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PubMed1984

[Malignant melanoma in Japan: unique distribution and effect of DAV chemoimmunotherapy (part II)].

This study, based on a cooperative group project involving 4 major medical institutes in Japan, presents the second survey of malignant melanoma patients (198 cases) where an attempt is made to systemically evaluate the survival rates of these patients with respect to the tumor thickness and location of primary lesions, and the response to chemoimmunotherapy. More than 50% of total collected cases showed the primary lesions on the limbs. The most common type and site of involvement is the acral lentiginous melanomas involving the plantar areas (more than 30). The survival rates affecting the limbs were better than those affecting the non-limb areas. However, the comparison of the survival rates did not reveal any difference between those cases affecting the plantar and non-plantar areas. The difference in the prognosis of melanoma patients appeared to be related to the tumor thickness. By historical comparison, the DAV (DTIC, ACNU, VCR) treated group exhibited a better survival rate than the non-DAV treated group. Furthermore, the DAV group with immunoadjuvant therapy (mainly OK-432) showed a better prognosis than the DAV group without any immunoadjuvant therapy.

Adolescent↗
PubMed1982

[Physiological effects and antitumor efficiency of ACNU in postoperative patients with stomach cancer--an evaluation of the treatment combined with FT-207 or 5-FU dry syrup].

In 26 patients with cancer of the stomach, bone marrow function, cell mediated immunity and plasma CEA level were examined after administration of ACN-U. ACNU was given intravenously and intermittently with 5-FU given orally daily. Results 1) Delayed myelosuppression was observed in every cases and reached to the nadir in 2-7 weeks after ACNU administration. 2) Bone marrow suppression and recovery therefrom were observed earlier in platelet counts than in RBC and WBC counts. 3) Suppression of cell mediated immunity was not observed later than 4 weeks after ACNU administration. 4) Plasma CEA level decreased or stopped to increase after ACNU administration in 5 out of 8 patients having a high CEA level before treatment. 5) Regression of tumor size was observed in 4 out of 5 patients in whom a tumor was palpable. Conclusion ACNU has a strong antitumor activity and may be more effective if combined with antimetabolite agent, such as 5FU. Total dosage of ACNU given safely in one series was considered to be 150-200mg. Next series of ACNU administration should be started after restoration of platelet counts more than 100,000/mm3 was obtained.

Antineoplastic Agents↗
PubMed1982

[A case report of macroglobulinemia responded to AAAP-therapy].

A 60-year-old woman was referred to us because of tumors on the occipital and the bilateral submaxillary areas. Biopsy proved them to be well-differentiated lymphosarcoma. On admission, systemic lymphadenopathy was noted and there was 26% of plasmacytoid cells in the bone marrow of the sternum. Monoclonal gammopathy of IgM,K type was found; her disease was diagnosed as a macroglobulinemia (IgM: 8,460 mg/dl). VENP-therapy consisted of vincristine 1 mg/w, cyclophosphamide 50 mg/d procarbazine 50 mg/d and prednisolone 30 mg/d was applied for about four weeks, but in vain. Transaminase levels were elevated (GOT 575 U, GPT 480 U) and the superficial lymphnodes did hardly diminish. Therefore, after improvement of the liver dysfunctions, 5 courses of AAAP-therapy, which was consisted of ACNU 50 mg/d (IV drip over 4 hrs), adriamycin 20 mg/d (IV push), methotrexate 25 mg/d (IV push) and prednisolone 60 mg/d (IV push) once a week or three were employed with excellent clinical effects. The superficial lymphnodes disappeared, M-protein and plasmacytoid cells in the bone marrow markedly decreased. An interval of the initial remission reached to 17 months. As previously reported, AAAP-therapy was also effective to multiple myeloma and acute lymphocytic leukemia of B-cell type. Therefore, AAAP-therapy would be one of the best chemotherapies for B-cell malignancy including macroglobulinemia.

Antineoplastic Agents↗
PubMed1980

Potentiation of therapeutic effects of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride by 6-thioguanine in mouse tumor systems: comparison with other antimetabolites.

Antitumor activities of a combination chemotherapy with a water-soluble nitrosourea, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU), and a single dose of 6-thioguanine were studied using three obstinate murine tumor systems, i.e., Lewis lung carcinoma, B16 melanoma, and an advanced stage of L1210 leukemia systems. Therapeutically synergistic effect was observed either definitely against 1- or 2-day-old Lewis lung carcinoma and 6-day-old L1210 leukemia or moderately against 1-day-old B16 melanoma. Single intravenous treatment on day 7 after subcutaneous implantation of Lewis lung carcinoma, when the tumors had already metastasized to the lungs, produced a significant regression of tumor and a significant increment in survival time of tumor-bearing mice. In comparative studies, the combination of ACNU and 6-thioguanine showed a greater and a wider spectrum of antitumor activities against these tumors than those obtained by the combination with ACNU and a single dose of 5-fluorouracil, methotrexate, or 6-mercaptopurine. Increment in lethal toxicity for normal and tumor-bearing mice was not observed by the combination of ACNU and 6-thioguanine in contrast to definite increases in this toxicity by the combination of ACNU and 5-fluorouracil. The present experimental results may suggest the clinical utility of the combination chemotherapy with ACNU and 6-thioguanine in the treatment of several solid tumors as well as acute leukemias.

Animals↗
PubMedDate not supplied

Distribution, excretion, and metabolism of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea (ACNU) in rats and mice after iv administration.

Distribution, excretion, and metabolism of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea (ACNU) in healthy rats and mice or tumor-bearing mice were studied with the 14C label in each of two positions of the molecule, the ethylene and pyrimidine moieties. After iv injection of 4 mg/kg of ACNU-14C, radioactivity was distributed widely and disappeared rapidly from the body. The half-life of intact ACNU in rat plasma was about 12 minutes. In both animal species, 72%-95% of the radioactivity was excreted into urine within 24 hours. Early dissociation of renal clearance rate was observed between pyrimidine-14C and ethylene-14C, the former being more rapidly excreted than the latter. Ethylene-14C of ACNU was distributed into tumor tissues of X-5563 plasmacytoma-bearing mice, and a tumor level of radioactivity was observed to be twofold higher than the blood level at 3 hours after injection. The concentrations of several metabolites in plasma and urine were determined. Among these compounds, we found an intramolecular carbamoylating product of ACNU. These results suggest that the isocyanate derived from ACNU does not react with any biologic macromolecules, and that the chloroethyl moiety of ACNU has a very important role in the manifestation of the antitumor activity.

Animals↗
PubMed1980

Therapeutic synergism elicited by the combination of 6-thioguanine and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride: synergistic cytocidal activity against L1210 cells in vitro.

In order to clarify the mechanism of therapeutic synergism elicited by a combination of 6-thioguanine and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU), the cytocidal activity towards L1210 leukemic cells in vitro of these two drugs, alone and in combination, was examined by the soft agar cloning assay and the regrowth assay methods. More than 10-fold greater cell-killing activity than the expected additive survival (the product of fractional survival obtained for each drug alone) was observed on treatment with the combination of these drugs in both assay methods. More-over, dose- and treatment schedule-dependent antitumor activity of this combination treatment against L1210 leukemia in vivo was clearly reflected in the cytocidal activity towards L1210 cells in vitro. These findings suggest that the therapeutic synergism elicited by the combination of ACNU and 6-thioguanine results from synergistic cytocidal activity towards tumor cells.

Animals↗
PubMed1980

Lethal toxicity and myelotoxicity to mice of the combination of 6-thioguanine and 3-[(4-amine-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride.

In order to determine the mechanism of therapeutic synergism elicited by a combination of 6-thioguanine and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU) against various murine tumors, side effects of host animals due to the combination of these two drugs were examined. The combination toxicity index of these drugs given simultaneously was determined to be 1.5, i.e., this indicates that the combination of ACNU and 6-thioguanine is less-than-additive with respect to the lethal toxicity. More-over, this combination treatment appeared to be at least no more than additive with respect to bone marrow toxicities as judged on the basis of bone marrow cellularity and peripheral white blood cell counts. In addition, the effects of treatment schedules, which were clearly observed in the therapeutic effect, on the side effects due to this combination treatment were also examined. However, no specific decrease or increase in side effects on host animals on this specific treatment schedule or the other treatment schedule was seen.

Animals↗
PubMedDate not supplied

In vitro sensitivity of nitrosourea-induced neurogenic tumors to ACNU.

The effect of ACNU on the in vitro viability of a methylnitrosourea-induced gliosarcoma (T9) and two ethylnitrosourea-induced brain tumors, TR-481 (a malignant neurinoma) and EB-679 (a glioma) was studied. T9 was highly sensitive to ACNU, demonstrating loss of cells following a 3 hour exposure time to 5 microgram/ml; TR-481 was sensitive to 40 microgram/ml of ACNU and EB-679 was highly resistant to 40 microgram/ml of ACNU. The in vitro sensitivity of the tumor cell lines to ACNU is: T 9 greater than TR-481 greater than EB-679. This data indicates that variability of response to both concentration and exposure time of ACNU of malignant brain tumor cells must be taken into consideration in planning in vitro and/or in vivo treatment of experimental brain tumors.

Animals↗
PubMed1982

[A case of malignant melanoma responded to chemotherapy including DTIC and local injection of OK-432].

A 33-year-old woman with malignant melanoma well responded to a chemotherapy including DTIC, ACNU, and VCR, and intralegional injection of OK-432. Four years prior to admission, a lentigo of 5 mm diameter at her left frontal chest was found, but, histological examination resulted in no distinctly malignant findings. In November 1979, multiple subcutaneous tumors appeared over posterior surface of the chest and left axillar region, which were gradually increasing in number and size, then she was admitted to our hospital in June, 1980. Biopsy of subcutaneous tumors revealed a malignant melanoma and its metastasis to skin. Immunochemotherapy was started immediately based upon this diagnoses. The patient received 100mg DTIC i.v. for 4 days, 100mg ACNU i.v. for one day and 1 mg VCR i.v. for one day. OK-432 was locally injected into some tumors as an immunotherapy. On completion of the third course of chemotherapy, all subcutaneous tumors were decreased in size, especially the tumors injected with OK-432. However, patient didn't respond to a repeated chemotherapy, thereafter malignant melanoma was metasized to uterus and peritoneum in May, 1981, and she died in September, 1981. Major side effects of this chemotherapy were nausea and mild transient leukocytopenia. The combination of chemotherapy including DTIC and local injection of OK-432 appeared to be effective for malignant melanoma.

Adult↗