Action of
            <i>p</i>
            -{Di(2-chloroethyl)}-amino-L-phenylalanine on Harding-Passey Mouse Melanoma

Luck, J. Murray

doi:10.1126/science.123.3205.984

Cited by 67 publications

(16 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…From these results it is concluded that there is a higher uptake of melphalan in tumour tissue (6.8p1gg-') than in healthy skin/subcutis (3.2 jg g-'), and data from the literature support this finding (Luck, 1956;Parsons et al, 1981). Melphalan (L-phenylalanine mustard) may be taken up more selectively by melanin-producing cells since phenylalanine is a metabolite of melanin (Luck, 1956).…”

Section: Dsiomentioning

confidence: 88%

See 1 more Smart Citation

Melphalan tissue concentrations in patients treated with regional isolated perfusion for melanoma of the lower limb

Klaase

Kroon²,

Beijnen³

et al. 1994

Br J Cancer

View full text Add to dashboard Cite

SmmaryIn 14 consecutive patients with recurrent melanoma of the lower limb a total of 35 biopsies were taken at the end of perfusion treatment to assess melphalan tissue concentrations in tumour, skin/subcutis and muscle tissue. In tumour tissue (n = 12) the mean melphalan concentration was 6.8 pg g-', which was significantly higher than that of healthy skin/subcutis (3.2 zg g-'; n = 10), but equal to that of muscle tissue (6.5 pg g-'; n = 13). The correlation between melphalan concentration in the tissues and the concentration in the perfusate was studied. The latter was assessed in the form of melphalan peak concentration and the area under the curve (AUCO,60) of the melphalan concentration-time curve. Tumour concentration proved to be correlated linearly with AUCO-.w (R = 0.6, P = 0.002) and muscle concentration with melphalan peak concentration (R = 0.8, P = 0.04). There was no relation between skin/subeutis concentrations and the perfusate parameters. Further research is warranted to study the relationship between melphalan tissue concentration, tumour response and regional toxicity.With regional isolated perfusion, high levels of melphalan can be achieved in the vasculature of a limb with no or negligible leakage to the systemic circulation (Kroon, 1988 (Kroon, 1988). Melphalan as single dose was gradually injected (over one circulation time of the circuit, i.e. within about 2-3 min) into the arterial line. The total perfusate volume measured a median of 750 ml with a haematocrit of about 0.25.During the perfusion perfusate samples were taken from the venous line at 5 min intervals and analysed for melphalan concentration by high-performance liquid chromatography (HPLC) assay (Chang et al., 1978). Melphalan peak concentration and AUCO.60 were assessed. Tumour, skin/subcutis and muscle biopsies were taken at the end of perfusion. The method of analysing the tissue samples was as described by Scott et al. (1990). The specimens were snap frozen and stored at -20'C for batch analysis. They were later thawed, weighed and homogenised in a known volume of acidic buffer. Duplicate specimens were then assayed by HPLC. Differences in melphalan concentration between tumour, skin/subcutis and muscle tissue were pairwise analysed using the Wilcoxon signed-rank test. Mean values are given with the standard deviation. ResultsA total of 35 tissue biopsies were taken, consisting of 12 tumour, 10 skin/subcutis and 13 muscle specimens (Table I). From eight patients three tissue biopsies were available for analysis. The mean melphalan concentration was 6.8 (4.8) lg g-' for tumour biopsies, 3.2 (2.5) pg gI for skin/ subcutis biopsies and 6.5 (3.7)1Lggg' for muscle biopsies. There was a significant difference in melphalan concentration between tumour and skin/subcutis biopsies (P = 0.01) as well as between muscle and skin/subcutis biopsies (P = 0.01).The mean melphalan peak concentration was 48.9 (18.2)ILgml-' and the mean AUCO.

show abstract

Section: Dsiomentioning

confidence: 88%

“…Melphalan (L-phenylalanine mustard) may be taken up more selectively by melanin-producing cells since phenylalanine is a metabolite of melanin (Luck, 1956). In addition, in vitro studies have demonstrated a greater capacity for melphalan transport into malignant cells (Parsons et al, 1981).…”

Section: Dsiomentioning

confidence: 99%

Melphalan tissue concentrations in patients treated with regional isolated perfusion for melanoma of the lower limb

Klaase

Kroon²,

Beijnen³

et al. 1994

Br J Cancer

View full text Add to dashboard Cite

show abstract

“…Most suitable are agents with a high degree of extraction in the perfused extremity and high total body clearance in case of systemic leakage, as well as those cleared at a slow rate from the perfused extremity and at a more rapid rate from the systemic circulation [51]. Following a report from Luck in 1956, demonstrating its efficacy in the treatment of melanoma in a mouse model [52], melphalan (l-phenylalanine-mustard) was selected for the first ILPs in melanoma and sarcoma patients [18]. Due to the excellent results in malignant melanoma [53,54], its pharmacokinetic advantages and its low toxicity, melphalan soon became the standard chemotherapeutic agent for regional perfusions [51,55].…”

Section: Cytostatic Agentsmentioning

confidence: 99%

Isolierte Extremitätenperfusion mit TNFα und Zytostatika: eine Revolution in der Behandlung lokal fortgeschrittener Weichgewebssarkome der Extremitäten

et al. 2009

View full text Add to dashboard Cite

Zusammenfassung. Grundlagen: Lokal fortgeschrittene Weichgewebssarkome der Extremitäten stellen mit dem Ziel der lokalen Tumorkontrolle und dem gleichzeitigen Funktionserhalt eine stetige operative Herausforderung dar. Die isolierte hypertherme Extremitätenperfusion mit TNF und Melphalan ist als neoadjuvante Therapieoption eingeführt worden, um Amputationen zu vermeiden, ohne die Prognose zu verschlechtern.Methodik: Literaturrecherche über die PubMed Datenbank mittels Entrez, kombiniert mit den Erfahrungen der Autoren.Ergebnisse: Anhand mehrerer Studien wurde belegt, dass durch die ILP ein Extremitätenerhalt in bis zu 80 % der Fälle bei tolerablen lokalen und systemischen Komplikationen zu realisieren ist. Die Lokalrezidivrate liegt zwischen 10-20 %.Schlussfolgerungen: Die isolierte Extremitätenperfu-sion mit TNF und Melphalan hat die Behandlung von lokal fortgeschrittenen Weichgewebssarkomen der Extremitäten durch eine deutliche Reduktion der Amputationsraten revolutioniert. Weitere Fortschritte können nach Einführung neuer Substanzen erwartet werden.

show abstract

“…Later, other nitrogen mustards were designed and evaluated in order to improve pharmacokinetics, efficacy, and selectivity for particular tissues. Among them were orally active chlorambucil [6], melphalan originally targeted against high phenylalanine-uptake melanomas [7], and cyclophosphamide developed as a prodrug targeting phosphoamidase-overexpressing cancers [8]. Similarly, uracil mustard (uramustine) effective against CLL and lymphomas was designed with the expectation of more efficient delivery to target DNA [9], and hydantoin-containing spirohydantoin mustard (spiromustine) was designed to cross the blood-brain barrier for the treatment of CNS tumors [10].…”

mentioning

confidence: 99%

The design, synthesis and anticancer activity of new nitrogen mustard derivatives of natural indole phytoalexin 1-methoxyspirobrassinol

Mezencev¹,

Kutschy²,

Salayová³

et al. 2009

neo

View full text Add to dashboard Cite

Nitrogen mustards cis- 1-methoxy-2-deoxy-2-[N,N-bis(2´-chloroethyl)amino]spirobrassinol (4) and trans-1-methoxy-2-deoxy-2-[N,N-bis(2´-chloroethyl)amino]spirobrassinol (5) derived from 1-methoxyspirobrassinol, an indole phytoalexin produced by the Japanese radish Raphanus sativus var. hortensis were designed as prospective dual-action compounds with DNA-alkylating effect and glutathione-depleting effects that may sensitize cancer cells to alkylating agents. Both new compounds demonstrated cytostatic/cytotoxic effects on various leukemia and ovarian cancer cell lines and dsDNA-destabilizing effects in vitro. Compound 4, the more promising of the two compounds, exerts earlier onset of anticancer effects on Jurkat cells via induction of apoptosis compared to the traditional alkylating anticancer agent melphalan. In addition, it demonstrated higher potency on ovarian cancer OVCAR-3 cell line and lower fold resistance between Jurkat and Jurkat-M cells selected for the resistance to melphalan. Therefore, compound 4 may be less affected by certain cancer drug resistance mechanisms than melphalan and it may become a prototype of a new class of anticancer active nitrogen mustards that combine DNA-damaging and DNA-damage-sensitizing properties.

show abstract

Action of p -{Di(2-chloroethyl)}-amino-L-phenylalanine on Harding-Passey Mouse Melanoma

Cited by 67 publications

References 2 publications

Melphalan tissue concentrations in patients treated with regional isolated perfusion for melanoma of the lower limb

Melphalan tissue concentrations in patients treated with regional isolated perfusion for melanoma of the lower limb

Isolierte Extremitätenperfusion mit TNFα und Zytostatika: eine Revolution in der Behandlung lokal fortgeschrittener Weichgewebssarkome der Extremitäten

The design, synthesis and anticancer activity of new nitrogen mustard derivatives of natural indole phytoalexin 1-methoxyspirobrassinol

Contact Info

Product

Resources

About