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Dexrazoxane(DXZ)is a drug used for treating extravasation(EV)of anthracycline antitumor antibiotics based on 2 of its mechanisms of action through Topo II. In Japan, it has been used in approximately 150 patients as of January 2016, but there is no detailed report. Three DXZ treatments were carried out for 2 cases in our facilities. One case involved a patient's right forearm while 2 cases occurred involved the left and right forearms of each of the patients, and both were Grade 2(CTCAE v4.0). The EV healed in all cases, and surgical procedures were not needed. Moreover, chemotherapy was performed without extending the treatment period. One year 8 months after administration there was no recurrence in both cases, and skin disorders did not develop. In our hospital, DXZ is managed based on the regimen as well as the anticancer agents, and administration within 6 hours from extravasation was made possible by the cooperation of pharmaceutical wholesalers. Nurses and pharmacists who engage in chemotherapy are encouraged to participate in the study sessions of the hospital, it has been the effort to learn the day-to-day knowledge and technology. DXZ is effective in treating the EV of anthracycline antitumor antibiotics and may be well tolerated. To properly use DXZ by integrating these cases, it is necessary to verify its effectiveness and safety.

A 53-year-old patient with recurrent ovarian clear cell adenocarcinoma developed fever (39°C) and cough on day 28 of liposomal doxorubicin chemotherapy, the 4th cycle of the 4th regimen since initial treatment. Drug-induced interstitial pneumonia was suspected from a chest CT image showing diffuse ground-glass opacities; however, we deduced pneumocystis pneumonia from the elevated serum beta-D-glucan levels. After effective treatment with sulfamethoxazole and amphotericin B, the patient's symptoms and radiological findings improved. Pneumocystis pneumonia is an opportunistic infection that poses a risk not only for patients undergoing aggressive immunosuppressive therapy, those infected with HIV, and those with transplants, but also for patients undergoing chemotherapy. When pneumonia is diagnosed during chemotherapy, it is essential to consider the possibility of pneumocystis pneumonia.

We report a case of drug-induced pneumomediastinum by bleomycin in testicular cancer, which is extremely rare ; to our knowledge, only 3 cases have been reported. A 28-year-old man presented with a left testicular mass. He underwent radical left inguinal orchiectomy that demonstrated a seminoma, pT3N0M0. Ten months after surgery, para-aortic lymph node metastasis appeared, and he received three cycles of bleomycin, etoposide and cisplatin (BEP) chemotherapy. On day 13 of the fourth course of BEP, he complained of snowball crepitation of the neck and computed tomography revealed subcutaneous emphysema, extensive mediastinal air, and intraspinal air accumulation without pneumothorax. The pneumomediastinum and subcutaneous emphysema tended to deteriorate until 15 days after the onset of pneumomediastinum, but fortunately he had no signs or symptoms of infection. These findings resolved spontaneously after 1 month.

Epirubicin hydrochloride(EPI)is well known to cause phlebitis as a typical adverse drug reaction. By preventing the development of severe phlebitis, patients are expected to continue effective chemotherapy with EPI without a decrease in QOL. We have previously reported promising results of a new injection method to prevent phlebitis from occurring during EPI therapy thorough a prospective clinical trial in our hospital(Jpn J Cancer Chemother 36: 969-974, 2009). In the present study, we have compared the conventional injection method(EPI main -route method, n=15)with our new method, which has been consistently practiced at present(EPI sub -route method, n=77). We found that in the EPI main -route method, angialgia/phlebitis developed in 14 of 15 cases(Grade 3, 53. 3%), leading to alteration of the regimen in 3 cases. On the other hand, with the EPI sub -route method, incidence of angialgia/phlebitis was markedly decreased, and only 6 of 77 cases developed these adverse reactions(Grade 3, 0%). One possible explanation for these results is that the reduction of intimal stimulation by the EPI sub -route method might be caused by the dilution and washout of EPI with pre-medication, as well as the shortened infusion times of EPI. Therefore, on the basis of the above hypothesis, we conclude that the EPI sub-route method might be a more effective treatment for the expected prevention of angialgia/phlebitis.

We report a case of adriamycin-induced cardiomyopathy with severe functional mitral regurgitation and congestive heart failure (CHF). Mitral valve replacement (MVR) and papillary muscle approximation (PMA) were effective for this case. A 68-year-old man had adriamycin-induced cardiomyopathy and had required repetitive hospitalizations for CHF for the past 10 years. He also required additional CHF hospitalizations after implantation of a device to perform cardiac resynchronization therapy. His echocardiogram showed severe mitral regurgitation and reduced left ventricular function. We performed MVR and PMA for his functional mitral regurgitation. We preserved the tendinous cords of the anterior and posterior leaflets of the mitral valve. His echocardiogram showed improved left ventricular systolic function and reduced left ventricular volume. He has made satisfactory progress after the operation and he has not required further hospitalizations for CHF. MVR with preservation of bilateral tendinous cords and PMA are very effective procedures for functional mitral regurgitation and intractable cardiomyopathy.

The appearance of vasculitis is often observed following the use of epirubicin hydrochloride in outpatients. As it is important to continue to provide a safe treatment for outpatient with little or no side effects, the aim of this study was to reveal causes underlying the outbreak of vasculitis or the vasculitic state of patients who had undergone instillation of epirubicin hydrochloride as an adjuvant therapy following a breast cancer surgery. The study was conducted based on past investigation records. We extracted relevant factors such as age, previous illness, physical condition and dosage of epirubicin hydrochloride from past records which may all be connected to the outbreak of vasculitis. We administered one dose of epirubicin hydrochloride that was diluted into 50-100 ml of normal saline solution or 5% glucose and instilled over a period of 30 minutes. As a result of this instillation of epirubicin hydrochloride, 35 out of 45 cases displayed vasculitis. We did not observe any relationship among the aged (over 60), previous illness or physical condition (BMI over 25) and the appearance of vasculitis. When a dosage amount of more than 110 mg of epirubicin hydrochloride was administered, 23 out of 29 cases displayed vasculitis. From the past records, it was observed that the cause of vasculitis was dependent on the administrative method itself. As previous studies reported that vasculitis was low when epirubicin hydrochloride was retained in blood vessels for only a short time, our study, however, concentrated on how to administer epirubicin hydrochloride. Our results suggested that an adoption of a single dosage system may suppress the outbreak of vasculitis.

We examined the efficacy, toxicity, and survival rate of patients treated with local administration of adriamycin (ADM) for malignant pleural effusion and pericardial effusion in breast cancer. From May 1996 to December 2002, we injected ADM into the pleural cavity for 21 courses and into the pericardial cavity for 2 courses in 18 patients. Thirteen patients showed CR (including 2 cases were injected into pericardial cavity), 2 PR, and 4 PD, and the overall response rate was 78.9%. Toxicities included nausea/vomiting, elevated fever, chest pain, and so on in 15 patients (83.3%). No severe toxicities, however, were observed. The overall survival rate after the removal of the drainage tube was 42.5% at 1 year and 16.5% at 2 years. The survival in patients with a first recurrence, and CR or PR was significantly better than other patients. We conclude that local administration of ADM is useful for treatment, without severe toxicities, of malignant pleural effusion and pericardial effusion in breast cancer.

Amrubicin is a completely synthetic anthracycline derivative. In contrast, however, the anthracyclines used clinically thus far have been produced by fermentation or semisynthesis. Amrubicin is structurally distinguishable from other anthracyclines by the amino group at the 9-position and its unique sugar moiety. Amrubicinol, the C-13 hydroxy- metabolite of amrubicin, is associated with a 5 to 200 times greater cytotoxicity than amrubicin. Amrubicin exhibited superior in vivo antitumor activity to doxorubicin in the human tumor xenograft model. Using this model, the level of amrubicinol (active metabolite) was shown to be higher than that of doxorubicin in tumor tissues, but lower in normal tissues. These results suggest potent therapeutic activity for amrubicin because of the selective distribution of its highly active metabolite, amrubicinol, in tumors. These anti-tumor effects of amrubicin are considered to be induced by DNA topoisomeraseII inhibition. In clinical studies, amrubicin has demonstrated potent single agent activity as compared to a standard regimen in untreated patients with extensive small cell lung cancer. Its major toxicity was myelosuppression (especially neutropenia).

A 68-year-old man was admitted to our hospital for treatment of a recurrent bladder tumor. Histological examination performed after transurethral resection of the bladder tumor (TUR-BT) revealed a nephrogenic adenoma without any evidence of malignancy. After TUR-BT, total cystectomy was performed to control severe irritative symptoms. Prolonged cystitis and intravesical pirarubicin therapy after TUR-BT may have played an etiological role. Our case is the 25th case of nephrogenic adenoma of the bladder reported in the Japanese literature.

Cardiac toxicity due to anti-neoplastic agents has been recognized since doxorubicin, one of the most effective anthracyclines, was introduced in the early 1970s. Although the frequency of cardiac toxicity is relatively low compared with hematological and gastrointestinal toxicity, management of cardiac toxicity is crucial because of the possibility of irreversible cardiac damage. Recently, high dose-intense chemotherapy with G-CSF and stem cell transplantation, and mediastinal irradiation, produce even more toxic effects on the heart. This review describes some of the cardiac toxicity of anthracyclines and trastuzumab, and discusses attempts at management. The mainstay of management of cardiac toxicity is serial, adequate monitoring of cardiac functions.

A 51-year-old man underwent partial hepatectomy in July 2000 for metastatic liver tumor after gastrectomy for gastric cancer. He received seven cycles of hepatic arterial infusion with mitomycin C 20 mg during induced hypertension with angiotensin II from October 2000 to April 2001. His body temperature sometimes rose above 38 degrees C in June and jaundice appeared in August 2001. Blood biochemistry tests showed an elevated value of alkaline phosphatase, gamma-glutamyl transpepsidase and total bilirubin. Based on an enhanced CT scan of the liver showing a low-density area along intrahepatic biliary tracts and hepatic arteriography showing stenosis of the proper hepatic artery, we diagnosed bile duct necrosis and hepatic necrosis. Bile duct necrosis is a serious complication in arterial infusion chemotherapy, and the infusion chemotherapy should be suspended or the dose should be reduced for patients with abnormalities shown by hepato-biliary function tests.

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.

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.

A 76-year-old woman was admitted with a one-month history of low grade fever and dizziness. She had a palpable right supraclavicular lymph node. Abdominal ultrasonography showed swollen lymph nodes around the abdominal aorta. A specimen from the right supraclavicular lymph node showed malignant lymphoma (diffuse large B cell type). We started chemotherapy according to the low-dose THP-COP protocol (pirarubicin, cyclophosphamide, vincristine and prednisolone) on the 31st hospital day. Since no adverse effects were detected after two low-dose cycles, the patient received a third course with standard doses on the 87th hospital day. The total dose of pirarubicin was 72 mg/m2. Two days after the third course started, she suffered from dyspnea caused by congestive heart failure. A chest X-ray showed advanced cardiomegaly, severe congestion and bilateral pleural effusion. These conditions improved with transvenous administration of diuretics, a vasodilator and phosphodiesterase inhibitor. In this case, congestive heart failure developed even though the total dose of pirarubicin was lower than in previous reports of this complication. When the THP-COP protocol is indicated in elderly patients, cardiotoxicity should be monitored even if the total dose of pirarubicin is very low.

The purpose of this study was to investigate the correlation between efficacy and dose intensity of postoperative adjuvant chemotherapy with MMC and UFT. A total of 1,410 patients from 180 institutions were allocated into a low-dose group and a high-dose group. The patients in the low-dose group received MMC at 8 mg/m2 on the day of surgery and 3 capsules of UFT (300 mg in tegafur) daily for 6 months. The patients in the high-dose group received MMC at 8 mg/m2 on the day of surgery, and in weeks 4, 10, 16, and 22 after surgery and 6 capsules of UFT (600 mg in tegafur) daily for 6 months. The patients in the high-dose group tended to exhibit higher survival rates than those in the low-dose group, although the difference was not significant. For the n(+)ps(-) patients, however, the survival rates were significantly higher in the high-dose group (p = 0.043). The recurrence-free rates showed a similar tendency. The incidence rates of adverse events were significantly higher in the high-dose group than in the low-dose group. Compliance was poorer in the high-dose group. Although the number of adverse events increases, a better prognosis can be expected with a high dose. These results confirmed a dose-dependency in adjuvant chemotherapy with MMC and UFT.

We describe herein two newly diagnosed patients with acute myelogenous leukemia (AML), who were treated twice with an idarubicin hydrochloride (IDR)-containing regimen as a response-orientated induction therapy. Both patients had severe gastrointestinal tract hemorrhage complications at their nadir. The two patients were as follows: a 35-year-old male, FAB-M4, and a 47-year-old female, FAB-M0. They received the same induction chemotherapy (IDR 12 mg/m2 for four days and cytarabine 100 mg/m2 for ten days). No response (NR) was obtained in either, so they underwent the same regimen again. During the period of myelosuppression, they developed severe gastrointestinal hemorrhage. One died of sepsis, and the other of acute respiratory distress syndrome without a recovery in bone marrow. The fetal gastrointestinal tract complications may have been due to severe myelosuppression and mucosal damage in these patients. Careful observation will be needed to prevent such severe complications after the treatment with IDR.

Myocardial damage may be induced by several categories of drugs. Adriamycin is one of the most effective chemotherapeutic agents. Unfortunately, it develops a distinctive and life-threatening congestive heart failure by well-characterized, dose-dependent cardiac toxicity. Left ventricular ejection fraction determined using echocardiography or radionuclide angiography does not decrease sensitively and linearly with the adriamycin dose level. Cardiac function is preserved until a critical degree of myocardial damage is reached, after which myocardial performance deteriorates rapidly. Biochemical monitoring may be a novel sensitive and specific method for detecting subclinical myocardial damage. Abnormal cardiac adrenergic neuron activity evaluated with radiolabeled MIBG, impaired myocardial glucose utilization measured with F-18-FDG and plasma brain natriuretic peptide levels increased due to cardiac dysfunction may be particularly sensitive markers of adriamycin cardiotoxicity. It is hoped that prospective clinical study reveals the values of these biochemical markers.

To evaluate the efficacy of docetaxel therapy against anthracycline-resistant breast cancer, twenty patients were treated with docetaxel. Of the 20 patients pretreated with anthracycline, 17 were clinically anthracycline-resistant and the remaining three were refractory to anthracycline on histoculture drug response assay. Nine patients had loco-regional recurrence and 11 had distant +/- loco-regional recurrence. Docetaxel (49-60 mg/m2) was administered every 4 weeks, and was infused 1-13 times (median; 3 times). Of the 19 evaluable patients, eight (42%) showed partial response with the docetaxel therapy. Durations of the response ranged from 1 to 8 months (median; 4 months). Major adverse effects of the therapy were alopecia, neutropenia, and leucocytopenia. Hypersensitivity reaction was observed in one case. In addition, severe adverse effects such as grade 2 pneumonia and grade 4 diarrhea were found in one patient each. In conclusion, although the adverse effects are not negligible, docetaxel therapy is effective against anthracycline-resistant breast cancer.

In order to determine the clinically optimal dose of KRN8602, a new anthracycline derivative, in combination therapy for acute leukemia, we performed a pilot late phase II study in combination with cytarabine (Ara-C) for acute myelogenous leukemia (AML), and with vincristine (VCR) and prednisolone (PSL) for acute lymphocytic leukemia (ALL). KRN8602 was given at a dose of 12 or 15 mg/m2 for 5 consecutive days, Ara-C at a dose of 100 mg/m2 for 7 consecutive days, VCR 1.4 mg/m2 (max. 2.0 mg/body) weekly for 4 weeks, and PSL 40 mg/m2 for principally 28 consecutive days. Of 14 patients with relapsed or refractory leukemia entered in the study, thirteen patients were evaluable for safety and 12 were evaluable for response. In AML, there was 1 partial response (PR) in 4 patients at a dose of 12 mg/m2. Against 1 complete response (CR) and 3 PRs in 4 patients at a dose of 15 mg/m2. In ALL, there was 1 PR in 1 case at a dose of 12 mg/m2, and 1 CR and 2 PR in 3 at a dose of 15 mg/m2. Major toxicities were nausea/vomiting and anorexia, but incidences and grades of toxicities were not dose-dependent, and all toxicities were tolerable and manageable. From these results it is concluded that the optimal dose of KRN8602 is 15 mg/m2 for 5 consecutive days in combination with Ara-C for AML, and with VCR and PSL for ALL.

We performed an early phase II study of KRN8602, a new anthracycline derivative for refractory or relapsed acute leukemias. KRN8602 was given at a dose of 15 mg/m2 for 3 to 5 consecutive days, repeating every 3-4 weeks. Among 53 patients entered in the study, 51 were evaluable for safety, and 46 were evaluable for efficacy. The response rate at schedules of 3 and 4 consecutive days was 9.1% (1 PR/11), while that at a schedule of 5 consecutive days was 22.9% (3 CR + 5 PR/35). With the 5 consecutive day schedule, the response rates were 21.4% (1 CR + 2 PR/14) for acute myelogenous leukemia and 29.4% (2 CR + 3 PR/17) for acute lymphocytic leukemia, but no response was observed in 4 patients with blastic crisis of chronic myelogenous leukemia. Major toxicities were nausea/vomiting and anorexia, however, all these toxicities were clinically manageable. From these results it is concluded that KRN8602 is effective against acute leukemias, and the optimal dose is 15 mg/m2 for 5 consecutive days.

A 10-center cooperative clinical study with a new formulation of epirubicin hydrochloride injectable solution (Epirubicin-RTU) was conducted in patients with hepatocellular carcinoma. Epirubicin-RTU 60 mg/m2 was injected into the hepatic artery and a three-week drug-free interval followed. Of 15 patients with hepatocellular carcinoma registered in this study, 14 patients were eligible, and they all completed the entire course. The objective was to investigate the safety of treatment with Epirubicin-RTU in 14 eligible patients. The adverse drug reactions frequently observed in these 14 eligible cases were leukopenia, neutropenia, thrombocytopenia, alopecia, and fever. They were all reversible and tolerable. With these results. Epirubicin-RTU was considered to be a safe pharmaceutical product to inject into the hepatic artery.

A 7-center cooperative clinical study with a new formulation of epirubicin hydrochloride injectable solution (Epirubicin-RTU) was conducted in patients with superficial bladder carcinoma. Epirubicin-RTU at the dose of 60 mg/30 ml was administered by intravesical instillation once daily for three (3) consecutive days and a 4-day drug-free interval followed; then the above intravesical instillation of Epirubicin-RTU was repeated for three consecutive days. All 20 registered cases were eligible, and 18 cases completed the whole course of the study. In 18 completers, CR was observed in 12 cases and PR was observed in one (1) case, for an efficacy rate of 72.2%. The primary adverse reaction was bladder irritation including pollakiuria 85.0% (17/20), miction pain 85.0% (17/20), and hematuria 80.0% (16/20), which were all reversible and tolerable. In urinalysis, urinary sediment showed leukocytes and erythrocytes, and proteinuria was observed. All were reversible. From the above results, this new formulation of Epirubicin-RTU was considered useful for the treatment of superficial bladder carcinoma.

We performed a clinical phase II study of KRN8602, a new anthracycline derivative, for relapsed or recurrent malignant lymphoma. KRN8602 was given at doses of 12-15 mg/m2 for 3 consecutive days, repeating every 3-4 weeks. Among 44 patients entered into the study, 36 were evaluable for safety, and 35 were evaluable for efficacy. The response rate was 18.2% (6PR/33) for non-Hodgkin's lymphoma and 0% (0/2) for Hodgkin's disease. Major toxicities were bone marrow suppression and gastrointestinal toxicity. Leukopenia was observed in 77.8%, thrombocytopenia in 44.4%, hemoglobin decrease in 44.4%, nausea and vomiting in 94.4% and anorexia in 80.6%. However, all toxicities were clinically manageable.

123I-metaiodobenzylguanidine (MIBG) myocardial single photon emission computed tomography (SPECT), 123I-beta-methyliodophenyl pentadecanoic acid (BMIPP) myocardial SPECT, and holter ECG recording were performed in patients with non-Hodgkin's lymphoma who underwent chemotherapy including pirarubicin (THP), in an attempt at early detection of cardiac toxicity from THP. Twenty-six patients with untreated non-Hodgkin's lymphoma who received THP-COPBLM therapy were studied. For THP-COPBLM therapy. THP was administered at a dose of 40 mg/m2 every 21 days and the total dose was 250 mg/m2 on average (40 approximately 400 mg/m2). 1) The washout rate (WR) correlated with the total THP dose, and was considered to be a useful index of cardiac sympathetic nervous dysfunction. 2) The left ventricular ejection fraction (LVEF) correlated negatively with the total dose of THP. 3) The total dose of THP showed a correlated positively with the extent score and severity score determined by BMIPP. 4) The WR correlated with the frequency of premature ventricular contraction. Animal studies have indicated that THP has less cardiac toxicity than doxorubicin, but the present study showed that cardiac toxicity occurred at a total THP dose of about 360 mg/m2 in elderly patients. Accordingly, when THP is used to treat elderly patients, multimodal evaluation of cardiac is necessary to detect cardiotoxicity and to determine the optimal dosage.

The antitumor activity of adriamycin (ADR) was enhanced by combination with theobromine or pentoxifylline. Theobromine increased the concentration of ADR in the tumor without any effects on that in the heart and the liver. The influence of the combination of theobromine or pentoxifylline with ADR on the lipid peroxide level (indicating the ADR-induced side effect) and on DNA biosynthesis (indicating the side effect and antitumor activity) were examined. When ADR was administered into mice, the lipid peroxide level in the liver and the heart increased. However, the combination of theobromine or pentoxifylline did not enhance the ADR-induced increment of the lipid peroxide level in the liver, and moreover, it inhibited that in the heart. The decrease of DNA biosynthesis in the liver and the heart, induced by ADR, were not enhanced by combination with theobromine or pentoxifylline. On the other hand, the combination of theobromine with ADR significantly increased the inhibition of DNA biosynthesis in the tumor. These findings indicate that the combination of theobromine or pentoxifylline with ADR have no effect on the side effects of ADR in the liver and the heart, with the increase of antitumor activity of ADR in the tumor, and it is suggested that these drugs will be of value as a biochemical modulator of ADR.

We investigated the possible side effects and efficacy of arterial infusion of SMANCS as compared to Lipiodol + epirubicin TAE for multiple recurrent tumors after hepatic resection. As a result, no significant difference in GOT, GPT, and total bilirubin was observed between the two groups. No significant difference was found in white blood cell count and platelet count, and there was no significant difference in clinical side effects between the two groups. Grade III response rates after arterial infusion of SMANCS were found in 4 patients (66.6%), and these results showed no significant difference as compared to Lipiodol + epirubicin TAE. Proper hepatic arterial infusion of SMANCS appeared to be useful in multiple recurrent tumors from the standpoints of safety and the rate of Lipiodol deposition.

We evaluated the cytotoxic effects of mitomycin C (MMC) in rabbit eyes. A sponge soaked with MMC was placed on the bared sclera after conjunctival incision. We used four concentrations of MMC in distilled water: 0%, 0.04%, 0.1%, and 0.4%. MMC was applied to one eye only, with the fellow eye serving as control. The eyes were studied for intraocular pressure (IOP) and by fluorophotometry at 3, 7, 14, and 28 days of treatment. Eyes treated with 0.04% and 0.4% MMC were studied histologically at 3 and 28 days. All the MMC-treated eyes showed no significant changes regarding IOP (56 eyes) or fluorophotometric features (28 eyes) regarding aqueous humor dynamics and blood-aqueous barrier. Pathologic changes of the ciliary epithelium, including intracellular vacuoles and swelling of mitochondria, were more pronounced in eyes treated with 0.4% MMC than those treated with 0.04%. These changes were more manifest in areas inner to the site of application than in the opposite area. Topical application of 0.04% MMC thus showed no evident toxic effects on the function of the ciliary body and other pathological changes were minor.

We investigated whether artificial surfactant modified pulmonary fibrosis following the intratracheal administration of bleomycin (BLM 3.75 mg/kg) in rats. Twenty-four hours after the administration of bleomycin, the lungs were washed twice with surfactant-TA (S-TA, 1 mg/ml, 6 ml x 2 times), and replaced with 0.5 ml of 10 mg/ml S-TA. Fourteen days later the animals were sacrificed and the lungs were assayed for collagen content and pathologic changes. BLM-treated rats showed both increases in wet lung weights and lung collagen content, and a loss in body weights (due to lung injury and fibrosis), but these changes were significantly inhibited by the intratracheal administration of S-TA. In vitro studies demonstrated that S-TA inhibited lung fibroblast proliferation in a dose dependent manner (0.01-0.5 mg/ml). This inhibition was also seen in native rat lung surfactant and its protein and lipid components. However, S-TA, did not change the number of rat type II pneumocutes in culture, and likely protected type II cells from dedifferentiation. S-TA inhibited BLM-induced pulmonary fibrosis, probably by directly inhibiting lung fibroblast proliferation.

For a sample of 136 adults on whom Doxorubicin (DXR) had been used, we looked for the ejection fraction (EF) by echocardiography and examined its relationship with the amount of DXR. Our results showed that as the amount of DXR increased the EF decreased significantly, particularly with aging. The use of previous mediastinal radiation and 5-FU, etc. on breast cancer patients had no effect on the EF. From our examination of patients developing congestive heart failure, we repeatedly performed echocardiography and found that DXR can be safely used until the EF decreases to 55 percent. In this way, we can find many patients with whom it is possible to use DXR in larger amounts than 550 mg/m2. In general, large quantities of DXR can be used on young people, but for elderly people, large quantities of DXR should be used with caution.

The effect of the anthracycline analogue, pirarubicin, on cardiac function was examined. One hundred and four patients with gynecologic malignancies were treated with 40-50 mg/body THP ADM every 3 to 4 weeks by iv bolus injection. Three out of 104 cases that had developed cardiac failure received more than 1,500 mg. One case receiving 1,340 mg developed cardiac failure and expired 3 years after completion of treatment for malignancy. From the above experience, it is concluded that the MTD of pirarubicin seems to be 1,500 mg/body or 1,100 mg/m2.

A late Phase II multicenter study with menogaril was conducted nationwide in patients with malignant lymphoma [non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD)], and ATLL, menogaril was orally administered at 100 mg daily after breakfast, for seven consecutive days with two- or three-week drug withdrawal, then menogaril administration was repeated. For malignant lymphoma, in 81 patients with NHL and 5 patients with HD registered, 70 and 5 patients were evaluable for efficacy, respectively. The efficacy rates were 32.9% (6 CRs + 17 PRs/70) for NHL and 20.0% (1 PR/5) for HD, respectively; that for the NHL patients with prior anthracycline antibiotic chemotherapy was 30.5% (5 CRs and 13 PRs/59). For ATLL, among the 16 patients registered, 15 were evaluable for efficacy, and the efficacy rate was 40.0% (2 CRs and 4 PRs/15). Adverse drug reactions frequently observed in the patients with malignant lymphoma and ATLL included bone-marrow suppression and gastrointestinal symptoms such as anorexia, and nausea/vomiting. With these results, menogaril was considered to be effective for the treatment of non-Hodgkin's lymphoma and ATLL.

An early Phase II study with TUT-7 (menogaril), a new anthracycline antitumor antibiotic, was conducted in patients with various malignant tumors at 81 departments of 65 institutions nationwide. One course of TUT-7 treatment consisted of seven (7) or fourteen (14) consecutive days of administration at 75 or 100 mg/body/day with two-week drug withdrawal; at least two courses of treatment were given in principle. Among the 165 patients registered, 145 patients were eligible and 128 patients were evaluable for antitumor efficacy. In 11 patients with malignant lymphoma, one (1) had CR and five (5) had PR (54.5%); in three (3) patients with prostate cancer, one (1) had PR (33.3%); and in 12 patients with uterine cervical cancer, two (2) had PR (16.7%). Adverse drug reactions frequently observed were digestive organ disorders (anorexia and nausea/vomiting) and malaise. The abnormality in laboratory tests observed frequently was myelosuppression (leukopenia and neutropenia).

Echocardiographic reports on 144 adults receiving anthracycline therapy and 18 controls were reviewed for the possible relationship between dosage and ejection fractions. The cardiotoxicity of each anthracycline drug was evaluated as follows: Pirarubicin = 0.8, Mitoxantrone = 3.4, Daunorubicin = 0.5, Aclarubicin = 0, and Epirubicin = 0.6 with Doxorubicin = 1 as a control. As a whole, the ejection fractions, which decreased subsequently compared with increasing amount of dosage, showed a remarkable decrease at the dosage level of 600 mg/m2. However, the ejection fractions differed among individual patients. It was predicted that heart failure would not develop when the ejection fractions exceeded 55%. It is desirable to stop anthracycline therapy when the ejection fractions drop to 55%.

Cardiac function was evaluated in 53 elderly patients with hematologic malignancies who were being treated with doxorubicin (DXR). The left ventricular ejection fraction was measured by radionuclide angiocardiography, the washout rate by 123I-MIBG myocardial SPECT, the extent and severity scores by 123I-BMIPP myocardial SPECT, and the frequency of premature ventricular contractions by Holter electrocardiography. 1) In some patients, both the washout rate and the extent and severity scores were abnormally high before treatment. 2) Because the washout rate correlated with the total dose of DXR, it may be an early indicator of cardiac sympathetic nervous dysfunction. 3) The left ventricular ejection fraction correlated with the extent and severity scores, but not with the washout rate or with the frequency of premature ventricular contractions. 4) The washout rate correlated with the frequency of premature ventricular contractions. These data show that elderly patients had abnormal cardiac function even before treatment with DXR; that cardiac sympathetic dysfunction and cardiac mitochondrial dysfunction developed at total DXR doses of 250 to 300 mg/m2 or higher; and that the left ventricular ejection fraction was less than or equal to 50% in many patients. Consequently, when DXR is used to treat elderly patients, multimodal evaluation of cardiac function is necessary to detect cardiotoxicity and to determine the optimal total dose and the optimal dosage.

In order to investigate myocardial lipid metabolism in patients receiving chemotherapy regimens containing adriamycin (ADR) for hematological malignancies, 123I-beta-methyl iodophenyl pentadecanoic acid (BMIPP) myocardial SPECT was performed. Thirty-two patients with hematological malignancies received a mean total ADR dose of 245 mg/m2 (range: 0-550 mg/m2). A polar map based on data from 8 normal individuals was used to calculate the extent score (representing the area of decreased uptake) and the severity score (representing the severity of defects) in the patients given ADR. 1) There was a significant association between the total ADR dose and the extent and severity scores. 2) The left ventricular ejection fraction was significantly associated with the extent and severity scores. 3) The two scores were also significantly associated with the washout rate of 123I-metaiodobenzylguanidine (MIBG). These results suggest that 123I-BMIPP myocardial scintigraphy reflects dysfunction of the myocardial mitochondria and serves as a guide for determining whether administration of ADR should be discontinued or the dose reduced.

Seventeen patients with advanced breast cancer were treated with neoadjuvant intraarterial chemotherapy with high dose epirubicin. The following results were obtained. 1. Excellent down-staging effect (tumor reduction > 50% of its original size: 82.4%) was confirmed on primary lesions. In addition, an objective response rate of 37.5% was observed at the metastatic sites. 2. Leukopenia, which was the dose-limiting factor in this regimen, appeared at the frequency of 82.4%. Therefore, we needed G-CSF and/or a sufficient interval between each cycle. 3. A great number of cases and sufficient follow-up period will be indispensable to discuss survival in future investigation.

The acquired immunodeficiency of the host plays an essential role in the occurrence of infections even with low pathogenic bacteria. The increase of cases with MRSA and/or pseudomonas infection is one of the serious problems in hospital management in Japan for the elderly as well as pediatric patients. In the present study, mitomycin C (MMC)-treated hosts were prepared in young, adult and old mice to test the immunopotentiating action of the promising Chinese herbal medicine, Tohki-Rikuoh-Toh (TRT), Hotyu-Ekki-Toh (HET) and Juzen-Taiho-Toh (JTT). The effect of these herbal medicines on organ structure and its function in the MMC-treated hosts is clarified and discussed for medical use. 4-5, 8-10 and over 50 week old male C57BL/6 (Clea Japan Inc.) were injected with MMC at a dosage of 3 to 5 mg/kg to inhibit the bone marrow, thus creating a mouse model with reduced immunopotential. A powder extract of TRT, HET and JTT was administrated orally at a dosage of 500 mg/kg/day for seven consecutive days. The white cell number and the subset analysis were carried out by the FACS method. The bactericidal effect of the host was monitored by NBT reduction test. Peritoneal macrophages were prepared by the adherence technique. The macrophage phagocytic activity was examined by an ACAS system. After the administration of TRT, HET and JTT, the body weights recovered as much as 90%, especially in young animals which had been reduced to 75% of their normal values. After MMC-treatment, with the herbal medicines, HET was good for young mice while JTT was effective for the old ones. As for the effect on B cells, the plaque-forming cells (PFC) of spleen cells were compared among the groups. As a result, PFC in the HET group was 184% and the other two were 80 approximately 95% as compared to 76% in the MMC-treated ones. The number of white blood cells in the MMC-treated mice returned to 80% of their normal value. In addition, the phagocytic activity of macrophages increased to 50% although that of the non-treated group was only 20%. The phagocytic activity also recovered in the JTT and TRT of 131% to 95%, respectively compared to 11% in the MMC-treated control. When TRT, HET and JTT were administered orally to mouse models whose immunopotential had been inhibited, the herbal medicines activated both quantitatively and qualitatively, showing themselves to be effective interstitial medicines. In addition, the data from the animal models showed no side effects, confirming the complete efficacy of the drug. Moreover, there was no direct anti-bactericidal effect from these medicines, suggesting that the immunomodulating action of this medicine is host-mediated. It is interesting that quantitative and qualitative recovery were seen when HET was administered to MMC-treated young hosts while JTT was good for the old. With this investigation, the effective components are still unknown for different generations, and we need to clarify this aspect for better understanding of the efficacy of herbal medicines.

We conducted a randomized controlled study to evaluate the clinical usefulness of (2"R) -4'-O-Tetrahydropyranyladriamycin (THP)-based combination therapy subsequent to induction therapy which was consisted with THP, 5'-DFUR, and CPA in the treatment of advanced or recurrent breast cancer. In maintenance therapy, Arm C received CPA and TAM, and Arm T received these two drugs plus THP. Survival time of 50% for all cases in which maintenance therapy was conducted was 26.9 months in Arm T and 20.9 months in Arm C, showing no significant difference by the log-rank test (p = 0.64). Survival time in all cases in which therapy had been completed was 54.6 months in Arm T and 28.1 months in Arm C, showing a significant difference by the log-rank test (p = 0.03) although the number of cases was few. A few cases showed a decrease in total leukocyte count to below 2,000/mm3 at the time of induction therapy, but this was transient in all cases. No significant difference in count was noted between two arms at the time of maintenance therapy. However, many cases in Arm T showed decreased total leukocyte count and hemoglobin content, and thrombocytopenia. These results suggest that combination therapy including THP conducted as maintenance therapy after induction is useful in the prolongation of survival time in patients with advanced or recurrent breast cancer.

A 44 year-old woman with acute myeloid leukemia (AML, FAB, M4E) developed heart failure during treatment with anthracyclines for AML. She had not experienced heart disease and her left ventricular ejection fraction (LVEF) was 59% at the end of a successful remission induction therapy. Because her LVEF decreased to 33% after early consolidation therapy, the chemotherapy for AML was discontinued. The cumulative dose of daunorubicin, aclarubicin and mitoxantrone was 486 mg/m2, 135 mg/m2 and 55 mg/m2, respectively. In October 1990, four months after the end of the chemotherapy, heart failure (class III, NYHA) developed and did not improve by treatment consisting of dobutamin, digoxin and diuretics. Anthracycline cardiomyopathy was histologically confirmed by endomyocardial biopsy. Then we administered selective beta 1-antagonist, metoprolol (Seloken), with an initial dose of 5 mg/day which was doubled 3 times every 4 or 8 weeks to 40 mg/day, according to the treatment schedule of dilated cardiomyopathy. She recuperated satisfactorily (Class I, NYHA), and was discharged on February '91. Her LVEF gradually improved and it has been maintained at above 50% on an outpatient basis. The patient has been in complete hematological remission during this period. It seems that low dose selective beta 1-antagonist therapy has a potential to improve myocardial function in some patients with anthracycline cardiomyopathy.

Sixteen patients with advanced breast cancer were treated with neoadjuvant intraarterial chemotherapy with high dose epirubicin. The following results were obtained: 1) Excellent down-staging effects were confirmed. Response rate of the primary tumor was 81.3%. 2) Leukopenia was the dose-limiting factor, and 81.3% of patients had WHO grade 2 or more leucopenia. However, the regimen was completed with supportive therapies. 3) At a median follow-up of 17 months, improved survival rates were noted. The present study showed the efficacy of neoadjuvant intraarterial chemotherapy with high dose epirubicin in the treatment of locally advanced breast cancer.