What question did this study set out to answer?

To identify the human cytochrome P450 enzyme responsible for converting nemorubicin into its metabolite PNU-159682 and characterize the metabolite's antitumor activity.

February 15, 2005Clinical Cancer Research

Formation and Antitumor Activity of PNU-159682, A Major Metabolite of Nemorubicin in Human Liver Microsomes

View Full Paper

Ask AI

Bookmark

To identify the human cytochrome P450 enzyme responsible for converting nemorubicin into its metabolite PNU-159682 and characterize the metabolite's antitumor activity.
Incubated nemorubicin with human liver microsomes from 10 donors and a panel of 10 cDNA-expressed human cytochrome P450 enzymes, with and without CYP3A-specific chemical inhibitors and antibodies.
Tested the in vitro cytotoxicity of synthetic PNU-159682 across a panel of human tumor cell lines compared to nemorubicin and doxorubicin.
Assessed in vivo antitumor activity of PNU-159682 in mice bearing disseminated L1210 leukemia and MX-1 human mammary carcinoma xenografts.
Human liver microsomes metabolized nemorubicin to PNU-159682 exclusively via CYP3A4; the reaction was strongly suppressed by troleandomycin, ketoconazole, and anti-CYP3A4/5 antibodies.
PNU-159682 showed substantially higher in vitro cytotoxicity across human tumor cell lines compared to both parent nemorubicin and doxorubicin.
PNU-159682 exerted marked antitumor activity in vivo against both disseminated murine L1210 leukemia and MX-1 human mammary carcinoma models.

Structured PICO

Population

Human liver microsomes (HLM) from 10 donors, genetically engineered cell lines expressing individual human cytochrome P450s (CYP), in vitro-cultured human tumor cell lines, and tumor-bearing mice (disseminated murine L1210 leukemia and MX-1 human mammary carcinoma xenografts)

Intervention

Nemorubicin (MMDX) and its metabolite PNU-159682

Comparator

Doxorubicin and MMDX (for cytotoxicity comparison)

Outcome

Biotransformation of MMDX to PNU-159682 and antitumor activity/cytotoxicitysurrogate

The major human liver metabolite of nemorubicin, PNU-159682, is formed by CYP3A4 and exhibits potent antitumor activity.

Discussion

No takes yet. Share an insight, caveat, or question.

Implication

PNU-159682 potency in models supports CYP3A4-activated prodrug development; leaves open human translation and safety.

Cite This Study

Quintieri et al. (2005) studied this question.

synapsesocial.com/papers/6a8cef822fc7b5a11ff557c3 https://doi.org/10.1158/1078-0432.ccr-04-1845

View Full Paper

Ask AI

Bookmark

Formation and Antitumor Activity of PNU-159682, A Major Metabolite of Nemorubicin in Human Liver Microsomes

Key Points

Structured PICO

Discussion

Implication

Cite This Study

Formation and Antitumor Activity of PNU-159682, A Major Metabolite of Nemorubicin in Human Liver Microsomes

Key Points

Structured PICO

Discussion

Implication

Cite This Study

Also Consider

Also Consider