines for local excision. In the present review the following aspects were taken into consideration, when considering local surgical excision as a radical procedure for rectal cancer: the clinico-pathological features of the tumours, the various types of surgical techniques used in local excision, the need for an adjuvant or neoadjuvant oncological treatment, the variety of results obtained in a large number of studies, making this particular issue a topic that is currently subject to debate.

Temporary auxiliary partial orthotopic liver transplantation using a small graft for familial amyloid polyneuropathy.

Donor shortage is a major issue in liver transplantation. We have successfully performed temporary auxiliary partial orthotopic liver transplantation (APOLT) using a small volume graft procured from a living donor for recipients with familial amyloid polyneuropathy (FAP). The aim of this study was to evaluate this procedure by comparing it with standard living donor liver transplantation (LDLT). We compared 13 recipients undergoing this procedure with 23 recipients undergoing a standard LDLT for the treatment of FAP. The estimated donor graft volume and the graft volume/recipient's standard liver volume ratio were significantly smaller in the temporary APOLT group than in the standard LDLT group. Postoperative complications were comparable, although the hospital stay was longer in the temporary APOLT group. All the patients safely underwent a remnant native liver resection about 2 months after their first operation in the temporary APOLT group. No symptoms related to FAP developed before the remnant liver resection, and no significant differences in graft and patient survival were observed between the two groups. We successfully performed temporary APOLT using a small volume liver graft without postoperative liver failure for FAP. Temporary APOLT for FAP might be a useful alternative procedure for expanding the donor pool for LDLT.

Erlotinib 'dosing-to-rash': a phase II intrapatient dose escalation and pharmacologic study of erlotinib in previously treated advanced non-small cell lung cancer.

BACKGROUND: To evaluate the anticancer activity of erlotinib in patients with previously treated, advanced non-small cell lung cancer (NSCLC) whose dose is increased to that associated with a maximal level of tolerable skin toxicity (i.e., target rash (TR)); to characterise the pharmacokinetics (PK) and pharmacodynamics (PD) of higher doses of erlotinib. METHODS: Patients initially received erlotinib 150 mg per day. The dose was successively increased in each patient to that associated with a TR. Anticancer activity was evaluated. Plasma, skin, and hair were sampled for PK and PD studies. RESULTS: Erlotinib dose escalation to 200-475 mg per day was feasible in 38 (90%) of 42 patients. Twenty-four (57%) patients developed a TR, but 19 (79%) did so at 150 mg per day. Five (12%) patients, all of whom developed a TR, had a partial response. Median progression-free survival (PFS) was 2.3 months (95% CI: 1.61, 4.14); median PFS was 3.5 months and 1.9 months, respectively, for patients who did and did not experience a TR (hazard ratio, 0.51; P=0.051). Neither rash severity nor response correlated with erlotinib exposure. CONCLUSION: Intrapatient dose escalation of erlotinib does not appreciably increase the propensity to experience a maximal level of tolerable skin toxicity, or appear to increase the anticancer activity of erlotinib in NSCLC.

Toward improving human islet isolation from younger donors: rescue purification is efficient for trapped islets.

Several reports suggest that islets isolated from younger donor pancreata are of better quality for clinical islet transplantation. The relative inefficiency of the continuous gradient purification process (CGP) is one of the major obstacles to the utilization of these younger donor pancreata. This study demonstrates the benefits of utilizing an additional purification step, rescue gradient purification (RGP), to recover trapped islets and examines the possible superiority of these rescued islets. Seventy-three human islet isolations purified by RGP following CGP were divided into two groups based on age, and the isolation results were retrospectively analyzed (group I: age < or = 40, group II: age > 40). The quality of islets from both CGP and RGP were assessed by beta-cell fractional viability (beta FV) and ADP/ATP ratio. Significant increases in the percent islet recovery from RGP and the percent trapped islets in group I compared to group II were observed. Donor age correlated negatively to the percent islets recovered from RGP (R = 0.440) and to the percent of trapped islets (R = 0.511). RGP islets had higher beta FV and better ADP/ATP ratio compared to CGP islets. In conclusion, RGP improved the efficiency in the purification of trapped islets, which often come from younger donor pancreata. The better quality of beta-cells in RGP islets encourages us to perform RGP, considering the higher quality as well as the quantity of remaining islets.

In situ quantitative immunoprofiling of regulatory T cells using laser scanning cytometry.

Laser scanning cytometry (iCys; CompuCyte, Cambridge, Mass) has recently been developed to use fluorescence-based quantitative measurements on tissue sections or other cellular preparations at a single-cell level. The purpose of this study was to develop objective, quantitative immunoprofiling of regulatory T cells (T regs) on formalin-fixed/paraffin-embedded (FFPE) biopsy samples from transplanted allografts using iCys. We sought to evaluate the usefulness of iCys to analyzes the population of CD4 (+) Foxp3 (+) T regs among CD4 (+) T-cell and the entire T-cell (the total of CD4 [+] and CD8 [+] populations in human intestinal allograft biopsy samples. Primary antibodies (Foxp3 and CD4) which had been labeled using Alexa Fluoro 488 (Foxp3 Alexa488) and 647 (CD4 Alexa647) with polymer horseradish peroxidase and catalyzed signal amplification were incubated on 1 section. On the other section, CD8 and CD4 were labeled using Alexa488 and Alexa647 using the same protocol. Data acquisition was performed using iCys. The signal intensities of Alexa488 and Alexa647 were sufficient to analyze by iCys. Distribution of the integrals of Alexa488 and Alexa647 to visualize each cell population enabled calculation of the population of T reg among CD4 (+) T cells, CD4 (+) T cells among total T cells, and T reg among entire T cells. iCys and signal amplified immunofluorescent staining allowed objective quantitative immunoprofiling of in situ T reg populations, with precise quantitative analysis at a single-cell level on FFPE sections. This objective method may be applied on biopsy samples from various transplanted organs.

Purification method using iodixanol (OptiPrep)-based density gradient significantly reduces cytokine chemokine production from human islet preparations, leading to prolonged beta-cell survival during pretransplantation culture.

Purification is one of the most important steps in human islet isolation. Although Ficoll-based density gradients are widely used, OptiPrep-based density gradients are used in few centers. Cytokine/chemokine production from human islet preparations varies widely. Some cytokines/chemokines have been reported to have adverse effects on human islet preparations. Control of cytokine/chemokine production may be a key to improve islet quality and quantity, leading to better transplantation outcomes. The aim of the present study was to investigate the effects on islet preparations of purification methods using various density gradients on viability, cellular composition, and proinflammatory cytokine/chemokine production. After the digestion phase, the extracts were divided into 2 groups for purification using a semiautomated cell processor with Ficoll-based or OptiPrep-based density gradients. Islet preparations cultured for 2 days were assessed regarding islet cell viability (fluorescein diacetate/propidium iodide [FDA/PI]), fractional beta-cell viability by FACS, and beta-cell content using iCys. Cytokine/chemokine production from islet preparations was also measured by Bio-plex. After purification, the purity, islet equivalents (IEQ), and islet recovery rates were comparable between the 2 groups. Although FDA/PI and fractional beta-cell viability showed no significant difference, survival of beta cells during culture was significantly higher in the OptiPrep compared with the Ficoll-based density gradient group. There were significantly lower tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, interferon (IFN)-gamma, IL-6, and MIP-1beta productions from the OptiPrep-based density gradient group. OptiPrep-based density gradients reduced cytokine/chemokine production by islet preparations. In addition, OptiPrep-based density gradient purification significantly reduced the loss of beta-cell mass during pretransplantation culture.

Effect of pituitary adenylate cyclase-activating polypeptide in islet transplantation.

INTRODUCTION: Pituitary adenylate cyclase-activating polypeptide (PACAP) is an islet substance serving as an intra-islet amplifier of glucose-induced insulin secretion similar to exendin-4. It has been reported that systemic administration of PACAP maintained beta-cell mass, delayed the onset of hyperglycemia, and protected beta cells from glucose toxicity. Moreover, PACAP increases glucose-stimulated insulin release in vitro and in vivo. In this study, we investigated the possibility of PACAP use in human islet transplantation. METHODS: Human islets were cultured in the presence or absence of PACAP (10(-12) mol/L) for 48 hours. We assessed beta-cell viability using FACS, cellular composition analysis by iCys/LSC, and glucose-stimulated insulin secretion. In vivo, islets were transplanted beneath the kidney capsule of Streptozotocin-induced diabetic immunodeficient mice. An intravenous glucose tolerance test (IVGTT) was also performed in the presence or absence of PACAP (Peptide International, Louisville, Ky, United States; 1.3 nmol/kg). RESULTS: There were significant improvements in terms of beta-cell viability and cellular composition between islets cultured with or without PACAP, respectively (P < .05). Moreover, glucose-stimulated insulin secretion significantly improved in islets cultured with PACAP compared with controls, respectively (P < .05). Treatment of recipient mice with PACAP resulted in beneficial effects on insulin secretion (PACAP vs control, 13.2 vs 1.9 mU/L), in IVGTT. However, no significant difference was observed in glucose levels between the 2 groups. CONCLUSIONS: Our study indicated that PACAP significantly improved beta-cell viability and survival during culture, and increased insulin secretion in vitro and in vivo. However, blood glucose levels in vivo after an IVGTT did not significantly improve, probably due to increased glucagon secretion from alpha cells. PACAP supplementation to culture medium could be of assistance to improve clinical islet transplantation outcomes.

Effect of human islet rescue gradient purification on islet yield and fractional Beta cell viability.

It is difficult to consistently obtain sufficient postpurification islet numbers from younger donors because of the higher proportion of trapped islets after pancreas digestion. Continuous gradient purification (CGP), which is currently used in several islet processing centers, sometimes is not efficient in the purification of trapped islets. Rescue gradient purification (RGP) could improve postpurification islet yields, resulting in an increased number of islet cell products that could be transplanted. Sixty-eight human islet isolations, in which CGP was followed by RGP were analyzed. The quality of islets from CGP and RGP was assessed by beta-cell fractional viability (betaFV) and ADP/ATP ratio. Donor age negatively correlated with the proportion of the islets rescued by RGP (R = -0.52; P < .01) and to the percentage of trapped islets (R = -0.46; P < .01). Age-related differences were observed in pancreas weight, digestion time, and islet yields from CGP, respectively. Importantly, islets from RGP had an 11% higher betaFV compared with islets from CGP. ADP/ATP ratio was also lower in RGP islets versus CGP islets. RGP improved the efficiency of islet purification from younger pancreata and did not affect islet cell viability, which was actually higher in RGP fractions, indicating that rescued trapped islets from the pellet and lower purity layers are not damaged by the extra purification step and may actually be more viable. RGP could be used to rescue high-quality islets from less than 30% pure islet fractions, which are often discarded in the clinical setting.

beta-Cell specific cytoprotection by prolactin on human islets.

INTRODUCTION: Many cytoprotective agents have been reported to improve islet isolation and transplantation outcomes. However, several of these agents improve all cell subsets within an islet preparation; selection of non-beta-cell components (eg, acinar cells) may have a negative effect on beta-cell function and survival. In this study, we examined the effect of prolactin (PRL) supplementation in the culture medium to determine whether it exerted beta-cell-selective cytoprotection on islet viability and function. MATERIALS AND METHODS: Human islets were precultured with or without recombinant human PRL (500 microg/L) for 48 hours. The fractional viability and cellular composition of non-beta-cell and beta-cell-specific components were assessed using FACS and Laser Scanning Cytometry (LSC). Islet potency was assessed in vivo by transplantation into chemically induced diabetic immunodeficient mice. RESULTS: The relative viable beta-cell mass and the relative islet beta-cell content in the PRL group were 28% higher (P = .018) and 19% higher (P = .029) than the control group, respectively. All transplanted mice achieved normoglycemia in both groups, indicating that PRL treatment did not alter islet function. CONCLUSION: PRL treatment improved beta-cell-specific viability and survival of human islets in vitro. The development of novel beta-cell-specific cytoprotective strategies may be of assistance in improving islet transplantation.

Domino liver transplantation in living donors.

Domino liver transplantation (DLT) has been developed as a method to expand the donor pool. In living donors DLT, the prime concern is to avoid any disadvantage to the donor and the first recipient. Seven DLTs were performed among 211 patients who underwent living donor liver transplantation. The domino recipients included six with hepatocellular carcinoma and one with citrullinemia. The domino grafts were obtained from patients with familial amyloid polyneuropathy (FAP) including the left liver in three cases and the right liver in four. Among the seven domino recipients, a 64-year-old woman with advanced hepatocellular carcinoma died of lung metastasis. The other six domino recipients are alive without FAP symptoms. In living donor liver transplantation, because the vessels of the graft from the first donor are not long enough for anastomosis, the hepatic vessels must be left as long as possible when removing the liver from the FAP patients in order to ensure sufficient safety for vascular reconstruction. With careful decision making during the procedure, such as where to divide the vessels in the FAP patients, DLT may help address the shortage of liver grafts.

Living-Donor Liver Transplantation for Hepatic Metastasis From Meningeal Hemangiopericytoma: A Case Report.

We report the case of a 58-year-old man referred to our hospital for liver tumor treatment. The patient had a history of neurosurgery for a meningeal hemangiopericytoma 16 years previously. Pre-operative imaging revealed a hypervascular tumor extending from Couinaud segment 4 to segment 8 of the liver, measuring 95 mm in diameter, indicating an atypical hepatocellular carcinoma. Because right trisectionectomy of the liver was considered to be high risk, living-donor liver transplantation (LDLT) was indicated. After transcatheter arterial embolization, LDLT was performed with the use of a left-lobe liver graft from the patient's son. Post-operative histological findings of the liver tumor were identical to those for meningeal hemangiopericytoma, therefore the patient was diagnosed with meningeal hemangiopericytoma that had metastasized to the liver. After LDLT, the patient had a healthy, active life for 2 years; then, a subcutaneous relapse was discovered in the left chest. The patient did not undergo any systemic chemotherapy in response to the relapse. After thoracic and orthopedic surgeries and radiotherapy for multiple metastases, the patient died 5 years and 5 months after LDLT. LDLT could be an effective treatment for localized metastatic hemangiopericytoma in the liver, but it should be indicated only for carefully selected patients.

An alternative method of arterial reconstruction after hepatic arterial thrombosis following living-related liver transplantation.

BACKGROUND: Hepatic artery thrombosis (HAT) remains an important cause of graft loss after liver transplantation. Emergency rearterialization methods are limited in cases of living-related liver transplantation in which the graft hepatic artery is thin and short. CASE: A 19-year-old woman who underwent living-related liver transplantation for biliary atresia developed HAT on the 4th postoperative day. During the emergency laparotomy the recipient hepatic artery was found to be too short to anastomose, so the recipient's right gastroepiploic artery was anastomosed to the graft hepatic artery. The patient is now alive and well 6 months after reoperation, and she has experienced no further episode of HAT. CONCLUSION: The right gastroepiploic artery can be used easily and safely for hepatic graft revascularization without causing ischemia of the stomach. An additional skin incision is not required, and the artery is long enough to anastomose to the graft artery directly. The method of hepatic graft rearterialization described here is an important option for patients who undergo living-related or split liver transplantation.

Long-term results of living-related donor liver graft transplantation: a single-center analysis of 110 transplants.

BACKGROUND: Difficulties of cadaveric donation and serious donor shortage have led to the development and popularization of living-related donor liver graft transplantation (LRLT). Because the history of this procedure is rather short, important aspects specific to this procedure have not been sufficiently documented. The objective of this study was to analyze a single center's 10-year experience with 110 LRLT in pediatric and adult patients with end-stage liver diseases. METHODS: The medical records of 110 consecutive patients who underwent LRLT were reviewed. The recipients were comprised of 72 children and 38 adults. The graft volume corresponded to 26-192% of the recipient's standard liver volume. The relationship between pretransplant covariates and patient and graft survival was analyzed. Actuarial patient/graft survival rates were determined at 1, 3, and 5 years. The type and incidence of posttransplant complications were analyzed, as was long-term graft function. RESULTS: The 1-, 3-, and 5-year actuarial patient and graft survival rates were 88%, 85%, and 85%, respectively. Log-rank test demonstrated that ABO-compatibility predicted patient survival rate, whereas patient age, underlying disease, patient's clinical status, donor-recipient relation, donor age, and graft volume/standard liver volume ratio did not. Long-term liver function remains excellent. All the donors have returned to normal daily lives with an uneventful course. CONCLUSIONS: LRLT is an efficacious procedure that provides excellent short-term and long-term survival. The indication criteria for both recipient and donor were legitimate in this series, except for transplant across ABO-incompatibility. Cautious expansion of this procedure may be justified under the situation of serious shortage of cadaveric donor.

6-Day continuous infusion of high-dose ifosfamide with bone marrow growth factors in advanced refractory malignancies.

Ifosfamide is an analogue of cyclophosphamide active in the treatment of numerous tumours. Although its use by continuous infusion seems to be responsible for less toxicity, differences of efficacy and toxicity, observed according to its doses and schedules of administration, still remain debated. The objective of this study was to assess the toxicity of high-dose ifosfamide given by continuous infusion over 6 days and its therapeutic activity in various advanced tumours. Twenty-six patients were treated with 14 g/m2 ifosfamide, an equal dose of MESNA, and routine granulocyte- or granulocyte/macrophage-colony-stimulating factor during the intercycle. Courses were repeated every 3 weeks until disease progression or unacceptable toxicity occurred; 75 cycles were administered. The mean number of cycles per patient was 3 (range 1-11). Extrahaematological toxicity was manageable in most patients, WHO grade II or more neurological (5 patients) and renal (5 patients) toxicities occurring in those heavily pretreated with platinum compounds and presenting peritoneal disease. WHO grade III or more neutropenia occurred in 60% of cycles, while grade III-IV thrombocytopenia and anaemia were observed in 19% of them. Three partial responses (germ-cell tumour, chondrosarcoma, soft-tissue sarcoma) and one complete response (metastatic osteosarcoma) were assessed, all in patients with tumours refractory or resistant to standard-dose ifosfamide, which underlines the possibility of circumventing the resistance to ifosfamide given in conventional schedules. The present results confirm previous reports of changes in the therapeutic index of ifosfamide according to its dose and administration schedule.

Antitumor activity and low intestinal toxicity of S-1, a new formulation of oral tegafur, in experimental tumor models in rats.

S-1, a new oral antitumor agent, is composed of 1-(2-tetrahydrofuryl)-5-fluorouracil (Tegafur, FT), 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. FT which is a masked compound of 5-fluorouracil (5-FU) acts as an effector, while both CDHP and Oxo which do not have antitumor activity themselves act as modulators. In this study, the antitumor activity and intestinal toxicity of S-1 were investigated using experimental tumor models in rats, and compared with those of other oral fluoropyrimidines, namely 5-FU, FT, FCD (1 M FT/0.4 M CDHP) and UFT (combination of FT and uracil). In rats bearing subcutaneous Yoshida sarcoma, S-1 inhibited tumor growth at the lowest dose (ED50 value: S-1 5, UFT 22, FT 82, FCD 5, and 5-FU 19 mg/kg per day), and induced the least host body weight suppression, leading to the highest therapeutic index (TI) (S-1 4.5, UFT 1.4, FT 1.8, FCD 2.0, and 5-FU 1.4). S-1 also showed a higher therapeutic effect than UFT against AH-130 and Sato lung carcinoma. After administration of S-1 and UFT at equitoxic doses, S-1 showed a higher and more prolonged concentration of 5-FU than UFT both in plasma (AUC0-infinity: S-1 28 nmolh/ml, UFT 15 nmol.h/ml) and in tumor tissue (AUC0-infinity: S-1 95 nmolh/g tissue, UFT 52 nmolh/g tissue), leading to a higher 5-FU level incorporated into the RNA fraction (F-RNA level) in tumor tissue (AUC0-24: S-1 7.0 nmolh/mg RNA, UFT 4.3 nmolh/mg RNA) and 5-8% higher thymidylate synthase (TS) inhibition in tumor tissue at every time-point through 24 h. Compared with other oral fluoropyrimidines after administration of the maximal tolerable dose (MTD), S-1 caused the lowest rates of intestinal toxicities, such as diarrhea and occult blood in feces. S-1 also showed a higher antitumor effect on Yoshida sarcoma implanted intracolonically than UFT at an equitoxic dose (tumor weight: S-1 64 +/- 30 mg, UFT 133 +/- 52 mg; P < 0.05). These results suggest that CDHP, which is a potent inhibitor of 5-FU degradation, increases the antitumor activity of FT, and that Oxo, which is an inhibitor of 5-FU phosphorylation, locally protects the gastrointestinal tract from 5-FU-induced toxicity without decreasing the antitumor activity.

Structural study of isoflavonoids possessing antioxidant activity isolated from the fermentation broth of Streptomyces sp.

Structures of three antioxidant isoflavonoids isolated from the cultured broth of Streptomyces sp. OH-1049 were shown to be 4',7,8-trihydroxyisoflavone (1), 3',4',7-trihydroxyisoflavone (2) and 8-chloro-3',4',5,7-tetrahydroxyisoflavone (3), respectively. Among them, 3 is a novel isoflavonoid possessing a chlorine atom in the molecule. Compound 1 was synthesized and its antitumor activities were tested against IMC carcinoma, S180, P388 leukemia and P388/ADM leukemia in vivo. As a result, 1 showed 139% increase in life span (ILS) against S180 bearing mice whereas it showed slight or no ILS against IMC carcinoma, P388 leukemia and P388/ADM leukemia bearing mice.