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Alternating immunochemotherapy of advanced gastric carcinoma: a randomized comparison of carbazilquinone and PSK to carbazilquinone in patients with curative gastric resection.

A total of 103 patients with advanced gastric carcinoma were randomized after curative surgery to receive an alternate administration of carbazilquinone (CQ) and PSK (Krestin) or carbazilquinone alone. Each course of therapies started 1 week after the surgical operation and therapy schedules consisted of 9 courses. In each course of 6 weeks, CQ (2 mg/m2/week) was administered on day 0, 8, and 15. In combined immunochemotherapy group, PSK was given orally in 3-divided doses of 2 g/m2/day from the day of the third CQ administration for consecutive 4 weeks. Estimated survival rate and cumulative survival curve were compared utilizing the data up to 7 years after the operation. There was no overall significant difference in survival rates between the CQ plus PSK group and the CQ alone group, but a group of patients whose disease was classified as S1 + S2(N1-2) survived significantly longer when treated with the combination of CQ and PSK. Neither in more advanced cases (greater than S3 or greater than N3) nor in cancers of early stages, the addition of PSK provided an additive effect. The favorable result obtained in one subgroup treated with PSK, suggests that the use of this agent in treating gastric cancers should be carefully evaluated in terms of serosal infiltration and nodal metastasis.

Adenocarcinoma↗

Anticancer drug sensitivity in vitro in the bladder cancer cell line, KK-47 and prophylactic use of carbazilquinone and urokinase in bladder cancer.

Using colony formation technique and KK-47 cell line established from a human bladder transitional cell carcinoma, the effect of 6 anticancer drugs, thio-TEPA, Bleomycin, mitomycin C, carbazilquinone, Adriamycin and cis-Platinum, were compared. On the results of tests performed to establish the drug concentration required to achive a 50% inhibition of cell survival, carbazilquinone was chosen for the prevention of recurrences of bladder cancer. The two groups studied consisted of 56 patients (previously untreated groups) who were rendered free of tumours by surgical intervention and of 19 patients (thio-TEPA failures group) who had experienced a persistent recurrence of tumours after prophylactic thio-TEPA instillations and were presumed free of the recurrence of tumours after the next surgical intervention. The 2 groups were subjected to prophylactic combined intravesical instillation therapy with carbazilquinone and urokinase. In the previously untreated group, 6 of the 56 patients (10.7%) had a recurrence of tumours, and the recurrence rate after 21 months was 16.7%, using the actuarial method. In the thio-TEPA failures group, 12 of the 19 patients (63.2%) had a recurrence of tumours, a rate at 21 months of 76.1%. A considerable drop in the recurrence rate was obtained by the combined instillation therapy in the previously untreated group. The results in the thio-TEPA failures group suggested the presence of a cross-resistance between both alkylating agents, and of a persistent susceptibility to multifocal lesions. No bone marrow depression was observed but an episode of anaphylactic shock attributable to the use of carbazilquinone occurred in 1 out of a total 75 patients.

Adult↗

Interactions of anticancer quinone drugs, aclacinomycin A, adriamycin, carbazilquinone, and mitomycin C, with NADPH-cytochrome P-450 reductase, xanthine oxidase and oxygen.

The properties of the interactions of anticancer quinone drugs, aclacinomycin A, adriamycin, carbazilquinone, and mitomycin C with nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P-450 reductase and xanthine oxidase under anaerobic and aerobic conditions were studied. Km values of NADPH-cytochrome P-450 reductase for these drugs were in the range of 40-227 microM, and that of deflavo xanthine oxidase in the range of 39-over 200 microM. Under anaerobic conditions, when xanthine was used as an electron donor, deflavo xanthine oxidase catalyzed the reductive glycosidic cleavage reaction of anthracyclines and nicotinamide adenine dinucleotide was ineffective as an electron donor. In the electron spin resonance study, the formation of the semiquinone or free radical state of the quinone drugs in both enzyme systems were evidenced. A weak and symmetric signal was obtained from aclacinomycin A, and a symmetric signal from adriamycin was changed into an asymmetric and strong. The hyperfine structure was obtained from carbazilquinone in the oxidase system. In the studies of ultraviolet-visible spectra of the quinone drugs in the reductase system, the spectra of aclacinomycin A and adriamycin were changed to their 7-deoxylaglycones, and the formation of small amounts of the fully reduced form were observed after long incubations. The spectrum of carbazilquinone was changed to the hydroquinone form and mitomycin C was converted into mitosene analogues. Under aerobic conditions, superoxide radicals and hydrogen peroxide were effectively produced in the presence of anticancer quinone drugs in both enzyme systems. The superoxide-dependent hydroxy radical production, which was measured by ethylene production from methional, was observed in the presence of aclacinomycin A and adriamycin in the deflavo xanthine oxidase system. From these results, the possible reactions in the interactions of anticancer quinone drugs with these enzymes and oxygen are discussed.

Aclarubicin↗

Generation of hydroxyl radical by anticancer quinone drugs, carbazilquinone, mitomycin C, aclacinomycin A and adriamycin, in the presence of NADPH-cytochrome P-450 reductase.

The generation of hydroxyl free radicals in the system consisting of purified NADPH-cytochrome P-450 reductase and anticancer quinone drugs, such as carbazilquinone, mitomycin C, aclacinomycin A and adriamycin, has been confirmed by two methods. In the spin trapping study, using N-tert-butyl-alpha-phenylnitrone as the spin trapping agent, four drugs generated hydroxyl radical-trapped signals, and the formation of the spin adduct was dependent on time and the enzyme concentration. Among the four drugs, the generation time of signal was in the order of carbazilquinone, aclacinomycin A, adriamycin and mitomycin C, but the magnitude of signal intensity was different. In both aclacinomycin A and adriamycin, the signal disappeared in a few minutes. Catalase completely inhibited the formation of the spin adduct, while superoxide dismutase did not significantly inhibit, but effected in some manner. The generation of hydroxyl radical was also confirmed by the ethylene production from methional. Among the four drugs, the order of the magnitude of ethylene production was different from that of signal intensity by ESR study. Catalase potently inhibited the ethylene production, while superoxide dismutase effected in some manner. From these results, the interactions of anticancer quinone drugs with NADPH-cytochrome P-450 reductase and oxygen, and the possible relations of the enzymes to the radical related actions of these drugs are discussed.

Aclarubicin↗

Comparative studies on the antitumor effect on intravenous administration of carbazilquinone and mitomycin-C.

Comparison between Carbazilquinone and Mitomycin-C, both of which contain aziridinyl, carbamoyloxy, and quinonyl groups, was made for their therapeutic effect upon intravenous administration. Although both agents exhibited a significant effect on plasmacytoma X5563 in C3H/He mice to a similar extent, Mitomycin-C was not as effective on lympholeukemia L-1210 and on the lung metastasis of Ehrlich carcinoma in (C57BL/6 X DBA/2)F1 (BDF1) mice as was Carbazilquinone. Possible interpretations regarding this discrepancy are discussed.

Animals↗

Effect of peplomycin plus carbazilquinone and mitomycin on non-small cell carcinoma of the lung.

The effects of two chemotherapeutic regimens, peplomycin (PLM) plus carbazilquinone and PLM plus mitomycin, on non-small cell carcinoma of the lung were evaluated by a randomized controlled trial. Seven partial responses were observed in 53 evaluable patients, for an overall response rate of 13.2%. There was no difference in response rate or in median survival time between PLM plus carbazilquinone (11.5% and 32 weeks) and PLM plus mitomycin (14.8% and 25 weeks). Seven patients developed interstitial pneumonitis, and four died of pulmonary fibrosis. It was concluded that the chemotherapeutic regimens that include PLM are only marginally effective against non-small cell carcinoma of the lung, with relatively frequent pulmonary fibrosis.

Adenocarcinoma↗

Effect of alternating administration of PS-K and carbazilquinone in tumor-bearing mice.

In order to establish procedure for immunochemotherapy, the delayed hypersensitivity reaction (DHR) was investigated in tumor-bearing mice treated with an immunopotentiator, basidiomycetes polysaccharide (PS-K). DHR in the group given continuous administration of immunopotentiator was initially much stronger than that in the untreated group; however, the reactions were the same by the 4th week. The tumor-bearing group give intermittent administration of immunopotentiator retained strong DHR throughout the course, even though prolonged continuous administration failed to maintain such elevated immunoresponses. Alternating treatment with PS-K and carbazilquinone induced much higher DHR and much longer survival. The experimental results showed that continuous administration of an immunopotentiator led to decreasing immune responses in tumor-bearing mice. Intermittent administration of immunopotentiator was proved to be effective in restoring tumor suppression.

Adjuvants, Immunologic↗