Inhibitory effects of prostaglandin A2 on c-myc expression and cell cycle progression in human leukemia cell line HL-60.

The effect of prostaglandin A2 (PGA2) on c-myc expression was investigated in a human promyelocytic leukemia cell line, HL-60, which responded to PGA2 with a dose-dependent growth inhibition. Northern blot analysis indicated that treatment with PGA2 at 0.5 to 5.0 micrograms/ml remarkably reduced the steady state level of c-myc mRNA within 3 h, and then it gradually recovered according to the order of concentration of the drug. In contrast to c-myc, the level of class I HLA mRNA, as an internal control, was not diminished by PGA2 treatment. Further, this reduction of c-myc was not disturbed by cycloheximide, suggesting that this PGA2 action on c-myc expression is independent of de novo protein synthesis. Cytofluorometric analysis revealed that the exposure of HL-60 cells to PGA2 at 0.5 or 5.0 micrograms/ml arrested the cells in the G0-G1 phase of the cell cycle. This accumulation of the cells in G0-G1 phase continues until 24 or 36 h at 0.5 or 5.0 micrograms/ml, respectively. The G0-G1 arrest of the cell cycle was also recovered as the inhibition of c-myc was released. This recovery may be due to the loss of activity of PGA2 in culture medium. This study clearly showed that PGA2 treatment arrested HL-60 cells in the G0-G1 phase of the cell cycle and was associated with the reduction of c-myc mRNA.

Novel responses of peripheral lymphocytes of cancer patients to chemical induction of sister chromatid exchanges.

Sensitivities to sister chromatid exchange (SCE) induction by chemicals of peripheral lymphocytes from 26 cancer patients were estimated under conditions identical to those for healthy humans which had been reported (Cancer Res., 43: 439-442, 1983). The sensitive individual was defined as one whose cells give a mean induced SCE frequency more than 2 standard deviation units above the population mean of induced SCEs in cells from the healthy humans. When cells were treated with 3-amino-1-methyl-5H-pyrido[4, 3-b]indole in the presence of rat liver S9 mix, 8 in 10 stomach cancer patients, 4 in 4 colon cancer patients, 3 in 9 lung cancer patients, 0 in 3 patients bearing other cancers, and 0 in 9 non-cancerous individuals were sensitive. The corresponding frequency of individuals in the healthy population, reported previously, was 1 in 33 persons. Thus, the frequency of sensitive individuals in the combined group of stomach and colon cancer patients was very significantly higher than were frequencies in control groups. Three in 10 patients with stomach cancer and 4 in 16 patients with other cancers were sensitive to induction of SCE by methyl methanesulfonate. Six in these 7 methyl methanesulfonate-sensitive patients were also 3-amino-1-methyl-5H-pyrido[4,3-b]indole sensitive. The frequency of methyl methanesulfonate-sensitive individuals in the healthy populations was 2 in 50. There was no patient who was sensitive to SCE induction by 4-nitroquinoline 1-oxide. The frequency was not significantly different from the healthy population, in which 3 in 50 persons were sensitive. These results suggest that a particular cancer correlates with the sensitivity of peripheral lymphocytes to SCE induction by particular chemicals.

Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer. CPT-11 Gastrointestinal Cancer Study Group.

PURPOSE: A phase II study was conducted to evaluate the antitumor effect and toxicity of CPT-11 in patients with metastatic colorectal cancer. PATIENTS AND METHODS: From December 1989 to March 1991, 67 patients with metastatic colorectal cancer were enrolled in this study. Sixty-three patients were assessable for toxicity and response. Their median age was 57 years (range, 24 to 72). Forty-six patients (73%) had a good performance status of 0 or 1. Fifty-one patients (81%) had received prior chemotherapy. The major sites of metastasis were liver (63%) and lung (44%). CPT-11 was administered as a 100 mg/m2 weekly intravenous infusion, or as 150 mg/m2 every 2 weeks. The dose was reduced based on the grade of leukopenia and diarrhea, if necessary. RESULTS: A partial response was obtained in 17 of 63 assessable patients (27%; 95% confidence interval, 16% to 38%). The response rate in patients with prior radiotherapy or chemotherapy was 25% (13 of 52). Liver metastases showed a 15% (six of 40) response and lung metastases showed a 39% (11 of 28) response. The median duration of partial response was 127 days (range, 49 to 353) and the median overall duration of response was 208 days (range, 99 to 381). The major toxicities (> or = grade 3) were leukopenia (16%), diarrhea (13%), nausea and vomiting (13%), and alopecia (11%). Adverse effects were generally well tolerated and reversible. Treatment could be continued on an outpatient basis for patients without severe toxicity. Hemorrhagic cystitis was not encountered in this study. CONCLUSION: CPT-11 showed promising antitumor activity against metastatic colorectal cancer that was resistant to prior therapy. Further clinical trials of combination chemotherapy using CPT-11 are justified.

Accumulation of 2-deoxy-2[18F]fluoro-D-glucose in human cancers heterotransplanted in nude mice: comparison between histology and glycolytic status.

UNLABELLED: The success of tumor imaging with PET and 2-deoxy-2-fluoro[18F]-D-glucose (18FDG) is based on preferential accumulation of 18FDG in tumors. METHODS: Fluorine-18-FDG uptake was measured in nine human cancers heterotransplanted in nude mice and compared with histologic subclassification. RESULTS: Mean 18FDG uptake by the human cancers was considerably less than that by the host's heart, but values at 60 min after injection were about 2.5 times as high as the liver and kidney, about two times as that for the muscle and about six times that for the blood. Comparison of 18FDG uptake and histological grade in four gastric, two pancreatic and three colonic cancers showed that 18FDG uptake increased with loss of differentiation. CONCLUSION: This nude mice model system is useful for studying correlations between physiological and morphological parameters of heterotransplanted human cancers.

The inhibitory effects of 5-fluorouracil on the metabolism of preribosomal and ribosomal RNA in L-1210 cells in vitro.

Addition of 5FU to the culture medium of mouse L-1210 cells resulted in inhibition of the maturation process of ribosomal RNA precursors in vitro. In the presence of 10(-6) M 5FU for 2 h, the 45S preribosomal RNA was processed to 32S preribosomal RNA, but 28S rRNA was not produced. The processing to 18S rRNA was intact at this drug concentration. Higher concentrations of 5FU for a longer incubation period affected the RNA processing more severely. At 10(-5) M of the drug for 24 h the processing to 28S rRNA and 32S preribosomal RNA. When the cells were labeled with 14C-UR for 2 h following 3H-5FU at 10(-6) M for 24 h, the radioactivities of newly synthesized RNA labeled with 14C-UR accumulated in the region of 45S and 32S preribosomal RNA, and no processing to 28S rRNA was observed. Radioactivity corresponding to 3H-5FU did not persist in the preribosomal RNA region, because further maturation proceeded in the condition of depletion of 5FU after the long incubation period. Thus, inhibition of the processing of preribosomal RNA to 28S rRNA was not brought about by the accumulation of 5FU-substituted 45S preribosomal RNA, but by some other, yet unknown, mechanism.

Comparative studies on the action of 7-N-[2-[[2-(gamma-L-glutamylamino)ethyl]dithio]ethyl]mitomycin C and of mitomycin C on cultured HL-60 cells and isolated phage and plasmid DNA.

The mechanism of action of a new mitomycin C (MMC) derivative, KT6149, was studied in human leukemia HL-60 cells and in isolated phage and plasmid DNA, and its effects were compared with those of MMC. Cell growth was markedly inhibited by KT6149, with an IC50 of 2 x 10(-9) M, that for MMC being 2 x 10(-8) M. DNA synthesis of HL-60 cells as determined by incorporation of [3H]-thymidine was also inhibited by KT6149, with an IC50 of 2 x 10(-7) M as compared with 2 x 10(-6) M for MMC. RNA and protein synthesis were less markedly inhibited at low concentrations. Alkaline sucrose density-gradient centrifugation revealed a significant decrease in sedimentation velocity for cellular DNA of the cells after 1 h treatment with KT6149 at concentrations higher than 10(-7) M. In contrast, no such change was observed for DNA of cells treated with MMC, even at a concentration of 10(-5) M. In a cell-free system, analysis by agarose gel electrophoresis patterns showed that the drug induced a decrease in the amount of covalently closed circular DNA of phage PM2 and an increase in that of open circular DNA in the presence of dithiothreitol (DTT), whereas MMC did not cause any change in DNA subfraction amounts. Furthermore, the electrophoretic mobility of linearized pBR322 DNA in alkaline agarose gel was significantly decreased by KT6149 in the presence of DTT and FeSO4, no such change being observed in the case of MMC. The results clearly indicate that the inhibitory effects of KT6149 on the growth and DNA synthesis of HL-60 cells are more potent than those of MMC and that KT6149-induced DNA damage is due to single-strand scission and to cross-linking of DNA, suggesting a mode of activation different from that of MMC.

The mechanism of action of quinocarmycin citrate (KW 2152) on mouse L1210 cells in vitro.

The effects of the antitumor antibiotic, quinocarmycin citrate (KW 2152), on L1210 cells were studied in vitro. The cellular growth was completely inhibited at 10(-6) M KW 2152, and after 2 days no viable cell was seen. The incorporation of 3H-thymidine, 3H-uridine, or 3H-leucine into the acid-insoluble fraction was not affected at 10(-4) M for 1 h; however, when the cells were treated with 10(-6) M for 24 h, the radioactivity appearing in the acid-insoluble fraction was reduced to 20%, 30%, and 48%, respectively, of the control. The single strand scission of the DNA of L1210 cells was seen at 10(-7) M for 24 h, as revealed by an alkaline, sucrose density gradient. However, no damage to plasmid pBR322 was observed even at 10(-6) M KW 2152 for 24 h, as revealed by 0.8% agarose gel electrophoresis, indicating that some soluble factors of the cells might contribute to the damage to the DNA of L1210 cells. The processing of pre-rRNA of the cells was not inhibited at 10(-6) M of the drug for 24 h of incubation.

Phase II study of NK313 in malignant lymphomas: an NK313 Malignant Lymphoma Study Group trial.

Liblomycin (NK313) is a bleomycin analog that has proved to be associated with less pulmonary toxicity and with more potent antitumor activity than bleomycin in animal tumors. In a phase I study, pulmonary toxicity was not observed, whereas myelosuppression was the dose-limiting factor. The maximum tolerated dose was 140 mg/m2 given once a week for 4 weeks. In the present phase II study, patients with malignant lymphomas received liblomycin at 80 or 100 mg/m2 by intravenous infusion over 15 min once a week for 4 weeks. A total of 39 patients were entered, and 31 [4 with Hodgkin's disease (HD) and 27 with non-Hodgkin's lymphoma (NHL)] were evaluable. The median age of the patients was 52 years (range, 22-74 years), and their performance status ranged from 0 to 3. In all, 28 of the patients had a history of intensive anticancer chemotherapy. Responses were evaluated according to WHO criteria. We obtained 1 complete remission and 9 partial remissions (PRs), for an overall response rate of 37%, in the 27 patients with NHL, whereas 1 PR was achieved in the 4 patients with HD. In all, 9 PRs (32.1%) were obtained in patients who had been exposed to prior chemotherapy, including 4 PRs (33.3%) in 12 patients who had previously been treated with bleomycin. Myelosuppression and nausea and vomiting were the major toxicities, which occurred in about 50% of the patients, and myelosuppression was severe in two patients treated at a dose of 100 mg/m2. We concluded that liblomycin demonstrated significant antitumor activity against malignant lymphomas.

[Therapeutic evaluation of combination therapy using C-425, human native immunoglobulin liquid preparation for i.v. administration, with antibiotics in severe infections in the field of internal medicine].

A novel human native immunoglobulin liquid preparation for intravenous injection, C-425, was used in combination with antibiotics to study its efficacy, safety, and usefulness in 262 patients with severe infections which had not responded to antibiotic therapy of 3-day or more duration. As a result of the Committee judgement, 12 of the 262 patients were excluded from this study; 87 were included only in safety analysis; 163 (62.2%) were included in efficacy, safety, and usefulness analyses (complete inclusion). The complete analysis of 163 patients consisted of 93 patients (57.1%) with suspected septicemia, 33 (20.2%) with pneumonia, and 18 (11.0%) with septicemia. Eighty percent or more of the patients had severe underlying diseases such as leukemia and malignant lymphoma. Clinical efficacy of C-425 was judged by the doctors in charge to be "excellent" or "good" in 49.1% of the total cases. The rate of effectiveness was calculated at 74.8% when "excellent", "good" and "fair" cases were all included. Similarly, the rate of effectiveness calculated from the results of Committee judgment was 53.4% when "excellent" and "good" cases were included, and 68.7% when "excellent", "good" and "fair" cases were included. Microbiological assessment was conducted in 19 patients. Causative organisms were eliminated in 11 patients, decreased in number in 1, persisted in 5, and replaced in 2. The rate of elimination was 57.9%. Side effects appeared in 6 of 250 patients (2.4%). It was judged that 3 patients (1.2%) of the 6 were affected by the drug or suspected to be affected, but they were not considered clinically important. Hepatic disfunction was found in 4 patients (1.6%) of the 250; but it was not clarified whether this was related to the drug. From these results, C-425 was considered to be an effective and very safe drug for treating severe internal infections.

[Chemotherapy of scirrhous gastric cancer].

Cancer chemotherapy plays a central role in the treatment of recurrent or unresectable scirrhous gastric cancers classified mainly as Borrmann type 4. Though we have no specifically effective drugs for scirrhous gastric cancer, 5-FU and its derivative, MMC, anthracyclines, CDDP, CQ and ACNU are known to be relatively effective single agents against this tumor. In an attempt to enhance the effect of single agents, several combined chemotherapy regimens have been devised and tested. These regimens included 5-FU + MMC, UFT + MMC, UFT + CDDP, MTX.5-FU, FAM, FAP, EAP and ELF regimen. At present, combined therapies using 5-FU and MTX or CDDP may be the most attractive of these combined regimens.

[Electrolyte abnormalities associated with cancer: a review].

There are a variety of water and electrolyte disorders in patients with cancer. These disorders occur during the growth of tumors, generally as a consequence of inadequate intake and absorption of electrolytes, renal failure secondary to tumor or rapid tumor destruction and production of metabolically active substances by the tumor. In this paper, the electrolyte abnormalities associated with cancer were reviewed. Hyponatremia is one of the most common clinical electrolyte abnormalities in advanced cancer. Some patients may have hyponatremia, in spite of increased total body sodium and absence of a defect in water diuresis. This status is designated as "sick cell syndrome" or "essential hyponatremia". In addition, the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in association with various tumors has been described. This syndrome is principally due to water retention, but can also be due to continuous urinary loss of sodium, and hypo-osmolality. Hypercalcemia is associated with coexistent primary hyperparathyroidism, prostaglandin (PGE2) or osteoclast-activating factor. It now seems likely that ectopic PTH is rarely the cause of hypercalcemia in nonparathyroid cancer. There are no data supporting the ectopic production of vitamin D-like substance as an important factor in the hypercalcemia of cancer. There are three general categories in which patients with hypercalcemia and cancer may be placed: those with bone metastases, those without bone metastases of solid tumors and those with hematologic malignancies. Hypokalemia is associated with ectopic ACTH- and insulin--producing tumors, and is often found in patients with mucin-secreting, potassium-losing adenocarcinoma of the colon.

[Drug administration in combination for management of cancer].

The use of drugs in combination for the management of cancer patients aims at the increased therapeutic advantage by elimination the problem of the heterogeneous sensitivity of cancer cells to anticancer drugs, and by delaying or preventing the development of drug resistance within given tumors. Theoretically, the effects of drugs in combination are classified as antagonistic, subadditive, additive and synergistic. Since these results hold for both tumors and hosts, the effects of combined drugs should be considered in terms of therapeutic index. From this viewpoint, the choice and administration schedule of drugs in combination must be synergistic or additive for the tumors and antagonistic or subadditive for the hosts in regard to combined effects. Thus, the rationale for combined drug therapy should be considered from the aspects of biochemical basis, drug resistance, cytokinetic and pharmacologic rationales, and toxicologic basis.

[Cancer chemotherapy with special reference to pharmacokinetics of nitrosoureas].

This paper provides an overview of cancer chemotherapy with special reference to the pharmacokinetics of the nitrosoureas. At physiological PH, the chloroethylnitrosoureas can be decomposed into an isocyanate and 2-chloroethyl diazene hydroxide. Therefore, it is clear that they have both alkylation and carbamoylation actions. In addition to the spontaneous chemical dissociation, the nitrosoureas can be metabolized by liver microsomal enzymes to more polar hydroxylated products, and certain nitrosoureas can be denitrosated by these enzymes to the parent urea. Since the lipid-soluble nitrosoureas and some of the water-soluble nitrosoureas such as ACNU and MCNU demonstrated to cross the blood-brain barrier, they have been used in the treatment of primary brain tumors and tumors and tumors of metastatic origin. It has been demonstrated from the results of our study and other reports that the alkylation of DNA by ACNU progresses more slowly as compared with that of other alkylating agents. This is an important finding in relation to the appearance of delayed myelosuppression of the nitrosoureas and in the design of dose schedules of these agents. The major clinical emphasis has been directed towards the more active chloroethylnitrosoureas with reduced myelosuppression, and attempts are now made for this purpose. Unfortunately, the results of phase I and II trials of the newly developed nitrosoureas suggest that these agents produce delayed and cumulative bone marrow toxicity. Antitumor activity of the nitrosoureas is frequestly observed in chronic myelocytic leukemia, malignant lymphoma, brain tumors and small cell carcinoma of the lung, and less frequently in gastrointestinal carcinoma, multiple myeloma and malignant melanoma. In order to enhance clinical effects of the nitrosoureas, further investigation of the design in therapeutic schedules on the basis of their pharmacokinetic characteristics will be needed.

[Cooperative research of UFT E phase II study. Cooperative Study Group of UFT E in Tohoku Area].

Phase II clinical research of UFT E granules (enteric coated) was carried out in 18 institutes (21 clinical dept.) by Study Group of UFT E in Tohoku Area, to investigate its effect and safety on cancer of the digestive organs. Of all the registered 26 cases, 21 cases were available for evaluation (perfect cases: 17 and imperfect cases: 4). Patients were administered UFT E 600 mg/body/day in principle. The response rate of the overall 26 cases was 14.3% and that of perfect 17 cases was 17.6%. PR was seen in 2 cases with far advanced gastric cancer and in 1 case with sigmoid colon cancer metastasized to lung, NC in 8 cases and PD in 6 cases. Side effects more than Grade II were seen in 4 cases (19%), of which 1 case caused diarrhea with leucopenia, 1 case caused diarrhea with anorexia, fever, pigmentation, stomatitis and general tiredness, 1 case caused anorexia and the other 1 case caused paresthesia on both legs with diarrhea and anorexia. Side effects in upper digestive tract were slight, making it possible to continue administration. But 1 case, which caused simultaneously Grade II anorexia, Grade II diarrhea and Grade III paresthesia on both legs, refused administration and dropped out. He recovered from those symptoms 5 days after discontinuance of administration. UFT E is able to administer for a long term because of its slight side effects on the upper digestive tract.

[Mechanism of action of anti-cancer drugs from the viewpoint of RNA metabolism].

The mechanism of action of anti-cancer drugs, especially 5-FU, was discussed on the basis of RNA metabolism. After its incorporation into cells, 5-FU is metabolized through the uracil pathway, and finally incorporated into various species of RNA. On the other hand, 5-FU metabolized to FdUMP forms a covalent ternary complex among TS and mTHF, and inhibits de novo TMP synthesis, resulting in the inhibition of DNA synthesis. However, 5-FU was found to exert an effect on TS- mutant FM3A cells which was almost as lethal as the effect on wild-type FM3A cells in the presence of thymidine. Therefore, this lethal effect could be attributable to the inhibition of RNA metabolism, rather than DNA metabolism. The effects of 5-FU on RNA metabolism in L1210 cells are as follows: (1) inhibition of the processing of preribosomal RNA to ribosomal RNA (2) inhibition of the synthesis of poly(A) RNA of mRNA (3) inhibition of tRNA methylation (4) impaired synthesis of snRNA, U4, U6. (5) inhibition of pre-rRNA methylation (6) enhancement of poly(A) RNA translation. With reference to the items listed above, a discussion was made on the basis of our experimental results.

[Prognostic factors affecting survival of advanced gastric cancer patients on cancer chemotherapy].

Diverse factors which affect survival of advanced gastric cancer patients after the initiation of chemotherapy were investigated for 487 cases hospitalized in our department from 1963 to 1984 using Cutler & Ederer's Life Table Analysis Method. The patients from 1978 to 1984 survived longer than those from 1963 to 1972 and from 1973 to 1977. The survival was prolonged significantly in the cases with localized tumors, histology of well- or moderately-differentiated carcinomas and better performance status (PS), and in the cases receiving combined chemotherapy with BRM or in those responsive to cancer chemotherapy. The patients receiving the regimen with fluoropyrimidines, anthracyclines or BRM survived longer than those without these drugs. The survival rate, with the passage of years stated above, tended to improve even in cases with unfavorable prognostic factors such as un-resectable primary lesion, over 60 years of age, extensive tumors or PS3 and PS4. The similar change in survival rate was observed in the cases with chemotherapy + BRM treatment, in those receiving fluoropyrimidines, and MMC or other alkylating agents. The favorable prognostic factors detected in our studies were similar to the ones found in the past reports. Even in the cases with unfavorable prognostic factors the improvement in survival rate was made with the passage of years. We are encouraged by the results obtained, which suggest the progress of cancer chemotherapy.

[Pharmacokinetic studies on fluorinated pyrimidine in cancer cell and tissue].

A number of the studies on pharmacokinetics of fluorinated pyrimidines have been precisely reported. In mice bearing Ehrlich ascites carcinoma, 5-FU showed highest concentration in the lung and kidney immediately after i.v. administration of 5-FU, and in the liver, it showed rather lower concentration but for a longer period. 5-FU in blood was transferred into ascites fluid rapidly, and thus, the level of 5-FU in ascites fluid became higher than that in blood. FT is a masked compound of 5-FU, having a tetrahydrofuryl group. Drug metabolizing enzyme, natural degradation, and thymidine phosphorylase are considered to be responsible for the molecular conversion of FT into 5-FU. In order to increase the level of drug metabolizing enzyme, P450 in the liver of tumor bearers, of which P450 level was extremely lower as compared to normal individuals, phenobarbital was very effective from our previous experiment. Clinically, phenobarbital 200mg/day for 3 successive days was administered in prior to FT, and a better response was obtained than FT alone. Prevention from degradation of 5-FU in the liver by uracil kept higher level of 5-FU in blood. HCFU and 5'DFUR are also masked form of 5-FU and are converted to 5-FU in the liver.

[Cancer chemotherapy in combination with angiotensin-induced hypertension].

It was observed experimentally that rise of the mean arterial blood pressure to about mmHg by angiotensin II resulted in a marked increase in blood flow in tumor tissue without increasing blood flow in normal tissue, such as the liver, brain, bone marrow and subcutis. This result clearly indicated the lack of autoregulation of blood flow in tumor tissue. Considering the physiological characteristics of microcirculation in tumor, it is possible to selectively increase tumor blood flow without affecting blood flow in normal tissues. This finding could be applied to cancer chemotherapy for enhancing drug delivery to tumor tissue selectively. Thus, based on these experimental results, clinical studies have been performed in 86 patients with various advanced cancers. Among 72 evaluable patients, there are 8 complete and 26 partial responders with an overall response rate of 47.2%. Nine of 19 patients with gastric cancer responded to the therapy. The clinical procedure and apparatus using in this treatment were described together with technical precaution.

[Clinical studies on induced hypertension chemotherapy based on functional characteristics of microcirculation of tumor vessels].

Selective increase in blood flow in tumor tissue by elevation of blood pressure induced with angiotensin II was observed, but no increase was noted in normal but tissue in rat. This result was found to be the cause of the lack of autoregulation of blood flow system in tumor tissue. This finding was clinically applied to cancer chemotherapy for enhancing drug delivery to tumor tissue selectively. Since 1978, clinical trials on induced hypertension chemotherapy (IHC) have been performed in 102 cases with various advanced cancers based on the results of animal experiments. A three-drug regimen with adriamycin, 5-FU and mitomycin C or adriamycin, vincristine and carboquone was mainly used in this study. Among 84 cases acceptable for evaluation, the treatment was evaluated as CR in 8 cases and PR in 33 cases. The overall response rate was 48.6%, and the response rate for carcinoma of the stomach was 50.0% (9/18). In the randomized controlled study, a marked enhancement of the clinical response rate for stomach cancer was observed as follows; 42.9% for IHC and 10.5% for the controls. Furthermore, the clinical response to IHC could dated earlier by this method. in earlier period after the onset of the treatment. From these results, it was concluded that IHC provides a new approach to cancer chemotherapy in method of its increase in drug delivery to tumor tissues selectively.

[Clinical study on angiotensin-induced hypertension chemotherapy (IHC)].

It has been found in experiments using rats that there is a lack of autoregulation of blood flow in tumor vessels and a selective increase of blood flow under angiotensin II-induced hypertension when the arterial blood pressure dose not exceed 150 mmHg, while there is no increase in normal tissues (Suzuki et al., JNCI:1981). On the basis of the functional difference of microcirculation, IHC has been developed clinically since 1978. In the procedure of treatment, the mean blood pressure of the patients was maintained at 140-150 mmHg when anti-cancer drugs were administered along with the continuous intravenous infusion of angiotensin II. In a randomized controlled study on gastric carcinoma treated with an AFM regimen, the response rate was 42.5% (8/21) in IHC vs. 10.5% (2/19) in non-IHC (p less than 0.05). The "initial response time" (15.5 vs. 28.8 days) and the "effective tumor reduction time" (36.7 vs. 57.5 days) were significantly shorter (p less than 0.01) in the IHC group. Frequency and grade of side effects were not different statistically. In an open trial, the overall response rate was 39.6% (54/134) and each response was closely related to the difference of drug sensitivity of tumor types. For example, it was 90.0% (9/10) in cancers of the head & neck, 66.7% (4/6) in the breast, 42.8% (12/28) in the stomach, 46.2% (6/13) in the pancreas, 23.1% (3/13) in the colon and 23.8% (5/21) in the lung. The effect on metastatic lymphnodes was 79.4% (27/34), which was higher than that of primary (48.1% : 26/54) and other organ metastases (34.6% : 18/52). Finally, this paper dealt with the problem of clinical evaluation of tumor lesions with a lot of fibrous granulation tissue and coagulative necrosis, and of the investigation of differential imaging.