Phase II trial of tirapazamine combined with cisplatin in chemotherapy of advanced malignant melanoma

Bedikian, A. Y.; Legha, Sewa S.; Eton, Omar; Buzaid, Antônio C.; Papadopoulos, Nicholas E.; Coates, S.; Simmons, T.; Neefe, John R.; Roemeling, Reinhard von

doi:10.1023/a:1008249232000

Cited by 25 publications

(9 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since then it has been evaluated in several clinical trials, including Phase III clinical trials for non-small cell lung carcinoma, where it is used in combination with cisplatin [67]. In combination with cisplatin, TPZ is also currently undergoing Phase II trials for breast cancer, head and neck cancer and melanoma [68][69][70][71]. In combination with a cisplatin-based chemoradiation treatment, it is being studied in randomized Phase II trials for advanced neck and head carcinomas [72].…”

Section: N-oxide-based Bioreductive Agentsmentioning

confidence: 99%

Sensor/Effector Drug Design with Potential Relevance to Cancer

Fry¹,

Jacob

2006

CPD

View full text Add to dashboard Cite

Many cancer cells exhibit a disturbed intracellular redox balance, making them distinctively different from their 'healthy' counterparts. Some tumors, such as solid lung carcinoma, are hypoxic, and its cells are therefore more reducing than normal, while others, such as the ones of breast and prostate cancer, proliferate under oxidative stress (OS). These biochemical differences between normal and tumor tissue are significant, and can be used to design effective, yet selective redox drugs. The resulting drug design can follow different avenues. The bioreductive approach is perhaps the most advanced, and uses changes in intracellular redox enzyme concentrations to activate otherwise inactive pro-drug molecules inside cancer cells by a reductive step, often followed by further chemical transformations, such as hydrolysis. Related anti-cancer compounds, such as varacin, employ an intricate combination of reduction and oxidation processes to develop their therapeutic potential inside cells. Another, just emerging approach considers the use of pro-oxidants and catalysts, taking advantage of the inherent efficiency and selectivity associated with OS-induced cell death. Even more complex tactics, such as chelator-assisted photodynamic therapy, exploit the intracellular metal homeostasis to target cancer cells. Together, all of these avenues try to endow molecules with a combination of sensor and effector properties, which might allow them to single out and selectively kill cancer cells without the need for cell-selective drug delivery systems. In the long term, such agents could be associated with high efficiency, good selectivity and dramatically reduced drug side effects.

show abstract

Section: N-oxide-based Bioreductive Agentsmentioning

confidence: 99%

Sensor/Effector Drug Design with Potential Relevance to Cancer

Fry¹,

Jacob

2006

CPD

View full text Add to dashboard Cite

show abstract

“…The prototype drug in this class is mitomycin C (MMC) (Rockwell et al, 1993), which is used in the treatment of breast (Hortobagyi, 1993), non-small-cell lung (Spain, 1993), head and neck (Coia, 1993), colorectal (Cummings et al, 1993) and gastric (Fujita et al, 1998) cancer. Interest in bioreductive agents has been raised by recent studies of combination treatment of MMC with radiation (Boyer, 1997), and by new agents, such as 3-hydroxymethyl-5-aziridinyl-1-methyl-2(1H-indole-4,7-dione)prop-β-en-α-ol (EO9) (Schellens, 1994) and tirapazamine (Bedikian et al, 1997;Miller et al, 1997). The one-electron reducing enzyme, NADPH:cytochrome P450 reductase (EC 1.6.2.4), may be the most important activating enzyme for MMC (Rockwell, 1993), but NAD(P)H:(quinone acceptor) oxidoreductase [EC 1.6.99.2] (DT-diaphorase), a two-electron reducing enzyme, is also a major activator in many systems (Begleiter et al, 1989(Begleiter et al, , 1992Riley and Workman, 1992;Ross et al, 1993).…”

mentioning

confidence: 99%

Enhanced cytotoxicity of mitomycin C in human tumour cells with inducers of DT-diaphorase

et al. 1999

View full text Add to dashboard Cite

Summary DT-diaphorase is a two-electron reducing enzyme that activates the bioreductive anti-tumour agent, mitomycin C (MMC). Cell lines having elevated levels of DT-diaphorase are generally more sensitive to MMC. We have shown that DT-diaphorase can be induced in human tumour cells by a number of compounds, including 1,2-dithiole-3-thione. In this study, we investigated whether induction of DT-diaphorase could enhance the cytotoxic activity of MMC in six human tumour cell lines representing four tumour types. DT-diaphorase was induced by many dietary inducers, including propyl gallate, dimethyl maleate, dimethyl fumarate and sulforaphane. The cytotoxicity of MMC was significantly increased in four tumour lines with the increase ranging from 1.4-to threefold. In contrast, MMC activity was not increased in SK-MEL-28 human melanoma cells and AGS human gastric cancer cells, cell lines that have high base levels of DT-diaphorase activity. Toxicity to normal human marrow cells was increased by 50% when MMC was combined with 1,2-dithiole-3-thione, but this increase was small in comparison with the threefold increase in cytotoxicity to tumour cells. This study demonstrates that induction of DT-diaphorase can increase the cytotoxic activity of MMC in human tumour cell lines, and suggests that it may be possible to use non-toxic inducers of DT-diaphorase to enhance the efficacy of bioreductive anti-tumour agents.

show abstract

“…CIV and to LM reduced the cytotoxicity of the chcmoiherapculic agents cisplatin. This may explain at least in part the inefficiency of cDDP in the treatment of patients with uveal melanoma that progressed to liver metastasis (35), the median survival rale being extended of only a few months at the most (4.8). Despite their anchorageindependence (17).…”

Section: Discussionmentioning

confidence: 99%

Role of the extracellular matrix proteins in the resistance of SP6.5 uveal melanoma cells toward cisplatin

Bérubé

Talbot²,

Collin³

et al. 2005

Int J Oncol

View full text Add to dashboard Cite

Abstract. Uveal melanoma is the most frequent primary intraocular tumor in the adult population. This malignancy has a high mortality rate and responds poorly to existing chemotherapy. Recently, the tumor environment has been found to exert a profound influence on drug response through cell interaction with components from the extracellular matrix (ECM). In the present study, wc investigated whether individual components from the ECM may affect cell survival and/or cell death induced by the cytotoxic agent cisplatin on the SP6.5 uveal melanoma cell line. Tumor cells were shown by immunofluorescence analyses to be surrounded by the ECM proteins fibronectin (FN), type IV collagen (CIV) and laminin (LM). both at the primary and metastatic sites. Binding of SP6.5 cells lo FN. LM and CIV is primarily dictated by the expression of membrane bound integrins from the Bl family as revealed by cell adhesion assays conducted on ECM-coated culture plates. Analysis of cell death by flow cytometry demonstrated that culluring SP6.5 cells in the presence of FN. CIV and LM. substantially reduced the percentage of cells undergoing apoplosis after cisplatin treatment when compared with those seeded on a nonpermissive matrix. These results suggest that adhesion of the SP6.5 uveal melanoma cells to the ECM proteins FN. CIV and LM might therefore confer resistance to the chemoiherapeulic agent cisplatin. The cellular resistance induced by the ECM proteins toward cisplatin could explain in part the local recurrence of metastasis derived from uveal melanoma often observed clinically after chemotherapy.

show abstract

Phase II trial of tirapazamine combined with cisplatin in chemotherapy of advanced malignant melanoma

Abstract: The TPZ-cDDP combination has definite activity against chemotherapy-naïve patients with cutaneous melanoma and warrant further studies in combination with other cytotoxic agents.

Cited by 25 publications

References 13 publications

Sensor/Effector Drug Design with Potential Relevance to Cancer

Sensor/Effector Drug Design with Potential Relevance to Cancer

Enhanced cytotoxicity of mitomycin C in human tumour cells with inducers of DT-diaphorase

Role of the extracellular matrix proteins in the resistance of SP6.5 uveal melanoma cells toward cisplatin

Contact Info

Product

Resources

About