Antibiotics exhibiting immunomodulatory activities were found among antitumor antibiotics. These antibiotics had antileukemic activity. Neothramycin and mazethramycin, which are classified as anthramycin-group antibiotics, activated macrophages so that they became antitumor effector cells. Aclacinomycin and oxanosine inhibited generation of suppressor cells in tumor-bearing mice and oxanosine enhanced antitumor effector cells. Therapy using spergualin produced specific antitumor immunity in cured mice. The immunomodulatory activities of auromomycin and bactobolin were also reported.

Experimental evidences were presented to show induction by cancer chemotherapeutic agents of terminal differentiation of several cultured myeloid leukemia cell lines and fresh leukemia cells from patients with myelogenous leukemia. A description was also given of recent clinical trials to improve the therapy of patients with refractory acute myelogenous leukemia by administration of small doses of cancer chemotherapeutic agents resulting in enhanced populations of mature granulocytes in the peripheral blood of patients. These cancer chemotherapeutic agents are suggested to induce differentiation of several cultured leukemia cell lines both in vitro and in vivo by mechanisms distinct from those of their cytotoxic actions. Based on these findings, possible therapeutic implications of the differentiation-stimulating actions of the cancer chemotherapeutic agents on host response-modifying actions are discussed.

Nausea and vomiting induced by cisplatin are very severe and intractable to standard antiemetics. During the past several years, many studies of antiemetic management in the patients receiving cisplatin have been performed. In this paper recent advances in the management of cisplatin-induced emesis were reviewed. To date, high dose (2 mg/kg every 2 hours 3-5 times) metoclopramide is considered to be the most effective drug against emesis induced by high-dose (100-120 mg/m2) cisplatin, and a combination therapy of metoclopramide, dexamethasone, diphenhydramin and lorazepam appears to be the most effective. In antiemetic management the problem of anticipatory emesis and delayed or persistent emesis must be considered as well as acute chemotherapy-induced emesis. On the other hand, we have experienced that antiemetic trials are more ineffective in women than in men, so it is more important to control chemotherapy-induced emesis in women. For obtaining more effective control of cisplatin-induced emesis, a combination of antiemetic agents affecting more than one of several neurotransmitter receptors is necessary. In Japan, antiemetic trials have only strated, so we must make an effort to work towards reducing the distressing emesis induced by cisplatin.

A Phase II study of a new anthracycline, (2''R)-4'-0-tetrahydropyranyladriamycin (THP), was conducted in 162 patients with various hematological malignancies in a multi-institutional cooperative study. THP was given intravenously at a dose of either 10-30 mg/body for 3-5 consecutive days or 40-60 mg/body at 3-week intervals. Of 22 patients with AML, complete remission (CR) was observed in 2 patients and partial remission (PR) in 2. Of 18 patients with ALL, CR was observed in 5 and PR in 3. Of 68 patients with NHL, CR was observed in 11 and PR in 22. Of 8 patients with HD, CR was observed in 4 and PR in 2. One CML case showed CR and one ATL case showed PR. PR was noted in one of 2 patients with mycosis fungoides. Overall remission rate was 43.1% (CR 23 cases and PR 33 cases). The predominant toxicity was myelosuppression. Leukopenia (less than 4,000/mm3) was noted in 67 (77.6%) and thrombocytopenia (less than 10 X 10(4)/mm3) in 24 (27.0%). Nausea/vomiting and anorexia were common, and were observed in 61 (43.3%) and 65 (46.1%) cases, respectively. Hair loss and cardiotoxicity were mild and recovered quickly on discontinuation of THP. Thus, THP was found to be effective for various hematological malignancies including acute leukemia and malignant lymphoma.

The large majority of colorectal cancers are well or moderately differentiated adenocarcinomas. Their biological behavior is not as malignant as that of stomach cancer, with a tendency of slow growth and limited spread. Surgery is therefore the first choice for management of these cancers even in cases where complete removal of the tumor is not expected, surgery is useful for the prolongation or improvement of the quality of life. However, the correct choice of operation for such cases is very important. The extent of resection and dissection must be decided based upon the degree of cancer spread. Both must be sufficient, but not excessive. In cases in the early stage where cancerous growth has not spread beyond the submucosal layer, local or segmental excision may be a good enough treatment. On the other hand, for far advanced rectal cancer involving adjacent organs, combined resection and pelvic evisceration is curatively effective. Several pathological findings of resected specimens influencing prognosis were investigated in the present study. In cases which appeared to be diffuse infiltrative spreading type in macroscopic appearance or poorly differentiated, undifferentiated, or mucinous types of cancer in their histological features, survival rates were low. However, these were uncommon and over half of them were much too far advanced to receive curative resection. Irradiation combined with hyperthermia or heavy chemotherapy were applied, but were mostly ineffective. For these uncommon types of cases as well as far advanced cases, we have no effective treatment other than surgery at this time.

The accumulation of (2''R)-4'-O-tetrahydropyranyladriamycin (THP) was studied in rats received intravenous administration of 14C-THP at a dose of 0.5 mg/kg/day for 14 consecutive days by determining blood and tissue levels and the excretion of the radioactivity. The radioactivity levels in plasma and blood cells after the multiple administration were higher than those after single administration. The half-life of the radioactivity after the multiple administration was longer in the blood cells but not in the plasma than the half-life after a single administration. Tissue levels of the radioactivity after the multiple injection were 2 to 4 times as high as the levels after a single injection except for the brain and testes in which a large accumulation of the radioactivity was observed. However, little accumulation of unlabeled THP was found in most tissues when determined by HPLC. The accumulation of radioactivity in tissues, therefore, was due to metabolites of THP. The disposition of 14C-THP was also examined in rats which had previously received unlabeled THP (0.5 mg/kg/day) for 13 days. The pretreatment did not affect the disposition of 14C-THP seriously, although the pretreatment raised tissue levels slightly and a rebound of plasma level of 14C-THP, and lowered the fecal excretion ratio. No induction of hepatic drug metabolizing enzymes was observed in rats after repeated administrations of THP for consecutive 14 days.

(2''R)-4'-O-Tetrahydropyranyladriamycin-HCl (THP), a new antitumor antibiotic, was intravenously injected to New Zealand White rabbits at a dose of 2.5 mg/kg every 2 weeks for 6 weeks (3 courses) or at a dose of 0.5 mg/kg/day daily for the first 5 days of a 2-week course for 6 weeks (3 courses). The total dose was 7.5 mg/kg in both dosing schedules. The peripheral leucocyte and erythrocyte counts decreased. The leucocyte count decreased to 57% of the initial count on Day 3 in the first course and then increased gradually. The decrease was smaller in the divided dosing schedule than the single dosing. The nucleated cells, especially immatured myelocytes and erythroids reduced remarkably. Subsequently the matured myelocyte ratio in bone marrow cell constituents increased and the M/E ratio increased. These changes were observed on Day 3 and reverted by Day 9 in each course. The divided dosing schedule resulted in a higher nadir. All the changes in the peripheral blood and the bone marrow reverted even after the 3 course-treatment.

New Zealand White rabbits were treated with (2"R)-4'-O-tetrahydropyranyladriamycin-HCl (THP), a new antitumor antibiotic, by an intravenous bolus injection at a dose of 1, 2 or 4 mg/kg. The peripheral leucocyte counts decreased markedly at doses of 2 and 4 mg/kg 1 to 7 days after injection, and the lymphocytes and neutrophils were affected. The nucleated cell count decreased in the bone marrow. Especially 3 days after injection, remarkable reductions of erythroids and immatured myelocytes were observed, with a subsequent rise of the matured myelocytes ratio in bone marrow cell constituents. These changes resulted in a marked increase of M/E ratio. Doxorubicin also showed an inhibitory effect on the bone marrow function of rabbits but the effect was slightly lower than THP. These changes of bone marrow cells reverted 7 days after injection and the recovery of the reduced peripheral leucocyte was also observed 14 days after injection. Therefore, it can be concluded that THP showed suppressive but reversible effects on the bone marrow function of rabbits.

Cardiovascular effects of (2''R)-4'-O-tetrahydropylanyladriamycin X HCl (THP) and doxorubicin (adriamycin, ADM) were studied in hamsters. In experiments to observe acute effects, THP was administered intravenously at a dose of 12.5, 25.0 or 50.0 mg/kg, and ADM at 1.56, 3.13 or 6.25 mg/kg was given to different subjects. The THP caused slight ECG alterations at a dose of 12.5 mg/kg. At a dose of 25.0 mg/kg or 50.0 mg/kg, THP caused moderate to remarkable alterations in ECG like a widening of PR and PRc interval, A-V block, ST segment depression and T wave flattening. The ADM caused moderate to remarkable alterations in ECG at a dose of 3.13 mg/kg or 6.25 mg/kg, including arrhythmia, bradycardia, A-V block, ST segment changes and T wave flattening. These changes caused by THP and ADM recovered within 5 approximately 10 minutes after injection. Alterations in the ultrastructure of the myocardium caused by THP at a dose of 50.0 mg/kg included some cells with slight changes like swelling of mitochondria, focal intracellular edema, and enlargement of myofibrils. The ADM, at a dose of 3.13 mg/kg, induced severer swelling of mitochondria than THP, dilatation of sarcoplasmic reticulum, intracellular edema, and disorganization of myofilaments. At a dose of 6.25 mg/kg of ADM, these changes became more pronounced. In experiments to observe subacute effects, hamsters were treated with THP or ADM by daily intraperitoneal injections for 15 consecutive days, and then allowed to be recovered for 15 days. Dose levels of THP or ADM were 0.125, 0.25, 0.5 and 1.0 mg/kg. General toxicity, ECG, hematological and blood biochemical analysis, and electron microscopic examination were studied. In the ECG study, THP-treated hamsters showed a reversible elevation of R wave amplitude at a daily dose of 0.5 mg/kg. Widening of PR and PRc interval, elevation of R and S wave amplitude, and reduction of T wave amplitude were observed at a daily dose of 1.0 mg/kg of THP. Hamsters treated with ADM showed increase of heart rate, reduction of T wave amplitude, and shortening of PR and PRc interval at a daily dose of 0.5 mg/kg. Severe changes were observed at a daily dose of 1.0 mg/kg of ADM including an increase of heart rate, elevation of R wave amplitude, reduction of S and T wave amplitude, and shortening of QT interval. The electron microscopic examination revealed that THP-treated hamsters showed separation of intercalated discs, formation of myelin structure, and dilatation of T-tubules at a daily dose of 1.0 mg/kg. Similar changes were caused by ADM at a daily dose of 0.25 to 1.0 mg/kg.(ABSTRACT TRUNCATED AT 400 WORDS)

General pharmacology of (2"R)-4'-O-tetrahydropyranyladriamycin hydrochloride (THP) was studied in experimental animals. Intravenous administration of THP showed no significant effect on the respiratory and cardiovascular systems, such as blood pressure, heart rate, ECG and respiration in anesthetized rabbits and dogs. But in rats and cats, THP produced a transient decrease in blood pressure resulted from vasodilation. The hypotension was not inhibited by antihistaminics. Contraction of isolated guinea-pig atria was stimulated by THP at high concentrations (10(-4) g/ml). THP inhibited the spontaneous movement of isolated rabbit ileum and rat uterus (virgin and pregnant) at high concentrations (10(-4) g/ml). In some isolated guinea-pig ileum preparations, THP partially (6 approximately 36%) antagonized the contraction inducing by acetylcholine, histamine, serotonin and barium chloride. Urine volume and urinary excretion of electrolytes were increased by intravenous injection of 5.0 mg/kg THP. Vascular permeability was progressed when administered intracutaneously. Hemolytic effect was shown at high concentrations (10(-4) g/ml) but no effect on the coagulation was found. No significant effect of THP was observed on the general behavior and central nervous system, autonomic nervous and peripheral nervous systems. Also, THP had no significant effect on gastrointestinal propulsion in mice, the mucous membranes of the stomach and duodenum of rats, or gastric acid and bile secretion in rats.

This paper describes effects of (2"R)-4'-O-tetrahydropyranyladriamycin hydrochloride (THP) on perinatal and postnatal rats. The drug was administered intravenously to female rats at 0.01, 0.03 or 0.1 mg/kg daily from day 17 of pregnancy to 21 days after delivery. Results were described below. At any dose levels tested, THP did not affect the body weight gain, food and water consumption by pregnant rats, and length of gestation period or delivery rate. However, at the highest dose level, THP decreased spleen weight. THP, at any dose levels, did not have toxic effect on development, physiological functions, behavior, mating, fertility or pregnancy of the first generation offspring (F1). At the highest dose of 0.1 mg/kg, however, THP produced delayed ossification of sacrococcygeal vertebra in the second generation fetuses (F2). The results suggest that the maximum "no effect" dose of THP to pregnant rats and offsprings is 0.03 mg/kg/day intravenously.

This paper describes the embryotoxicity and teratogenic effects of (2"R)-4'-O-Tetrahydropyranyladriamycin (THP). The drug was administered intravenously to female rats at 0.01, 0.03, 0.1 or 0.3 mg/kg daily from day 7 to day 17 of pregnancy and to female rabbits at 0.01, 0.05 or 0.1 mg/kg daily from day 6 to day 18 of pregnancy. Results were summarized as follows. Rats THP, at the highest dose of 0.3 mg/kg, decreased body weight gains of pregnant females. This dose caused a decrease in body weights of fetuses, tendencies to increase the rate of death of fetuses or of resorption, an increase in the number of lumbar vertebrae and a delayed ossification of forelimbs of fetuses. Other parameters were not affected by THP at any dose levels. At any dose levels, THP did not produce external, visceral or skeletal malformations in the offspring (F1), nor did it affect the development, physiological functions, behavior, mating, fertility or pregnancy of the offspring. However, at the highest dose level, THP decreased the weight of testes of the offspring. The results suggest that the maximum "no effect" dose level of THP to pregnant females and offspring is 0.1 mg/kg/day intravenously. Rabbits The highest dose of THP, 0.1 mg/kg, decreased the consumption of food and water by pregnant females, but at any dose levels, it did not affect their body weight gain. THP did not cause teratological effects such as external malformation or visceral and skeletal anomalies in the fetuses at any dose levels tested. The results suggest that the maximum "no effect" dose of THP is 0.05 mg/kg/day intravenously to pregnant females and above 0.1 mg/kg/day intravenously to fetuses.

The effect of a new antitumor antibiotic on the fertility was studied using SD rats. (2"R)-4'-O-Tetrahydropyranyladriamycin (THP) was administered to each rat at 0.01, 0.03 or 0.1 mg/kg daily. Males were given the drug intravenously for 63 days prior to mating and during the mating period; females were given the drug intravenously from 14 days prior to mating until day 7 of pregnancy. All the pregnant rats were sacrificed on day 20 of pregnancy, followed by external, visceral and skeletal observations of their fetuses. Results were summarized as follows. THP, at 0.1 mg/kg, suppressed body weight gain in females during the late period of pregnancy but did not affect body weight gain in males. THP, at 0.1 mg/kg, increased the numbers of dead fetuses and of resorptions. It caused no external, visceral or skeletal anomalies at any dose levels. The results suggest that, in rats, the maximum "no effect" dose of THP is 0.03 mg/kg/day intravenously regarding fertility and fetal development.

The efficacy of anticancer drugs and the development of drug resistance after chemotherapy for advanced breast cancer has been evaluated in vitro using the human tumor clonogenic assay (in vitro colony assay technique.) The rates of in vitro chemosensitivity to various anticancer drugs in untreated patients were similar or somewhat higher than the clinical efficacy reported for single clinical use of the drugs. The results of in vitro chemosensitivities to the drugs against previously treated patients showed decreased chemosensitivities to the drugs which had been used, especially adriamycin and mitomycin C. In contrast to this, in vitro chemosensitivities to 5-FU, methotrexate and L-PAM were unchanged after exposure to combination chemotherapy consisting of these drugs. This result suggests that the development of resistance to these drugs is minimal at the doses used in our protocol. The overall chemosensitivity rate for anthracyclines including adriamycin in vitro was only 5% (5/93) for previously treated patients, compared with 41% (35/83) for vinca alkaloids (p less than 0.005). This finding indicates that combination chemotherapy including vinca alkaloids is the appropriate selection for second line chemotherapy for advanced breast cancer patients who have been treated previously with adriamycin.

Subrenal capsule assay(SRC assay) has been reported to be an effective and rapid method for predicting the tumor sensitivity of individual patients to anti-cancer agents. In order to establish a more objective method of determining sensitivity in SRC assay the DNA content was measured by the schmidt-Thannhauser-Schneider method and the protein content was estimated using Bio-Rad protein assay, after removal of a tumor implanted in the subrenal capsular space of ddY mice. Percentage inhibition of DNA/protein had a high correlation with that of relative increase of tumor weight, although three groups treated with mitomycin-C, 5-fluorouracil and cyclophosphamide indicated different values of tumor sensitivity. From these results, the percentage inhibition of DNA/protein seems to be more objective than microscopic measurement for predicting tumor sensitivity.