Phase II Trial of Indicine N-Oxide in Relapsed Acute Leukemia of Childhood

Miser, James S.; Smithson, William A.; Krivit, William; Hughes, Carla H.; Davis, Dianne M.; Krailo, Mark; Hammond, G. Denman

doi:10.1097/00000421-199204000-00008

Cited by 12 publications

(4 citation statements)

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“…Regarding the plant families Asteraceae, Composites, or Leguminosae, many of their members produce pyrrolizidine alkaloids-potent cytotoxic, carcinogenic, and/or anti-carcinogenic compounds [84,85]-which probably act by crosslinking DNA [86]. One of these compounds, indicine N-oxide, advanced to clinical trial [87,88], but unremarkable Mans, da Rocha, Schwartsmann anti-tumor effects and unacceptably severe, irreversible hepatotoxicity led to the termination of its further development.…”

Section: Compound Acquisition Through Ecological Survey/rational Searchmentioning

confidence: 99%

Anti-Cancer Drug Discovery and Development in Brazil: Targeted Plant Collection as a Rational Strategy to Acquire Candidate Anti-Cancer Compounds

2000

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Throughout medical history, plant products have been shown to be valuable sources of novel anti-cancer drugs. Examples are the VINCA: alkaloids, the taxanes, and the camptothecins, derived from the Madagscan periwinkle plant Catharantus roseus, the Pacific yew Taxus brevifolia, and the Chinese tree Camptotheca acuminata, respectively. For this reason, the South-American Office for Anti-Cancer Drug Development has implemented a large-scale project of acquisition and testing of compounds isolated from South American medicinal plants. The species are selected on the basis of a potentially useful phytochemical composition by consulting ethnopharmacological, chemosystemic, and ecological information. The collected samples are dried and first extracted with an organic solvent, then with distilled water. These crude extracts are evaluated at a concentration of 50 microg/ml for antiproliferative activity against one cell line. Extracts that significantly inhibit the growth of the cells (>/=50%) at relatively low concentrations (

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Section: Compound Acquisition Through Ecological Survey/rational Searchmentioning

confidence: 99%

Anti-Cancer Drug Discovery and Development in Brazil: Targeted Plant Collection as a Rational Strategy to Acquire Candidate Anti-Cancer Compounds

2000

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“…As indicine-N-oxide showed promising results as an anticancer agent in in vitro and in vivo assays, clinical trials were conducted for acute leukemia; however, due to severe hepatotoxicity, the compound was not further tested [113,114]. One clinical trial investigated the effect of indicine-N-oxide on patients with progressive acute leukemia refractory to standard chemotherapeutics.…”

Section: Anticancer Propertiesmentioning

confidence: 99%

Pyrrolizidine Alkaloids—Pros and Cons for Pharmaceutical and Medical Applications

Jayawickreme,

Świstak,

Ozimek

et al. 2023

IJMS

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Heterocyclic organic compounds named pyrrolizidine alkaloids (PAs) belong to a group of alkaloids and are synthesized by either plants or microorganisms. Therefore, they are naturally occurring secondary metabolites. They are found in species applied in the pharmaceutical and food industries, thus a thorough knowledge of their pharmacological properties and toxicology to humans is of great importance for their further safe employment. This review is original because it synthesizes knowledge of plant and microbial PAs, which is unusual in the scientific literature. We have focused on the Boraginaceae family, which is unique due to the exceptional richness and diversity of its PAs in plant species. We have also presented the microbial sources of PAs, both from fungi and bacteria. The structure and metabolism of PAs have been discussed. Our main aim was to summarize the effects of PAs on humans, including both negative, toxic ones, mainly concerning hepatotoxicity and carcinogenicity, as well as potentially positive ones for pharmacological and medical applications. We have collected the results of studies on the anticancer activity of PAs from plant and microbial sources (mainly Streptomyces strains) and on the antimicrobial activity of PAs on different strains of microorganisms (bacteria and fungi). Finally, we have suggested potential applications and future perspectives.

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“…Further, no clinically significant objective responses were noted in patients, thus disappointingly ceasing the scientific investigation into indicine N-oxide. Miser et al (155) carried out a phase II clinical trial in children with relapsed acute leukemia and although indicine N-oxide showed some anti-leukemic activity, it was associated with severe and irreversible hepatotoxicity. PA appears to be a compound of interest for anti-cancer therapy due to its cytotoxic and angiogenesis inhibiting property.…”

Section: Pas and Cancermentioning

confidence: 99%

Hepatotoxicity of Pyrrolizidine Alkaloids

et al. 2015

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PURPOSE: This article aimed 1) to review herbal medicine containing pyrrolizidine alkaloids (PA)-induced toxicities of the liver; 2) to encourage the recognition and prevention of common problems encountered when using complementary and alternative medicine and 3) to review the toxic effects of herbal remedies containing PAs. DESIGN AND METHODS: We performed a systematic literature search using the PubMed and Google Scholar engines. The search was not restricted to languages. We also provide an interpretation of the data. CONCLUSIONS: Herbal remedies containing PAs can induce liver damage, including hepato- sinusoidal obstruction syndrome or veno-occlusive disease. Preventing overdose and monitoring long-term use of such remedies may avoid glutathione depletion leading to mitochondrial injury, and therefore avoid liver cell damage. Moreover, immediately stopping the herbal medication prevents further harm to the liver. Chronic consumption of hepatotoxicants can lead to cancer formation and promotion. The role of active metabolites in PA-induced liver toxicity and their mechanism of action require further investigation. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Phase II Trial of Indicine N-Oxide in Relapsed Acute Leukemia of Childhood

Cited by 12 publications

References 0 publications

Anti-Cancer Drug Discovery and Development in Brazil: Targeted Plant Collection as a Rational Strategy to Acquire Candidate Anti-Cancer Compounds

Anti-Cancer Drug Discovery and Development in Brazil: Targeted Plant Collection as a Rational Strategy to Acquire Candidate Anti-Cancer Compounds

Pyrrolizidine Alkaloids—Pros and Cons for Pharmaceutical and Medical Applications

Hepatotoxicity of Pyrrolizidine Alkaloids

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