The novel alkylating prodrug J1: diagnosis directed activity profile ex vivo and combination analyses in vitro

Wickström, Malin; Haglund, Caroline; Lindman, Henrik; Nygren, Peter; Larsson, Rolf; Gullbo, Joachim

doi:10.1007/s10637-007-9092-1

Cited by 36 publications

(37 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tumour cells from patients have previously been shown to detect the diagnosis-specific activity of established agents [5] and this approach has also been used to indicate the activity spectrum of new agents such as disulfiram, etodolac analogues and the melphalan analogue J1 [26][27][28]. Cell lines, in general, have lost many of their diseasespecific characteristics, and show very limited ability to predict for activity in a certain diagnosis, both when tested in vitro and when xenografted into mice [29,30].…”

Section: Discussionmentioning

confidence: 99%

In vitro activity of bortezomib in cultures of patient tumour cells—potential utility in haematological malignancies

et al. 2008

Self Cite

View full text Add to dashboard Cite

Bortezomib represents a new class of anti-cancer drugs, the proteasome inhibitors. We evaluated the in vitro activity of bortezomib with regard to tumour-type specificity and possible mechanisms of drug resistance in 115 samples of tumour cells from patients and in a cell-line panel, using the short-term fluorometric microculture cytotoxicity assay. Bortezomib generally showed dose-response curves with a steep slope. In patient cells, bortezomib was more active in haematological than in solid tumour samples. Myeloma and chronic myeloid leukaemia were the most sensitive tumour types although with great variability in drug response between the individual samples. Colorectal and kidney cancer samples were the least sensitive. In the cell-line panel, only small differences in response were seen between the different cell lines, and the proteasome inhibitors, lactacystin and MG 262, showed an activity pattern similar to that of bortezomib. The cell-line data suggest that resistance to bortezomib was not mediated by MRP-, PgP, GSH-; tubulin and topo II-associated MDR. Combination experiments indicated synergy between bortezomib and arsenic trioxide or irinotecan. The data support the current use of bortezomib but also points to its potential utility in other tumour types and in combination with cytotoxic drugs.

show abstract

Section: Discussionmentioning

confidence: 99%

In vitro activity of bortezomib in cultures of patient tumour cells—potential utility in haematological malignancies

et al. 2008

Self Cite

View full text Add to dashboard Cite

show abstract

“…Most of the research efforts using PCPTC models have focused on prediction of clinical activity of cancer drugs for individual patients [5,6]. However, nonclonogenic in vitro assays performed on PCPTC from different diagnoses can detect tumor-type specific activity of standard [7] and investigational cancer drugs [8,9]. Thus, PCPTC should constitute a potentially valuable tool for preclinical drug development of cancer drugs.…”

Section: Primary Cultures Of Patient Tumor Cells (Pcptc) Is An Alternmentioning

confidence: 99%

Phenotype-based drug screening in primary ovarian carcinoma cultures identifies intracellular iron depletion as a promising strategy for cancer treatment

Gullbo

Fryknäs

Rickardson

et al. 2011

Biochemical Pharmacology

Self Cite

View full text Add to dashboard Cite

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The results indicate the feasibility of using PCPTC for cancer drug screening and that intracellular iron depletion could be a potentially important strategy for cancer therapy.

show abstract

“…13 It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis. 14 Melphalan is a hydrophilic drug, and as such, it does not penetrate cell membranes easily, which is limiting to its anticancer potential. In contrast, melflufen (melphalan flufenamide), a new peptide-conjugated alkylator, is highly lipophilic and therefore penetrates the cell membrane easily.…”

Section: Introductionmentioning

confidence: 99%

Melflufen, a peptide‐conjugated alkylator, is an efficient anti‐neo‐plastic drug in breast cancer cell lines

et al. 2020

View full text Add to dashboard Cite

Melphalan flufenamide (hereinafter referred to as “melflufen”) is a peptide‐conjugated drug currently in phase 3 trials for the treatment of relapsed or refractory multiple myeloma. Due to its lipophilic nature, it readily enters cells, where it is converted to the known alkylator melphalan leading to enrichment of hydrophilic alkylator payloads. Here, we have analysed in vitro and in vivo the efficacy of melflufen on normal and cancerous breast epithelial lines. D492 is a normal‐derived nontumorigenic epithelial progenitor cell line whereas D492HER2 is a tumorigenic version of D492, overexpressing the HER2 oncogene. In addition we used triple negative breast cancer cell line MDA‐MB231. The tumorigenic D492HER2 and MDA‐MB231 cells were more sensitive than normal‐derived D492 cells when treated with melflufen. Compared to the commonly used anti‐cancer drug doxorubicin, melflufen was significantly more effective in reducing cell viability in vitro while it showed comparable effects in vivo. However, melflufen was more efficient in inhibiting metastasis of MDA‐MB231 cells. Melflufen induced DNA damage was confirmed by the expression of the DNA damage proteins ƴH2Ax and 53BP1. The effect of melflufen on D492HER2 was attenuated if cells were pretreated with the aminopeptidase inhibitor bestatin, which is consistent with previous reports demonstrating the importance of aminopeptidase CD13 in facilitating melflufen cleavage. Moreover, analysis of CD13high and CD13low subpopulations of D492HER2 cells and knockdown of CD13 showed that melflufen efficacy is mediated at least in part by CD13. Knockdown of LAP3 and DPP7 aminopeptidases led to similar efficacy reduction, suggesting that also other aminopeptidases may facilitate melflufen conversion. In summary, we have shown that melflufen is a highly efficient anti‐neoplastic agent in breast cancer cell lines and its efficacy is facilitated by aminopeptidases.

show abstract

The novel alkylating prodrug J1: diagnosis directed activity profile ex vivo and combination analyses in vitro

Abstract: In conclusion, the ex vivo profile suggests that further evaluation of J1 as the alkylating agent in for example aggressive breast cancer might be of particular interest, preferentially in combination with DNA-topoisomerase II inhibitors like etoposide.

Cited by 36 publications

References 30 publications

In vitro activity of bortezomib in cultures of patient tumour cells—potential utility in haematological malignancies

In vitro activity of bortezomib in cultures of patient tumour cells—potential utility in haematological malignancies

Phenotype-based drug screening in primary ovarian carcinoma cultures identifies intracellular iron depletion as a promising strategy for cancer treatment

Melflufen, a peptide‐conjugated alkylator, is an efficient anti‐neo‐plastic drug in breast cancer cell lines

Contact Info

Product

Resources

About