The role of methoxymorpholino anthracycline and cyanomorpholino anthracycline in a sensitive small-cell lung-cancer cell line and its multidrug-resistant butP-glycoprotein-negative and cisplatin-resistant counterparts

Vandergraaf, Wta; Mulder, Nh; Meijer, Coby; Devries, Ege

doi:10.1007/bf00689457

Cited by 8 publications

(2 citation statements)

References 23 publications

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“…This hypothesis may also give grounds for reconciliation of the sensitization of MDR cells with respect to non-MDR type drugs as well as sensitization of parental cells with respect to daunorubicin. Extensive studies on non-P-gp mechanisms of drug resistance are currently ongoing ( − ). It is worth mentioning in this respect that we have recently observed (data in preparation) several-fold sensitization of parental cells and hypersensitization of MDR cells by Pluronic copolymers on MDR and non-MDR Chinese hamster ovary (CH r C5 and AUX-B1) and human breast carcinoma (MCF-7 ADR and MCF-7) cell lines.…”

Section: Discussionmentioning

confidence: 99%

Hypersensitization of Multidrug Resistant Human Ovarian Carcinoma Cells by Pluronic P85 Block Copolymer

et al. 1996

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The chemosensitizing effect of Pluronic P85 block copolymer were studied using two human ovarian carcinoma sublines: the glycoprotein P (P-gp) multidrug resistant (MDR) SKVLB cells and non-MDR SKOV3 cells. The dramatic increase (up to 700 times) in the daunorubicin cytotoxic activity was observed in the presence of 0.01% (22 microM) to 1% (2.2 mM) copolymer in the case of SKVLB cells. By contrast, the copolymer induced a less than 3-fold increase in the drug activity in SKOV3 cells. As a result, the MDR subline demonstrated much higher response ("hypersensitivity") to the daunorubicin/ Pluronic compared to that of the non-MDR cells. The copolymer increased the cytotoxic effects of other MDR type drugs (doxorubicin, epirubicin, vinblastine, and mitomycin C) by a factor of 20-1000 and non-MDR type drugs (methotrexate and cisplatin) by a factor of 2-5.5. The daunorubicin influx in the cytoplasm and nuclei of SKVLB cells was also increased in the presence of the copolymer, while in SKOV3 cells, it remained practically unchanged. However, the hypersensitization of the MDR cells by the copolymer could not be merely explained by the P-gp modulation. Therefore, the possible role of the copolymer in inhibition of non-P-gp drug resistance is hypothesized, which may also explain the sensitization of MDR cells with respect to non-MDR type drugs as well as sensitization of parental cells. The concentration dependence of the IC50 in MDR cells indicates that just the copolymer unimers are responsible for the hypersensitization effect. The results obtained suggest that Pluronic P85 can be used as a delivery system to enhance the activity of antineoplastic agents against MDR tumors.

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Section: Discussionmentioning

confidence: 99%

Hypersensitization of Multidrug Resistant Human Ovarian Carcinoma Cells by Pluronic P85 Block Copolymer

et al. 1996

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“…Morpholinyl anthracyclines inhibit ribosomal gene transcription as well as topoisomerase I-mediated DNA-cleavage (Wassermann et al, 1988(Wassermann et al, , 1990. 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).…”

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confidence: 98%

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

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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.

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Nemorubicin

Broggini

2007

Topics in Current Chemistry

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Nemorubicin is a 3'-deamino-3'[2-(S)-methoxy-4-morpholinyl]derivative of doxorubicin. This derivative has been synthesized in the early 1990s by the Farmitalia CarloErba Research Center in Italy. The idea was to develop doxorubicin analogues able to circumvent the emergenceof chemoresistance, in particular the multi-drug resistance. The drug was reported to be active in vitroagainst both murine and human tumor cells resistant to doxorubicin. Similar results were obtained whenthe drug was administered in vivo to mice bearing multi-drug resistant tumors. The compound retained thesame activity also in alkylating agents and topoisomerase II resistant tumors and showed an increased potencyrelative to the parent drug doxorubicin. It is metabolized via P450 CYP3A enzyme to an extremely cytotoxicderivative. Both nemorubicin and its metabolite have a mechanism of action different from that ofdoxorubicin, with a key role played by the nucleotide excision repair system. The drug is activelytested in clinics as a single agent or in combination with cisplatin.

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The role of methoxymorpholino anthracycline and cyanomorpholino anthracycline in a sensitive small-cell lung-cancer cell line and its multidrug-resistant butP-glycoprotein-negative and cisplatin-resistant counterparts

Cited by 8 publications

References 23 publications

Hypersensitization of Multidrug Resistant Human Ovarian Carcinoma Cells by Pluronic P85 Block Copolymer

Hypersensitization of Multidrug Resistant Human Ovarian Carcinoma Cells by Pluronic P85 Block Copolymer

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

Nemorubicin

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