To investigate whether 99mTc-hexamethylpropyleneamine oxime (99mTc-HMPAO) can be a sensitive marker of lung injury, an animal model of lung injury was designed in the rabbits using the injection of a low dose (0.05 ml/kg) of oleic acid. In the injured rabbit lungs, electron microscope revealed morphologic changes localized in the microvascular endothelium (edematous change), although their chest radiographies and light microscope did not show any significant changes compared to the controls. In these situations, 99mTc-HMPAO showed a diffusely, high pulmonary uptake, which occurred rapidly within the first 1 min after the injection. Clinically, the lungs in the patients who had been administered with cytotoxic anti-cancer drugs showed a significantly higher 99mTc-HMPAO uptake compared to the controls. These findings indicate that 99mTc-HMPAO may have potential as a sensitive marker of chemical lung injury.

The cardiotoxic effects of Daunomycin (DM) ad Adriamycin (ADR), Anthracyclines (ATC), were studied mainly by echocardiography to evaluate their chronic cumulative cardiotoxicity and acute cardiotoxicity during consolidation therapy. Electrocardiographic findings were less sensitive and therefore less reliable for evaluation of the chronic cumulative cardiotoxicity and acute cardiotoxicity induced by ATCs during consolidation therapy. With echocardiography ESS/ESVI, the index of the left ventricular contraction, had the highest sensitivity among indices for cardiotoxicity. SF was useful for easy measurement and calculation of cardiotoxicity. Evaluation of the chronic cumulative cardiotoxicity of ATC drugs indicated that cumulative doses of 300 mg/m2 or more resulted in abnormally low ESS/ESVI levels suggesting cardiotoxicity in many cases, and doses of 500 mg/m2 or more caused abnormally low levels in all cases. Evaluation of acute cardiotoxicity showed that post-consolidation therapy ESS/ESVI levels were significantly lower than pre-consolidation therapy levels in the group treated with doses of 500 mg/m2 or more, but the condition was reversible except in those patients with heart failure. As for the relation between cumulative doses and cardiotoxicity, the indices studied showed no differences between DM and ADR. These results indicate that careful follow-up mainly by echocardiography is required after doses reaching 300 mg/m2 or more of ATC drugs.

Since we discovered verapamil as an MDR-reversing agent in 1981, many MDR-reversing compounds have been reported. This type of drug must be very effective but minimal side effects. We recently found that MS-209 and PSC-833 to be reversing agents that interact directly with P-glycoprotein and show good MDR-reversing effect, both in vitro and in vivo. MS-209 and PSC-833 are thus interesting compounds for clinical use in future.

Altered DNA topoisomerase I and II have been shown in many cell lines resistant to topoisomerase inhibitors, showing that topoisomerases are main molecular targets of these inhibitors. In this paper, recent studies on the mechanism of resistance to DNA topoisomerase I and II inhibitors are reviewed.

It has been known that many drug resistant factors including p-glycoprotein related to anticancer drug resistance. It is assumed that Glutathione s-transferase (GST) is one of the resistant factors. In this present study, we examined the relationship between GST (especially GST-pi) and drug resistance, and also possibility of overcoming of drug resistance for GST-pi related drug resistance. We studied whether GST-pi directly related to anticancer drug resistance by transfection of GST-pi antisense cDNA into human colonic cancer cell line (M 7609). By transfection, cytosolic GST-pi concentrations decreased and sensitivity for adriamycin increased. It was confirmed that GST-pi directly related to some anticancer drug resistance including adriamycin. Moreover, we also have found that ketoprofen, which is an inhibitor of GST-pi activity, increased Adriamycin sensitivity. That is, partial overcoming of drug resistance was obtained. In future, it will be expected that GST-pi inhibitors etc are tried for overcoming of drug resistance.

Multiple drug resistance (MDR) is a major problem of current chemotherapy. Establishment of multiple drug resistant cell lines in culture and isolation of P-glycoprotein-coding MDR genes have promoted understanding of the molecular mechanisms underlying drug resistance in tumors. Another gene, MRP, has been recently isolated from a multiple drug resistant cell line which did not express P-glycoprotein. Both genes have DNA sequence homology for each other and have been identified as members of ATP binding cassette (ABC) transporter superfamily. This review refers to recent progress in MDR and MRP study, and focuses on involvement of these two drug-resistance-related genes in acquiring drug resistance and their physiological functions.

Helper T cells can be divided into Th1 type cell which produces IL-2 and IFN-gamma and Th2 type cell which produces IL-4, IL-5, and IL-6. In general, cytokine has a pleiotropic action. Furthermore cytokines have redundancy in their action. IL-4 is a major product of Th 2 type cell and is an essential cytokine for IgE production, which is also induced by recently found IL-13. Additionally IL-4 is a key factor for the development of Th2 cell, which produces cytokines responsible for inducing allergic reaction. In this paper, we described the gene regulation, molecular structure and biological action including the anti-tumor activity of IL-4.

Sobuzoxane (MST-16) is an analogue of ICRF-159 which was once evaluated on the clinical efficacies in England. Zenyaku Pharm. Ind. in Japan synthesized many derivatives of bis (2,6-dioxopiperazine) and sobuzoxane was selected from the antitumor efficacies, the results of the toxicity tests and pharmacological profiles from these derivative. The compound was a new type topoisomerase II inhibitor, and G2M phase of the cell cycle was most sensitive. The clinical phase studies proved that sobuzoxane was quite effective for the treatment of malignant lymphoma (overall response rate in phase II study 29.7%) and adult T cell leukemia (response rate for acute type: 46.2%). The dose-limiting factor was leukopenia.

A multi-institutional late phase II study of KW-2307 (vinorelbine), a new vinca alkaloid derivative, in advanced or recurrent breast cancer was conducted in 26 nationwide hospitals. KW-2307 was intravenously administered at a dose of 20 mg/m2 once weekly. Eighty among the enrolled 82 patients were eligible. The overall response rate was 30.0% (24/80) with 4 CR, 20 PR, 5 MR, 22 NC, 17 PD and 12 unevaluable patients. The major side effect was leucopenia, which was the dose-limiting factor in this study. Other subjective or objective side effects included general fatigue, nausea-vomiting, anorexia, paresthesia, fever and stomatitis, but none of them was serious.

A multi-institutional early phase II study of KW-2307 (vinorelbine), a new vinca alkaloid derivative, in advanced or recurrent breast cancer was conducted in 15 nationwide hospitals. KW-2307 was intravenously administered once weekly at doses of 15 to 25 mg/m2. Sixty-five among the enrolled 69 patients were eligible. Response rates were 11.8% (2/17) with 15 mg/m2, 28.0% (7/25) with 20 mg/m2 and 17.4% (4/23) with 25 mg/m2, and the overall response rate was 20.0%. Once-weekly intravenous administration of 20 mg/m2 was estimated to be the optimal dose of KW-2307 from the results. The major side effect was leucopenia, which was the dose-limiting factor in this study. Other subjective or objective side effects included anorexia, nausea-vomiting, phlebitis, fever, general fatigue and stomatitis, but none of them was serious.

A multicenter early Phase II clinical study of KW-2307, a new vinca alkaloid derivative, in patients (pts) with lung cancer was conducted in 15 hospitals. Ninety-seven pts were enrolled, among whom 95 were eligible. Seventy of the eligible pts had non-small cell cancer (NSCLC) and 25 had small cell cancer (SCLC). PR was obtained in 13 (18.6%) of NSCLC pts and 3 (12%) of SCLC pts. Only those who had no previous chemotherapy showed PR in NSCLC pts, and the response rate in these pts was 29.5% (13/44). As to the correlation between dosage and tumor effect, a better effect was exhibited at higher doses, with response rates of 21.7% (5/23) and 38.1% (8/21) at 20 mg/m2 and 25 mg/m2, respectively. The major adverse effect of this drug was leukopenia (neutropenia), which was Grade 3 or 4 in many cases. Recovery from this complication, however, was rapid. Other adverse effects included mild hepatic dysfunction, anorexia, nausea/vomiting, fever, general fatigue, phlebitis and constipation. The incidence of peripheral nervous disorder such as the paresthesia commonly observed with vinca alkaloids, was as low as 10%, and the symptoms, if any, were mild.

The purpose of this study is to determine the value of 123I-MIBG scintigraphy to evaluate cardiotoxic effects of antineoplastic agents. We performed 123I-MIBG scintigraphy in 19 patients with malignant neoplasms treated with multiagent chemotherapy including adriamycin. Based on the initial and delayed myocardial images (planar and SPECT), segmental myocardial uptake and wash-out ratio of MIBG were obtained. Low uptake in the myocardium and rapid wash-out from the myocardium especially in the lateral and inferior segments, were noted in patients with cardiotoxicity. Such cardiotoxic effect is dose-dependent. This abnormal areas corresponded to decreased glucose metabolism observed by 18F-FDG PET images. This was suggestive of mitochondrial dysfunction or myocardial damage. There was mismatch in the defect when compared to the result of 201Tl perfusion scintigraphy, and LVEF obtained failed to demonstrate abnormalities. Therefore, 123I-MIBG scintigraphy may be an useful measure in detecting cardiotoxicity related to antineoplastic agents in early stage.

The chemosensitivities of 77 samples of human head and neck cancer were examined by in vitro succinate dehydrogenase inhibition (SDI) test. The tumor tissues obtained at biopsy specimens were exposed to doxorubicin (DXR) and pirarubicin (THP). The average decrease of the enzyme activity by THP was significantly greater than that by DXR. In 60 cases of squamous cell carcinomas, the chemosensitivity of poorly differentiated type tended to be higher compared to the well differentiated type. It is suggested from there results that THP is a more effective anticancer drug than DXR against human head and neck cancers. Clinically good responses were obtained in a systemic chemotherapy of such as head and neck adenoid cystic carcinomas by combining THP with other anticancer drugs such as CDDP (or CBDCA) and CPA.

In order to study preliminary the safety of 5'-DFUR treatment as postoperative adjuvant therapy, intermittent and continuous treatment regimens were administered to patients undergoing curative resection of carcinomas of the stomach and the colorectum. Two treatment schedules were employed: 5'-DFUR was either given continuously in a daily oral dose of 600 mg/patient (continuous group) or for 2 weeks in a daily oral dose of 1,200 mg/patient followed by 2 weeks of no treatment (intermittent group). Twenty-one stomach cancer patients and 34 colorectal cancer patients were registered in the study. The rates of adverse drug reactions in the patients who completed treatment were 20.0% (2/10) in the continuous group and 50.0% (4/8) in the intermittent group of gastric cancer patients, and 16.6% (2/12) in the continuous group and 17.6% (3/17) in the intermittent group of colorectal cancer patients. The main adverse drug reactions were gastrointestinal symptoms. The incidence of diarrhea, a problematic side effect of 5'-DFUR, was 4.5% (1/22) in the continuous group and 12.0% (3/25) in the intermittent group. There were no statistically significant differences between the continuous group and the intermittent group in regard to the incidence of adverse drug reactions and survival rate. In addition, as there were no serious adverse drug reactions, both treatment regimens were demonstrated to be highly safe when administered as postoperative adjuvant therapy.

Microtubules, which are composed of polymerized tubulin dimers, play an important role in various cell functions. For example, they maintain cell shape, form mitotic spindles in M phase of cell cycle, and carry an axonal transport in nerve cells. Microtubules have also been an important target of cancer chemotherapy. Vinca alkaloids depolymerize microtubules, the mechanisms of which action have extensively been investigated recently. Clinical trials of vinorelbine (navelbine), a new semisynthetic vinca alkaloid, are ongoing in Japan. One of advantages of the drug is reduced risk of neurotoxicity. Estramustine may act on microtubule-associated proteins (MAPs) as well as tubulin. It shows additive or synergistic cytotoxicity preclinically when used in combination with vinblastine. This combination was active against hormone-refractory prostate cancer. Another novel drug rhizoxin, which has a similar mechanism of action to that of vinca alkaloids, is also a promising cytotoxic agent and is examined clinically in Europe. Taxanes, which include paclitaxel (Taxol) and taxotere, are interesting drugs because they promote polymerization of tubulin and stabilize microtubules. They show promising antitumor activity against breast, ovarian and lung cancers. Phase I and II trials are ongoing in Japan. Paclitaxel may also potentiate cytotoxicity of radiation. There are several mechanisms of resistance to microtubule-acting drugs. One is multidrug resistance mediated by P-glycoprotein. Other mechanisms include mutation of tubulin.

A combined therapy using miconazole (MCZ) and G-CSF was evaluated in clinical patients who developed deep-seated mycoses and fever of unknown etiology following chemotherapy for malignant gyneco-obstetrical tumors. 1. Combined administration of 100 to 250 micrograms/day of G-CSF, 400 to 800 mg/day of MCZ, and various antibiotics (Group I) was evaluated in 7 patients with mycoses (fungemia and fungal infections of the digestive and respiratory systems). The efficacy of the treatment was found to be 3/3. When 200 to 1,200 mg/day of MCZ was combined with various antibiotics (Group III), the therapy was found to be slightly effective (2/4). The rate of fungal eradication was 3/5. 2. The efficacy of combined administration of 400 to 800 mg/day of MCZ, 100 to 250 micrograms/day of G-CSF, and various antibiotics (Group II) in patients with fever of unknown etiology (n = 8) was 4/4. The efficacy of combined administration of 400 to 800 mg/day of MCZ and various antibiotics (Group III) was 3/4. 3. Leukocyte counts were recorded in the 7 patients who had received G-CSF (Groups I and II). The counts rose from < 1,000/microliters before the chemotherapy to > 5,000/microliters in 6 patients (6/7) in 5 to 8 days following drug administration. The favorable clinical efficacy was recorded in all who received MCZ and antibiotics. 4. The objective or subjective adverse effects of this therapeutic modality were limited to mild nausea in a single case. No deviations from norm were noted in clinical or other tests.