Metabolic conversion of methoxymorpholinyl doxorubicin: from a DNA strand breaker to a DNA cross-linker

Lau, Derick H; Durán, George E.; Lewis, Alexander D.; Šikić, Branimir I.

doi:10.1038/bjc.1994.253

Cited by 24 publications

(20 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cell linebased differences in the IC 50 values of activated MMDX were more narrow, only ϳ2.3 fold, and did not correlate with the sensitivity of each cell line to MMDX itself (Table 2). This finding is consistent with earlier findings that MMDX and activated MMDX kill tumor cells by distinct mechanisms (Lau et al, 1989(Lau et al, , 1994.…”

Section: Cytotoxicity Of MMDX Activated By Rat and Humansupporting

confidence: 93%

“…Thus, the cytotoxicity of MMDX in cell culture can be markedly enhanced by preincubation with liver microsomes and NADPH in a metabolic process that is inhibited by the cytochrome P450 3A (CYP3A)-selective inhibitors triacetyloleandomycin and ketoconazole (Lewis et al, 1992;Quintieri et al, 2000;Baldwin et al, 2003). P450-activated MMDX induces DNA-DNA interstrand cross-links, in contrast to MMDX, which primarily induces protein-associated DNA single-strand breaks (Lau et al, 1989(Lau et al, , 1994. Other studies suggest that activated MMDX differs from the parent drug in terms of its spectrum of antitumor activity and pattern of resistance (Kuhl et al, 1993;Geroni et al, 1994;van der Graaf et al, 1995).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Antitumor Activity of Methoxymorpholinyl Doxorubicin: Potentiation by Cytochrome P450 3A Metabolism

Lü¹,

Waxman²

2004

Mol Pharmacol

View full text Add to dashboard Cite

Methoxymorpholinyl doxorubicin (MMDX) is a novel liver cytochrome P450 (P450)-activated anticancer prodrug whose toxicity toward cultured tumor cells can be potentiated up to 100-fold by incubation with liver microsomes and NADPH. In the present study, a panel of human liver microsomes activated MMDX with potentiation ratios directly correlated to the CYP3A-dependent testosterone 6␤-hydroxylase activity of each liver sample. Microsome-activated MMDX exhibited nanomolar IC 50 values in growth-inhibition assays of human tumor cell lines representing multiple tissues of origin: lung (A549 cells), brain (U251 cells), colon (LS180 cells), and breast (MCF-7 cells). Analysis of individual cDNA-expressed CYP3A enzymes revealed that rat CYP3A1 and human CYP3A4 activated MMDX more efficiently than rat CYP3A2 and that human P450s 3A5 and 3A7 displayed little or no activity. MMDX cytotoxicity was substantially increased in Chinese hamster ovary cells after stable expression of CYP3A4 in combination with P450 reductase. CYP3A activation of MMDX abolished the parent drug's residual cross-resistance in a doxorubicin-resistant MCF-7 cell line that overexpresses P-glycoprotein. CYP3A-activated MMDX displayed a comparatively high intrinsic stability, with a t 1/2 of ϳ5.5 h at 37°C. MMDX was rapidly activated by CYP3A at low (ϳ1-5 nM) prodrug concentrations, with 100% tumor cell kill obtained after as short as a 2-h exposure to the activated metabolite. These findings demonstrate that MMDX can be activated by CYP3A metabolism to a potent, long-lived, and cell-permeable cytotoxic metabolite and suggest that this anthracycline prodrug may be used in combination with CYP3A4 in a P450 prodrug activation-based gene therapy for cancer treatment.

show abstract

Section: Cytotoxicity Of MMDX Activated By Rat and Humansupporting

confidence: 93%

mentioning

confidence: 99%

Antitumor Activity of Methoxymorpholinyl Doxorubicin: Potentiation by Cytochrome P450 3A Metabolism

Lü¹,

Waxman²

2004

Mol Pharmacol

View full text Add to dashboard Cite

show abstract

“…The potency ratio (ratio of the IC 50 value for DX vs. the IC 50 value for MMDX) was 5.5 (not shown). This result agrees with reports regarding the in vitro sensitivity of other murine and human tumour cell lines to MMDX and DX (Grandi et al, 1990;KŸhl et al, 1993;Lau et al, 1994).…”

Section: Uptake and Release By A-nk Cellssupporting

confidence: 93%

“…This anti-cancer drug is biotransformed in the liver into more cytotoxic metabolites by means of a cytochrome P450-dependent process that can be simulated in vitro by incubating the drug with liver microsomes in the presence of NADPH (KŸhl et al, 1993;Lau et al, 1994). This metabolic potentiation by the hepatic microsomal enzymes may contribute to rendering MMDX highly active against liver tumour cell colonies.…”

mentioning

confidence: 99%

Delivery of methoxymorpholinyl doxorubicin by interleukin 2-activated NK cells: effect in mice bearing hepatic metastases

et al. 1999

View full text Add to dashboard Cite

SummaryThe possibility of using interleukin 2 (IL-2)-activated natural killer cells (A-NK) to carry methoxymorpholinyl doxorubicin (MMDX; PNU 152243) to liver-infiltrating tumours was explored in mice bearing 2-day established M5076 reticulum cell sarcoma hepatic metastases. In vitro, MMDX was 5.5-fold more potent than doxorubicin against M5076 tumour cells. MMDX uptake by A-NK cells correlated linearly with drug concentration in the incubation medium [correlation coefficient (r) = 0.999]; furthermore, as MMDX incorporation was readily reproducible in different experiments, the amount of drug delivered by A-NK cells could be modulated. In vivo experiments showed that intravenous (i.v.) injection of MMDX-loaded A-NK cells exerted a greater therapeutic effect than equivalent or even higher doses of free drug. The increase in lifespan (ILS) following A-NK cell delivery of 53 µg kg -1 MMDX, a dosage that is ineffective when administered in free form, was similar to that observed in response to 92 µg kg -1 free drug, a dosage close to the 10% lethal dose (ILS 42% vs. 38% respectively). These results correlated with pharmacokinetic studies showing that MMDX encapsulation in A-NK cells strongly modifies its organ distribution and targets it to tissues in which IL-2 activated lymphocytes are preferentially entrapped after i.v. injection.

show abstract

“…MMRDX showed a potent cytotoxic activity in vitro on various tumour cell lines, including MDR tumour cell lines (Danesi et al, 1993;Kuhl et al, 1993;van der Graaf et al, 1995;Bakker et al, 1997). Metabolic conversion of MMRDX by human liver microsomes and NADPH potentiated the cytotoxicity in an ovarian carcinoma cell line (Lau et al, 1994). In animal studies, MMRDX showed activity against MDR xenografts (Ripamonti et al, 1992).…”

mentioning

confidence: 99%

A prolonged methoxymorpholino doxorubicin (PNU-152243 or MMRDX) infusion schedule in patients with solid tumours: a phase 1 and pharmacokinetic study

Fokkema

Verweij

Oosterom³

et al. 2000

Br J Cancer

View full text Add to dashboard Cite

SummaryThe aim of this phase I study was to assess feasibility, pharmacokinetics and toxicity of methoxymorpholino doxorubicin (MMRDX or PNU-152243) administered as a 3 h intravenous infusion once every 4 weeks. Fourteen patients with intrinsically anthracycline-resistant tumours received 37 cycles of MMRDX. The first cohort of patients was treated with 1 mg m -2 of MMRDX. The next cohorts received 1.25 mg m -2 and 1.5 mg m -2 respectively. Common toxicity criteria (CTC) grade III/IV nausea and vomiting were observed in 1/18 cycles at 1.25 mg m -2 and in 2/11 cycles at 1.5 mg m -2 . Transient elevation in transaminases up to CTC grade III was observed in 2/16 cycles at 1.25 mg m -2 and 4/11 cycles at 1.5 mg m -2 . No cardiotoxicity was observed. At 1.25 mg m -2 CTC grade IV neutropenia occurred in 1/17 cycles. At 1.5 mg m -2 CTC grade III neutropenia was seen in 2/7 and grade IV in 3/7 evaluable cycles. Thrombocytopenia grade III was observed in 2/9 and grade IV in 1/9 evaluable cycles. One patient treated at 1.5 mg m -2 died with neutropenic fever. Therefore, dose-limiting toxicity was reached and 1.25 mg m -2 was considered the maximum tolerated dose for MMRDX as 3 h infusion. No tumour responses were observed. Pharmacokinetic parameters showed a rapid clearance of MMRDX from the circulation by an extensive tissue distribution. Renal excretion of the drug and its metabolite was negligible. In conclusion, prolongation of MMRDX infusion to 3 h does not improve the toxicity profile as compared with bolus administration.

show abstract

Metabolic conversion of methoxymorpholinyl doxorubicin: from a DNA strand breaker to a DNA cross-linker

Cited by 24 publications

References 17 publications

Antitumor Activity of Methoxymorpholinyl Doxorubicin: Potentiation by Cytochrome P450 3A Metabolism

Antitumor Activity of Methoxymorpholinyl Doxorubicin: Potentiation by Cytochrome P450 3A Metabolism

Delivery of methoxymorpholinyl doxorubicin by interleukin 2-activated NK cells: effect in mice bearing hepatic metastases

A prolonged methoxymorpholino doxorubicin (PNU-152243 or MMRDX) infusion schedule in patients with solid tumours: a phase 1 and pharmacokinetic study

Contact Info

Product

Resources

About