Bron: website: ASCO-2004

Na succesvolle dierproeven zijn afgelopen jaar drie patienten met een ongeneeslijke en inoperabele vorm van tumoren in het hoofd-halsgebied direct ingespoten met M4N. Zeer opmerkelijk is dat bij alle drie de patienten de tumoren snel en direct afstierven. Wel waren er ernstige bijverschijnselen, zoals pijn bij de plaats van injectie en een patient had hartklachten maar naarmate de artsen handiger en beter de injecties gaven werd ook de pijn minder. In 2001 werd een studie gepubliceerd waarbij M4N tumorsterfte veroorzaakte bij borstkankercellen in muizen en ook een studie bij dieren met melanoomcellen gaf tumorsterfte te zien door M4N toediening. Deze aanpak lijkt dus wel potentie te hebben. Natuurlijk een echt beginnende studie maar wie weet waar dit toe kan leiden. Onder de casestories staat het abstract met borstkankercellen uit 2001 en het abstract met melanoomcellen.

Phase I clinical results of intralesional injection of tetra-o-methy nordihydroguaiaretic acid (M4N) in refractory head and neck cancer.

Abstract No: 5614
Citation: Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 5614 Author(s): F. R. Dunphy, K. K. Dukelow, J. Provenzal, J. Crawford; Duke Comprehensive Cancer Center, Durham, NC

Abstract: Background:Patients with relapsed-refractory Head and Neck cancer have a poor prognosis with a 10% 2- year survival. Novel treatments are being explored in this poor prognostic group. M4N, a derivative from the plant, Larrea tridentata, has shown activity in murine models after intratumornal injection.

Methods: Intratumor injections were administered at the same dose each week x 3 weeks with a target dose of 20mg/cm3 tumor volume. Three patients (1 female and 2 males) were treated, median age 65 (54-82). The first received 10mg/cm3 x 3 weeks, the second received 15mg/cm3 x 3 weeks, the third received 15mg/cm3 x 1 week. Using fanning intratumoral injection technique a total of 7 intratumoral injections were performed. Pharmocokinetics were obtained preinjection and 1,2,4,8,24 hours post-injection on the first and last week of intratumoral injection.

Results: Major toxicity was brief heart-block requiring two hospitalizations in one patient observed after day 8 and day 15 injection. One patient developed a tracheal-cutaneous fistula one week after day 1 injection which necessitated removal from study. All patients experienced pain at the intratumoral injection site requiring intravenous morphine, median 25mg (range 10-40mg). In all three patients, injected tumor volumes were observed to respond by crusting within one week of the first injection, followed within two weeks by necrosis and ulceration. Two patients that completed 3 weeks of intratumoral injection were observed to have total necrosis of the injected tumor site, followed by disease progression outside the boundaries of the injected tumor volume.

Conclusions: M4N intratumor injection was feasible and showed promising antitumor activity in relapsed-refractory squamous cell cancer. Pain was the major complication, but was less intense as injection technique experience was acquired.This approch is worthy of futher investigation

Cancer Res. 2001 Jul 15;61(14):5499-504.

Tetra-O-methyl nordihydroguaiaretic acid induces G2 arrest in mammalian cells and exhibits tumoricidal activity in vivo.

Heller JD, Kuo J, Wu TC, Kast WM, Huang RC.
Department of Biology, The Johns Hopkins University, Baltimore, Maryland 21218, USA.

The transcription inhibitor tetra-O-methyl nordihydroguaiaretic acid (M4N) was found to arrest the proliferation of C3, C33a, CEM-T4, and TC-1 cells in culture at the G2 stage of the cell cycle. Investigation into the mechanism of arrest revealed that M4N reduces mRNA levels and subsequent protein production of the cyclin-dependent kinase CDC2, resulting in the inactivation of the CDC2/cyclin B complex (maturation promoting factor). When injected intratumorally in a C3-cell induced C57bl/6 mouse tumor model system, M4N demonstrated substantial tumoricidal activity that correlated with a reduction in tumor cell CDC2 protein levels. These findings suggest that M4N may be a useful chemotherapeutic agent for the control of unregulated cellular proliferation.

PMID: 11454698 [PubMed - indexed for MEDLINE]

Cancer Lett. 2001 Sep 28;171(1):47-56.

tetra-O-methylnordihydroguaiaretic acid inhibits melanoma in vivo.

Lambert JD, Meyers RO, Timmermann BN, Dorr RT. Arizona Cancer Center, The University of Arizona, P.O. Box 245024, 1515 North Campbell Avenue, Tucson, AZ 85724-5024, USA.

tetra-O-methylnordihydroguaiaretic acid is a derivative of a naturally-occurring lignan, nordihydroguaiaretic acid, that has previously been shown to inhibit various cancer types in vitro and in vivo. Additionally, nordihydroguaiaretic acid has been shown to have nephrotoxic effects in the rat. Here we show that tetra-O-methylnordihydroguaiaretic acid inhibits the growth of a number of tumor cell lines in vitro by inducing apoptosis in a non-schedule-dependent manner. Further, this compound inhibits the synthesis of DNA by melanoma cells and causes cell cycle arrest in G0/G1 and G2/M phases of the cell cycle. tetra-O-Methylnordihydroguaiaretic acid also inhibits the growth of both murine and human melanomas and human colon cancer in vivo without apparent hepatic or renal toxicity.

PMID: 11485827 [PubMed - indexed for MEDLINE]

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