A phase II study of temozolomide in hormone-refractory prostate cancer

Brussel, J.P. van; Busstra, Martijn B.; Lang, Margreet; Catsburg, Tilly; Schröder, Fritz H.; Mickisch, G.

doi:10.1007/s002800051027

Cited by 29 publications

(14 citation statements)

References 4 publications

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“…Kiebert et al, 2003). It has also been tested in patients with metastatic breast cancer (NCIC, 2001) and prostate cancer (van Brussel et al, 2000) but inherent drug resistance has resulted in no clinical benefit. Several groups have measured MGMT expression in human breast tumours and report activity that is low (Cao et (Chen et al, 1992) or high (Musarrat et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts

et al. 2005

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Tumour resistance to chemotherapy involving methylating agents such as DTIC (dacarbazine) and temozolomide is linked to expression of the DNA repair protein O 6 -alkylguanine-DNA alkyltransferase (MGMT). There is considerable interest in improving the efficacy of such O 6 -alkylating chemotherapy by the prior inactivation of MGMT. We have examined the effect of the modified guanine base, O 6 -(4-bromothenyl)guanine (PaTrin-2, Patrint, Lomeguatrib) on MGMT activity and cell or xenograft tumour growth inhibition by temozolomide in the human breast carcinosarcoma cell line, MCF-7. PaTrin-2 effectively inactivated MGMT in MCF-7 cells (IC 50 B6 nM) and in xenografts there was complete inactivation of MGMT within 2 h of dosing (20 mg kg À1 i.p.) and only slight recovery by 24 h. MGMT inactivation in a range of murine host tissues varied between complete and B60%, with extensive recovery by 24 h. PaTrin-2 (10 mM) substantially increased the growth inhibitory effects of temozolomide in MCF-7 cells (D 60 ¼ 10 mM with PaTrin-2 vs 400 mM without). In MCF-7 xenografts, neither temozolomide (100 mg kg À1 day À1 for 5 days) nor PaTrin-2 (20 mg kg À1 day À1 for 5 days) had any significant effect on tumour growth. In contrast, the PaTrin-2 -temozolomide combination produced a substantial tumour growth delay: median tumour quintupling time was increase by 22 days (Po0.005) without any significant increase in toxicity as assessed from animal weight. A PaTrin-2 -temozolomide combination may therefore be beneficial in the treatment of human breast cancers.

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Section: Discussionmentioning

confidence: 99%

O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts

et al. 2005

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“…Unfortunately, metastatic prostate cancer is resistant to a broad range of antineoplastic agents [1][2][3]. Over the past decade new and more effective treatments have been developed based on an increased understanding of the morphological and functional characteristics of prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

Multidrug Resistance in Prostate Cancer

Brussel

Mickisch²

2003

Oncol Res Treat

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Advanced hormone-refractory prostate cancer remains a therapeutic challenge, because all available pharmaceutical concepts have been ineffective in improving cancerspecific survival. Failure of chemotherapy may be caused by multidrug resistance (MDR) mechanisms protecting cancer cells against cytotoxic drugs, and the question arises whether prostate cancer is also using MDR principles resulting in resistance against chemotherapeutic agents. In consequence, an array of diverse pathways known to lead to MDR such as MDR1, MRPs, glutathione, and apoptosis have been examined and partially established at varying degrees in hormone-refractory prostate cancer. Thus, evidence keeps accumulating for the involvement of some MDR mechanisms in the chemoresistance of prostate cancer in vitro and in vivo. For some of them, e.g. MRP1, functional expression appears to be probable. This lends credit to the idea that reversal, circumvention, or overcoming of MDR pathways in advanced prostate cancer may be feasible and will lead to new avenues with improved treatment efficacy in otherwise intractable disease.

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“…Chemotherapeutic drugs damage cancer cells by a variety of mechanisms (e.g., DNA cleavage/alkylation and topoisomerase II inhibition) that are eventually translated into apoptotic signals. Unfortunately, prostate carcinoma, in contrast to several other cancers, does not respond well to single or multiple drug regimens, especially in the case of androgen-independent cancer (7)(8)(9)(10). In addition, chemical anticancer agents are nonspecific and, consequently, damage healthy tissues as well.…”

Section: Introductionmentioning

confidence: 99%

Suppression of Human Prostate Tumor Growth in Mice by a Cytolytic d-, l-Amino Acid Peptide

Papo

Braunstein²,

Eshhar³

et al. 2004

Cancer Research

112

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Gene-encoded host defense peptides are used as part of the innate immunity, and many of them act by directly lysing the cell membrane of the pathogen. A few of these peptides showed anticancer activity in vitro but could not be used in vivo because of their inactivation by serum. We designed a 15-amino acid peptide, composed of D-and L-amino acids (diastereomer), which targets both androgen-independent and androgendependent human prostate carcinoma cell lines (CL1, 22RV1, and LNCaP). Most importantly, we observed a complete arrest of growth in CL1 and 22RV1 xenografts treated intratumorally with the diastereomer. This was also accompanied by a lowering of prostate-specific antigen serum levels secreted by the 22RV1 xenograft. Furthermore, the diastereomer synergized with conventional chemotherapeutics. In contrast, the parental all L-amino acids peptide was highly active only in vitro and could not discriminate between tumor and nontumor cells. Fluorescent confocal microscopy, histopathologic examination, and cell permeability studies (depolarization of transmembrane potential and release of an encapsulated dye) suggest a necrotic mechanism of killing, after a threshold concentration of peptide has been reached. Its destructive killing effect and the simple sequence of the diastereomer make it an attractive chemotherapeutic candidate possessing a new mode of action, with potential to be developed additionally for the treatment of prostate carcinoma.

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A phase II study of temozolomide in hormone-refractory prostate cancer

Cited by 29 publications

References 4 publications

O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts

O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts

Multidrug Resistance in Prostate Cancer

Suppression of Human Prostate Tumor Growth in Mice by a Cytolytic d-, l-Amino Acid Peptide

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