Comparative studies of effects of carbazilquinone and mitomycin C on DNA, RNA and protein synthesis of Yoshida sarcoma and Yoshida ascites hepatomas.
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Animals↗
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Stimulation of microsomal NADPH oxidation by quinone group-containing anticancer chemicals.
Several anticancer chemicals containing a quinone group were found to stimulate the aerobic oxidation of NADPH by liver microsomes. The enzyme responsible for the above reaction was identified as NADPH-cytochrome c reductase (EC 1.6.2.4), one of the microsomal flavoproteins. The fact that a catalytic amount (20 micronM) of these anticancer chemicals was sufficient to oxidize all the NADPH (100 micronM) indicates that they function as electron carries from the flavoprotein to molecular oxygen. As a corollary, Mitomycin-C and Carbazilquinone stimulated oxygen uptake by Ehrlich ascites tumor cells in the presence of glucose that Daunomycin and Adriamycin failed to do so, although the reason for it remains to be elucidated. Carbazilquinone, in contrast to others, also stimulated the microsomal NADH oxidation.
Animals↗
Generation of free radicals of quinone group-containing anti-cancer chemicals in NADPH-microsome system as evidenced by initiation of sulfite oxidation.
The prerequisit of reduction for activation of Mitomycin-C and unstability of its reduced form suggested investigation of the possible formation of free radicals (semiquinone forms) of a series of quinone-containing anticancer chemicals in vitro. The ability of rat-liver microsomes to initiate sulfite oxidation in the presence of NADPH was markedly enhanced by the addition of these chemicals. This strongly suggests that these chemicals participated in the process in the form of reactive free radicals. The reaction was specific for NADPH. Carbazilquinone was unique among others in that NADH can replace NADPH and its higher ability to initiate sulfite oxidation. Microsomes from Ehrlich ascites and AH-109A hepatoma cells were also effective, though to a lesser extent than those from rat liver on a protein basis. Generation of free radicals, though their biological significance is not clear at present, may be deemed an inherent chemical property of these chemicals.
Animals↗
Beta-glucuronidase activity of Yoshida ascites hepatomas of different drug-sensitivity and its change after treatment of host rats with various anticancer agents.
Change in beta-glucuronidase activity of six Yoshida ascites hepatomas was examined after treatment of host rats with one of 12 anticancer agents. The hepatomas, AH-66F, AH-130, AH-109A, AH-60C, and AH-44, in decreasing order showed more or less distinct increase in beta-glucuronidase activity after treatment of the rats with Nitromin, Endoxan, 864-T, Carbazilquinone, Mitomycin-C, Toyomycin, Daunomycin, Neocarzinostatin, vincristine sulfate, 5-fluorouracil, or cytosine arabinoside only when the cytological effect was positive. Moreover, degree of the increase was generally correlated with that of cytological effect. Bleomycin was ineffective either enzymically or cytologically. AH-66 was insensitive to any of the agents tested in increasing beta-glucuronidase activity and showed only a very slight cytological response to some of the agents. Acid deoxyribonuclease behaved like beta-glucuronidase but to a lesser extent. The above order of drug sensitivity of the hepatomas was not in parallel with that of normal beta-glucuronidase level, which also did not correlate with the life span of host rats.
Animals↗
Temporary interruption of regional blood flow combined with local hyperthermia for cancer chemotherapy.
A striking chemotherapeutically curative effect on tumor was obtained by means of temporary interruption of regional blood flow combined with local hyperthermia. By analyzing various basic conditions required for this system using Ehrlich tumor implanted in the hind limbs of mice, the following were found to be essentially indispensable to obtain satisfactory chemotherapeutic effects: (a) a time interval of 1 to 3 min after systemic i.v. administration of drug to the mice, (b) use of a tourniquet on the tumor-bearing mouse limb to stop blood flow, and (c) warming at 37-41 degrees (d) for a period of at least 30 to 60 min. Among the chemotherapeutic drugs tested in the present study, Carbazilquinone (NSC 134679) was the most effective because it revealed the strongest antitumor effect despite its relative innocuousness to nontumorous adjacent normal tissues. Applying the present method, a large syngeneic mouse sarcoma transplanted to the limb 7 days before the experiment also completely regressed in 6 of 9 mice.
Animals↗
Synthetic analogs of antitumor drugs under development in Japan.
Synthetic studies on new antitumor drugs in Japan are mainly oriented toward analogs of known active structures. In the nitrosourea area ACNU, a pyrimidine analog of CCNU, is currently under clinical investigation and has myelosuppression as a side effect Nitrosoureas with a sugar moiety are of great interest and two compounds called GANU and MCNU are now ready for phase I study in Japan. Among new alkylating agents are included a series of bis-methanesulfonate of aminoglycols, an analog of cyclophosphamide called 4-hydroperoxy-cyclophosphamide, and aziridine derivatives which include the now commercially available carbazilquinone. In the antimetabolite field cyclocytidine is an analog of arabinosyl cytosine which has been extensively studied. A newer analog called N4-behenoyl-cytosine arabinoside is now being studied experimentally. In the fluorinated pyrimidine area Ftorafur has been extensively studied and a new compound FD-1 is of interest.
Alkylating Agents↗
Combination chemotherapy of 6-thioguanine with various antitumor agents against murine leukemia L-1210.
Antitumor activity of 6-thioguanine against L-1210 leukemia was studied in combination with various antitumor agents in clinical stages, such as mitomycin-C, carbazilquinone, cyclophosphamide, 3,3'-dimesyloxydipropylamine tosylate (864T), 4-hydroperoxyisophosphamide, and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chlorethyl)-1-nitrosourea hydrochloride (ACNU). The combination treatments with 6-thioguanine and each of six agents, especially with ACNU, showed a distinct therapeutic effect against the early L-1210 leukemia at dosage levels not producing any significant antitumor activity with each agent alone (ip-ip). The excellent antitumor activity of the combination of 6-thioguanine with ACNU was also proved in various sites of tumor inoculation and routes of drug administration systems, i.e., ip-iv, iv-ip, and iv-iv systems. Moreover, the effectiveness of the combination of these two drugs was clearly shown against advanced L-1210 leukemia which was refractory to each agent alone.
Animals↗
Mutagenicity of several classes of antitumor agents to Salmonella typhimurium TA98, TA100, and TA92.
The mutagenic activities of antitumor agents, including 5 antibiotics, 19 antimetabolites, 5 alkylating agents, 2 alkaloids, 1 enzyme, and 1 adrenal steroid hormone, were tested on Salmonella tyhimurium TA100, TA98, and TA92. Four of these, busulfan, carbazilquinone, 1-(4-amino-2-methylpyrimidine-5-yl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride, and pipobroman were shown for the first time to be mutagenic. Further, the known mutagenicities of five others, daunomycin hydrochloride, Adriamycin hydrochloride, mitomycin C, 6-mercaptopurine, and cyclophosphamide, were confirmed.
Alkylating Agents↗
Chemosensitivity of human bladder cancer cells in long-term culture and clinical responses to the selected anticancer drug.
In vitro sensitivity of an established cell line from human urinary bladder cancer to various chemotherapeutic agents was determined by 14C-leucine incorporation into the target cells. Of 12 drugs tested, Carboquone, Neocarzinostatin, Actinomycin D, Adriamycin, Mitomycin C and Chromomycin A3 produced intensive cytotoxic effects, while Thio-Tepa, Bleomycin, 5-Fluorouracil and Vincirstine were less cytotoxic, Intravesical instillation of Carboquone, one of the most toxic agents in vitro, resulted in complete or partial tumor remission in 6 of 9 patients with bladder cancer. Prophylactic effects of periodic intravesical Carboquone were also indicated in 7 of 8 patients who had experienced recurring superficial bladder tumors.
Antineoplastic Agents↗
A recent overview of chemotherapy for advanced stomach cancer in Japan.
This paper reviews the recent chemotherapy regimens performed in Japan for advanced stomach cancer. Results from the use of single agents, combination chemotherapy and arterial infusion are presented. The overall response rate to either single or combination therapy was 30-40%. The effectiveness of chemotherapy in patients with metastatic disease was dependent on the site of metastases. The overall duration of survival ranged from 2 to 6 months. Several new approaches to treatment are discussed.
Antineoplastic Agents↗
Damage of DNA and its recovery in AH-109A cells treated with carboquone in vivo.
A single injection of carboquone at a dose of 0.1 mg/kg body weight induced damage of DNA of AH-109A cells as revealed by alkaline and neutral sucrose density gradient centrifugation. A significant decrease in the sedimentation velocity of DNA on alkaline sucrose density gradient centrifugation was observed 15 min after the injection, and it returned to that of control after 60 min. Thereafter, the size of DNA decreased progressively. When the cells were lysed with 2% sodium dodesyl sulfate solution and analyzed on neutral sucrose density gradient centrifugation, a similar change in the sedimentation velocity was observed. The results obtained from the studies of intraperitoneal growth of AH-109A cells pretreated with carboquone in vivo and the survival of host animals well corresponded to the extent of the damage of DNA as revealed by alkaline and neutral sucrose density gradient centrifugation.
Animals↗
Stimulation of a reconstituted, microsomal NADH oxidase system by carboquone, a quinoid anticancer chemical.
Carboquone was found to greatly stimulate the aerobic NADH oxidation in the presence of both the partially purified NADH-cytochrome b5 reductase and cytochrome b5 prepared from hepatic microsomes by acting as an electron carrier from cytochrome b5 to molecular oxygen. Other quinoid anticancer chemicals, mitomycin-C, adriamycin, and daunomycin practically failed to do so.
Animals↗
Electron spin resonance study on the mode of generation of free radicals of daunomycin, adriamycin, and carboquone in NAD(P)H-microsome system.
The mode of generation of free radicals of daunomycin, adriamycin, and carboquone in the NADPH-rat liver microsome system was studied at room temperature by electron spin resonance (ESR) spectroscopy. ESR signals of all these quinoid anticancer chemicals were detected when dissolved oxygen in the reaction mixture was consumed since the radicals are easilyaut oxidizable. All the radicals had an appreciable lifetime under anaerobic conditions. However, there were differences in the mode of their generation between daunomycin and adriamycin, on the one hand, and carboquone, on the other, with respect to the lag time and the effect of the amount of chemicals, pH of the medium, kind of electron donors, NADPH and NADH, and the presence of excess of DNA. Especially, ESR signal reappeared after the first signal had decreased considerably, in the case of daunomycin and adriamycin but not in carboquone. Intact Ehrlich ascites tumor cells also gave rise to an ESR signal of adriamycin and carboquone, but the former signal was prevented from appearing in the presence of glucose.
Animals↗
[Studies of carboquone therapy on chronic myelogenous leukemia (author's transl)].
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Adult↗
[Regression of a recurrent malignant glioma by combined chemoradiotherapy utilizing carboquone, FT-207 and telecobalt--report of a case (author's transl)].
Current chemotherapy of malignant brain tumor bases on cell kinetics. Chemotherapeutic agents are devided into two, cell cycle specific (CCS) and cell cycle non specific (CCNS) agents. A case of malignant glioma successfully treated by chemo-radiotherapy using a new combination of the two agents , Carboquone (CQ) as CCNS, which has not appeared in literature, and FT-207 as CCS is reported. A malignant glioma in the right frontal lobe in a case of 51-year-old male was removed subtotaly on Dec. 10th, 1971 in our clinic. Three years and five months after the surgery, the patient was diagnosed as having a recurred malignant glioma in the left frontal lobe from the clinical symptoms. This was supported by a positive brain scan and carotid angiography. A total dose of 57mg of CQ was continuously into the left internal carotid artery during two months. Simultaneously, 16g of FT-207 as a total dose was given orally and 4,550 rads of Telecobalt-60 were irradiated. One month after the beginning of these treatments, clinical symptoms improved obviously. Four months later, the size of the tumor shadow on the brain scan decreased remarkably and the shifted anterior cerebral artery returned to normal position on the carotid angiogram. Anemia, leucopenia, thrombocytopenia, nausea, and anorexia were the side-effects of these treatments. But these complications disappeared six weeks after the termination of the treatments.
Azirines↗
Potentiation of anticancer effect of carboquone in vivo by glucose pretreatment.
Anticancer effect of carboquone was notably potentiated in tumor-bearing mice when they were pretreated with 5% glucose solution in the system of blood flow-interrupting hyperthermic chemotherapy. It was further found by quantitative analysis that the potentiation was much greater than increase in the general toxicity of the drug by administration of glucose. Mitomycin-C, on the other hand, revealed no such marked effect though it is considerably similar to carboquone in chemical structure.
Animals↗
Clinical studies on the combined immunochemotherapy with a streptococcal preparation (Picibanil) and other anticancer drugs.
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Antineoplastic Agents↗
[An operated case of the lung cancer associated with the esophageal necrosis due to the bronchial artery infusion (author's transl)].
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Antineoplastic Agents↗