Eiichi Furusawa

Toxins from cyanophytes belonging to the scytonemataceae

Two highly cytotoxic substances, scytophycins A and B, have been isolated from cultured Scitonema pseudohofmanni. Gross structures are proposed for scytophycins A and B, mostly on the basis of nuclear magnetic resonance spectral studies. The scytophycins are structurally related to tolytoxin, a toxic lipid found in field-collected Tolypothrix conglutinata var. colorata, another blue-green alga belonging to the family Scytonemataceae. At sublethal doses the scytophycins display moderate activity against P-388 lymphocytic leukemia and Lewis lung carcinoma in mice.

Identification of a cytotoxin from Tolypothrix byssoidea as tubercidin

Abstract Tubercidin, a biologically active pyrrolo[2,3-d]pyrimidine nucleoside previously isolated from Streptomyces tubercidicus , has been identified as a major metabolise of the cyanophyte Tolypothrix byssoidea .

Anticancer Potential of Viva-Natural, a Dietary Seaweed Extract, on Lewis Lung Carcinoma in Comparison with Chemical Immunomodulators and on Cyclosporine-Accelerated AKR Leukemia

Viva-Natural, extracted from a dietary seaweed, containing a macrophage-activating polysaccharide, has been confirmed to be active against intraperitoneally implanted Lewis lung carcinoma (LLC) and spontaneous AKR T cell leukemia. The antitumor potential against LLC has been evaluated in comparison with standard synthetic immunomodulators such as pyran copolymer (MVE-2), isoprinosine, levamisole, and tilorone while manipulating the immune systems by immunosuppressive agents, cyclophosphamide (CY) and 2-chloroadenosine. The anti-LLC activity of Viva-Natural has been found to be superior to that of isoprinosine but inferior to that of MVE-2. LLC-enhancing effect of CY could be partially reserved by the subsequent administration of Viva-Natural or MVE-2 but not by isoprinosine. 2-Chloroadenosine, a specific macrophage inhibitor, abrogated the anti-LLC activity of Viva-Natural and isoprinosine but not the activity of MVE-2. Levamisole and tilorone showed no anti-LLC activity. Ethanol-precipitable fraction of water-soluble part of Viva-Natural (crude polysaccharide) demonstrated curative activity similar to that of MVE-2. Viva-Natural reversed the potentiation effect of ciclosporin on the development of leukemia in AKR mice at preleukemic stage.

Therapeutic activity of pretazettine, a narcissus alkaloid on Rauscher leukemia: comparison with tazettine and streptonigrin.

Summary The therapeutic activity of narcissus alkaloid pretazettine HCl (PTZ) on established Rauscher leukemia has been demonstrated and compared with the isomer tazettine (TZ) and an antibiotc, streptonigrin (SN). PTZ and SN showed remarkable prolongation effect on the life span of the leukemic mice and the antiviral activity has been confirmed in mouse 3T3 cells infected with Rauscher virus. TZ showed no significant activity in the leukemic mice and was inhibitory to the virus growth in the cells at much higher doses than PTZ. It is suggested that the stereochemical rearrangement from PTZ to TZ inactivates the biological activity of PTZ. We thank Dr. M. A. Chirigos of NIH for supplying streptonigrin; Dr. S. A. Aaronson of NIH for supplying mouse 3T3 cells; and Dr. A. Hackett of Naval Biomed. Res. Lab., Calif., for supplying XC cells.

Therapeutic activity of narcissus alkaloid on Rauscher leukemia and comparison with standard drugs.

Summary An alkaloid (2-X), tentatively identified as pseudolycorine, has been isolated from Narcissus tazetta L. This alkaloid, primarily studied as a new antiviral agent derived from the screening of medicinal plants of the Pacific area, has been shown to exert a superior prolongation effect on the life span of established Rauscher leukemic mice having palpable splenomegaly, in comparison with standard antileukemic drugs. It was found that the alkaloid suppressed the development of splenomegaly and the increase in number of nucleated blood cells, and dropped the virus titer in plasma without apparent toxicity. A second alkaloidal complex, called residual alkaloid, also showed remarkable antileukemic activity.

Therapeutic Activity of Pretazettine, Standard Drugs, and the Combinations on Intraperitoneally Implanted Lewis Lung Carcinoma in Mice

Therapeutic effectiveness of pretazettine (PTZ) has been demonstrated in the intraperitoneally (i.p.) implanted Lewis lung carcinoma (LLC) in both syngeneic and allogeneic mice. The i.p. implanted LLC has been found to be sensitive to most standard drugs tested such as cyclophosphamide (CY), actinomycin D, 5-fluorouracil, methotrexate, 6-thioguanine and vincristine, in comparison to the subcutaneously (s.c.) or intravenously (i.v.) implanted LLC which was reported to be resistant to most standard drugs (s.c.-LLC) or resistant to actinomycin D, methotrexate and vincristine (i.v.-LLC). The effectiveness of PTZ was comparable to that of standard drugs in the i.p. implanted LLC system, and the combination therapy of PTZ with these standard drugs except vincristine was synergistically or additively effective. Also, the PTZ combination rescued the allogeneic mice from the risk of adverse (tumor-enhancing) effects of CY at moderate doses (25-50 mg/kg) given therapeutically.

Therapeutic Activity of Narcissus Alkaloids on Rauscher Leukemia: Antiviral Effect in Vitro and Rational Drug Combination in Vivo

Summary Narcissus alkaloid (pseudolycorine and the residual alkaloid) in comparison with standard inhibitors of reverse transcriptase (ethidium bromide, rifamycin SV, acetyl adriamycin, and cinerubin A) were tested for their antiviral activities against Rauscher leukemia virus in mouse embryo cell cultures. The narcissus alkaloid remarkably suppressed the virus replication in mouse embryo cells, while rifamycin SV, acetyl adriamycin and cinerubin A were moderately inhibitory, and ethidium bromide showed no effect. In the treatment of Rauscher leukemia in mice, with single-drug administration, the narcissus alkaloid showed a significant prolongation of the life span of leukemic mice, while acetyl adriamycin and cinerubin A were only slightly effective, and rifamycin SV and ethidium bromide were found to be ineffective. The triple combination treatments using narcissus alkaloids with 6-mereaptopurine and cyclophosphamide showed a superior prolongation effect on the survival time over two-combination treatments, which have been consistently demonstrated to be more effective than the administration of single agents. We thank Dr. M. A. Chirigos of NIH for testing on reverse transcriptase; Dr. A. Hackett of Naval Biomedical Research Laboratory, Oakland, CA for supplying XC cells; and Dr. M. A. Apple of the Cancer Research Institute of the University of California for supplying acetyl adriamycin and cinerubin A. Appreciation is also expressed to Dr. P. Yoder of University of Hawaii for his criticisms and comments on the manuscript.

Therapeutic Activity of Pretazettine on Ehrlich Ascites Carcinoma: Adjuvant Effect on Standard Drugs in ABC Regimen

A narcissus alkaloid, pretazettine hydrochloride (PTZ), has been shown to be active against Ehrlich ascites carcinoma. The Ehrlich cells are more sensitive to PTZ in DBA/2 mice than in Swiss mice. The therapeutic activity of the individual standard drugs in ABC (adriamycin, BCNU, and cyclophosphamide) regimen against Ehrlich ascites carcinoma has been increased remarkably by the adjuvant therapy of PTZ following the preliminary use of standard drugs. The independent inhibitory action of PTZ on cellular protein synthesis in the presence of the DNA-binding agent has been demonstrated in KB-cell cultures. Adriamycin-pretreated KB cells are found to be more sensitive to PTZ than nontreated cells.

Therapeutic activity of pretazettine, a narcissus alkaloid, on spontaneous AKR leukemia.

A narcissus alkaloid, pretazettine hydrochloride (PTZ) has been shown to be active against spontaneous AKR leukemia. The long-term treatment with PTZ begining at 5--7 months of age of a group of AKR mice containing 10--20% of advanced leukemic mice significantly prolonged the life span of the group. The therapeutic effectiveness of PTZ has been compared with several standard antileukemic drugs. PTZ decreased the AKR virus titer in the circulating blood of mice and its antiviral activity in AKR virus infected NIH/3T3 cells has been confirmed by XC assay.

Combination chemotherapy of Rauscher leukemia and ascites tumors by narcissus alkaloid with standard drugs and effect on cellular immunity.

Summary The therapeutic activity of the narcissus residual alkaloid A-2 against Rauscher leukemia has been compared with 10 standard anticancer drugs, and synergistic or additive combination pairs have been selected using a viral leukemia and two transplantable tumor systems. An increased beneficial effect has been demonstrated by a combination of the alkylating and DNA-binding agents and the alkaloid against the three malignant tumors, while a beneficial effect by combining the alkaloid and the antimetabolites (either 6-MP or 5-azacyti-dine) was seen only against the viral leukemia. The alkaloid has no suppressive activity against cellular immunity as tested by PHA reactivity and allogeneic tumor rejection systems.