Resistance in Malignant Tumors: Can Resistance Assays Optimize Cytostatic Chemotherapy?

Lippert, T. H.; Ruoff, H. J.; Volm, M

doi:10.1159/000112864

Cited by 6 publications

(4 citation statements)

References 61 publications

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“…Drug resistance is related to numerous changes in the tumor and its microenvironment 4 and can reflect both tumor and normal tissue. 5 An approach to reduce side effects and drug resistance is the usage of prodrugs. Prodrugs are chemically modified, preferably nontoxic, versions of the active anticancer agent.…”

Section: Introductionmentioning

confidence: 99%

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Chemical Reactivity Window Determines Prodrug Efficiency toward Glutathione Transferase Overexpressing Cancer Cells

et al. 2016

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Glutathione transferases (GSTs) are often overexpressed in tumors and frequently correlated to bad prognosis and resistance against a number of different anticancer drugs. To selectively target these cells and to overcome this resistance we previously have developed prodrugs that are derivatives of existing anticancer drugs (e.g., doxorubicin) incorporating a sulfonamide moiety. When cleaved by GSTs, the prodrug releases the cytostatic moiety predominantly in GST overexpressing cells, thus sparing normal cells with moderate enzyme levels. By modifying the sulfonamide it is possible to control the rate of drug release and specifically target different GSTs. Here we show that the newly synthesized compounds, 4-acetyl-2-nitro-benzenesulfonyl etoposide (ANS–etoposide) and 4-acetyl-2-nitro-benzenesulfonyl doxorubicin (ANS–DOX), function as prodrugs for GSTA1 and MGST1 overexpressing cell lines. ANS–DOX, in particular, showed a desirable cytotoxic profile by inducing toxicity and DNA damage in a GST-dependent manner compared to control cells. Its moderate conversion of 500 nmol/min/mg, as catalyzed by GSTA1, seems hereby essential since the more reactive 2,4-dinitrobenzenesulfonyl doxorubicin (DNS–DOX) (14000 nmol/min/mg) did not display a preference for GSTA1 overexpressing cells. DNS–DOX, however, effectively killed GSTP1 (20 nmol/min/mg) and MGST1 (450 nmol/min/mg) overexpressing cells as did the less reactive 4-mononitrobenzenesulfonyl doxorubicin (MNS–DOX) in a MGST1-dependent manner (1.5 nmol/min/mg) as shown previously. Furthermore, we show that the mechanism of these prodrugs involves a reduction in GSH levels as well as inhibition of the redox regulatory enzyme thioredoxin reductase 1 (TrxR1) by virtue of their electrophilic sulfonamide moiety. TrxR1 is upregulated in many tumors and associated with resistance to chemotherapy and poor patient prognosis. Additionally, the prodrugs potentially acted as a general shuttle system for DOX, by overcoming resistance mechanisms in cells. Here we propose that GST-dependent prodrugs require a conversion rate “window” in order to selectively target GST overexpressing cells, while limiting their effects on normal cells. Prodrugs are furthermore a suitable system to specifically target GSTs and to overcome various drug resistance mechanisms that apply to the parental drug.

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Section: Introductionmentioning

confidence: 99%

“…Another major problem that can limit the effectiveness of cancer treatment is drug resistance. Drug resistance is related to numerous changes in the tumor and its microenvironment and can reflect both tumor and normal tissue . An approach to reduce side effects and drug resistance is the usage of prodrugs.…”

Section: Introductionmentioning

confidence: 99%

Chemical Reactivity Window Determines Prodrug Efficiency toward Glutathione Transferase Overexpressing Cancer Cells

et al. 2016

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“…Drug toxicity [2] and tumour resistance to chemotherapeutic agents [3,4,5,6,7] are 2 principal reasons for treatment failure in a great majority of patients with metastatic cancer. Thus, the development of successful approaches to treat cancer will require combinations of drugs and/or treatment modalities to optimise the tumour response to therapy whilst modulating the harmful side effects.…”

Section: Introductionmentioning

confidence: 99%

Biochemical and Pharmacological Effects of Mitoxantrone and Acetyl-L-Carnitine in Mice with a Solid Form of Ehrlich Tumour

Niang¹,

Soukup²,

Živný

et al. 2011

Chemotherapy

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Background: Dysfunction of the carnitine system in non-tumour tissue following anticancer therapy has been reported. In this setting, supplementation with carnitine derivatives might increase the general metabolic activity of normal cells so that they might better withstand the adverse effects of chemotherapy aimed at tumour cells. Here we investigated the effect of acetyl-L-carnitine (ALC) alone and in combination with the antineoplastic agent mitoxantrone (MX) in an animal cancer model. Methods: The effects of MX and MX-ALC were assessed based on gain or loss of body weight and on local growth of a solid form of Ehrlich tumour inoculated into mice. We also performed biochemical analyses like serum activities of some enzymes signalling the functioning of the liver, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Total protein, albumin and bilirubin were also determined in serum. Under favourable conditions, the Ehrlich tumour readily forms metastases, and this is the reason why we performed histological studies of samples of both the liver and heart in order to identify changes that may have mediated the observed effect of the treatment. In addition to those studies, the survival time of treated animals against controls was also noted. Results: MX monotherapy was associated with lower body weight gain, fewer metastases, smaller tumour size, and lower dissemination. ALC alone promoted survival, but had no potentiating effect on MX therapy in terms of survival. Serum biochemistry changes associated with MX-ALC treatment consisted of a significant (p < 0.05) increase in AST with MX at 6 or 9 mg·kg^–1 plus ALC 200 mg·kg^–1 and a significant (p < 0.05) reduction in total protein compared to the corresponding MX group; serum albumin and bilirubin remained unchanged. Conclusion: ALC in combination with MX, regardless of the dose of MX, led to higher occurrences of metastases with dissemination to the kidneys, lungs, heart, and mediastinum compared to MX treatment alone. These histological findings indicate that ALC is inappropriate to combine with MX in the treatment of a solid cancer. The protective effect of ALC in combination therapy with the cytostatic drug MX was not supported in this study by our findings that the agent did not improve the therapeutic outcomes of MX therapy.

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“…Despite significant advances in the chemotherapeutic treatments of neoplastic diseases, success in the treatment of many solid tumours has been limited [1]. Drug toxicity [2] and resistance development during therapy remain the 2 principal reasons for treatment failure in a great majority of patients with metastatic cancer [3][4][5]. Chemotherapy is the major therapeutic approaches in several human life-threatening diseases including microbial infections, autoimmune diseases and cancers [6] and drug combinations are the key to most cancer treatments [7][8] Thus, the development of successful approaches to treat cancer will require combinations of drugs and/or treatment modalities to optimize the tumour response to therapy whilst modulating the harmful side effects.…”

mentioning

confidence: 99%

Biochemical and Pharmacological Effects of Mitoxantrone and Acetyl-LCarnitine in Mice with a Solid Form of Ehrlich Tumour

Niang¹

2015

Chemotherapy

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Resistance in Malignant Tumors: Can Resistance Assays Optimize Cytostatic Chemotherapy?

Cited by 6 publications

References 61 publications

Chemical Reactivity Window Determines Prodrug Efficiency toward Glutathione Transferase Overexpressing Cancer Cells

Chemical Reactivity Window Determines Prodrug Efficiency toward Glutathione Transferase Overexpressing Cancer Cells

Biochemical and Pharmacological Effects of Mitoxantrone and Acetyl-L-Carnitine in Mice with a Solid Form of Ehrlich Tumour

Biochemical and Pharmacological Effects of Mitoxantrone and Acetyl-LCarnitine in Mice with a Solid Form of Ehrlich Tumour

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