Hypothetical mechanism of therapeutic synergism induced by the combination of 6-thioguanine and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride.

Paper

Hypothetical mechanism of therapeutic synergism induced by the combination of 6-thioguanine and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride.

Published Oct 1, 1982 · S. Fujimoto, M. Ogawa, Y. Sakurai

Cancer research

Q1 SJR score

11

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0

Influential Citations

Semantic Scholar

Abstract

Comparative studies were carried out using various antimetabolites in order to determine whether the synergistic cell-killing effect on L1210 murine leukemia cells induced by a treatment combining 6-thioguanine (6-TG) and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU) resulted from “complementary inhibition.” The combinations of ACNU plus 5-fluorouracil and ACNU plus 5-bromo-2′-deoxyuridine induced 31- and 18-fold greater cell killing of L1210 cells in vitro over the expected additive survival (the product of the observed survival for each drug), respectively, whereas the cytocidal activity of the combinations of ACNU plus methotrexate and ACNU plus 6-methylmercaptopurine riboside was less than 2-fold greater. Moreover, therapeutic synergism defined by two parameters (survival time and/or cure incidence) against iv. L1210 leukemia was clearly elicited only by the combinations of ACNU plus 5-fluorouracil, 5-bromo-2′-deoxyuridine, or 6-mercaptopurine. As a result, the following possibility that the 6-TG incorporated into the DNA in place of guanine increases the amount of the DNA interstrand cross-linking by ACNU was considered and examined using the DNAs isolated from 6-day-old L1210 cells in the peritoneal cavity untreated or treated with 30, 3, and 0.3 mg of 6-TG per kg for 5 hr. Significant increases in the amount of binding of [ ethylene -}su14}/suC]ACNU to the DNA and in the amount of the DNA interstrand cross-linking determined by the hydroxylapatite technique were observed with the increase in the 6-TG dose and, maximally, approximately 6-fold greater binding and 6- to 12-fold increases in the double-stranded DNA fraction over those of control DNA were obtained by 4- and 2-hr incubations at 37°, respectively.

In Vitro Study

Study Snapshot

Combining 6-thioguanine and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU) effectively kills L1210 murine leukemia cells,

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Hypothetical mechanism of therapeutic synergism induced by the combination of 6-thioguanine and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride.

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References

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.

The combination of 6-thioguanine and ACNU is less-than-additive in lethal toxicity and bone marrow toxicity, with no specific decrease or increase in side effects observed on any treatment schedule.

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.

The combination of 6-thioguanine and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU) exhibits synergistic cytocidal activity against

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Combination chemotherapy with ACNU and 6-thioguanine shows greater antitumor activity and a wider spectrum of antitumor effects than single doses of 5-fluorouracil, methotrexate, or 6-mercaptopurine.

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The glucose moiety in water soluble nitrosoureas reduces bone marrow cytotoxicity without significantly altering antitumor activity.

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Large doses of drugs used intermittently and sequentially in combination may be the best strategy to prevent drug resistance in cancer chemotherapy.

Combination chemotherapy of 6-thioguanine with various antitumor agents against murine leukemia L-1210.

Combination chemotherapy of 6-thioguanine with various antitumor agents effectively treats early L-1210 leukemia and advanced L-1210 leukemia, showing a distinct therapeutic effect.

Citations

Treatment of pediatric low-grade gliomas with a nitrosourea-based multiagent chemotherapy regimen

This nitrosourea-based multiagent chemotherapy regimen is safe, effective, and provides prolonged disease stabilization in children with low-grade gliomas.

Combination of 6-thioguanine, procarbazine, lomustine, and hydroxyurea for patients with recurrent malignant gliomas.

The combination of 6-thioguanine, procarbazine, lomustine, and hydroxyurea is effective for patients with recurrent anaplastic gliomas and glioblastomas not previously treated with nitrosourea-based chemotherapy, but inactive for those previously treated with chemotherapy

A phase III randomized prospective trial of external beam radiotherapy, mitomycin C, carmustine, and 6-mercaptopurine for the treatment of adults with anaplastic glioma of the brain

The addition of mitomycin C to external beam radiotherapy had no significant impact on survival, and 6-mercaptopurine to BCNU did not provide a significant survival benefit.

Chemotherapeutic treatment of the diencephalic syndrome. A case report

Chemotherapy may be an effective alternative to focal brain irradiation for diencephalic syndrome, potentially reducing morbidity and allowing radiation therapy to be deferred for later age.

Combination therapy of ACNU and ifosfamide in tumor bearing mice with M2661 breast cancer, B16 malignant melanoma or C38 colon cancer.

The combination of ACNU and ifosfamide showed additive antitumor effects in B16 and C38 tumor lines, but no synergism was observed in M 2661 breast cancer.