Synergetic toxicity of DATR, a recombinant soluble human TRAIL mutant, in combination with traditional chemotherapeutics in rats

https://doi.org/10.1016/j.yrtph.2012.09.005Get rights and content

Abstract

The recombinant soluble human TRAIL mutant (DATR), derived from tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), is a promising agent for cancer therapy. The present study evaluated the synergetic toxicity of DATR in combination with traditional chemotherapeutics, including irinotecan, polyene paclitaxel and oxaliplatin in rats. Rats treated with polyene paclitaxel alone or in combination with DATR showed severe diarrhea, appetite inhibition, increasing sodium (Na+), potassium (Cl) and glucose (GLU) and serious disorders in the haematological system. Increasing total bilirubin (TBIL) and blood urea nitrogen (BUN) were detected in the rats treated with oxaliplatin alone or in combination with DATR. Furthermore, except that the BUN and Crea of male rats treated with irinotecan in combination with DATR were higher than those of treated with irinotecan, the addition of DATR does not increase the toxicity induced by irinotecan, polyene paclitaxel and oxaliplatin. In conclusion, DATR probably increases kidney lesions of rat with irinotecan, but does not increase the toxicity induced by polyene paclitaxel and oxaliplatin. This indicated that DATR has promising potential in clinical combination therapies. Furthermore, the toxicity induced by DATR on the liver, kidneys and haematological system should be considered carefully if DATR is used in combination with traditional chemotherapeutics.

Highlights

► DATR is a promising agent for cancer therapy. ► The toxicity of DATR in combination with traditional chemotherapeutics was studied. ► This work will provide guidance to the clinical applications of DATR.

Introduction

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has been identified as a powerful activator of programmed cell death, or apoptosis, in tumour cells, while sparing normal cells (Walczak et al., 1999, Ashkenazi et al., 1999, Ganten et al., 2005). Because of its wide range of antitumor activity in preclinical models, TRAIL has been studied for several years as a promising agent for cancer therapy. In recent years, with the increasing knowledge of TRAIL, combinations with targeted agents are considered to be an option to increase the efficacy of TRAIL therapy. The antitumor activity of TRAIL alone and in combination with chemotherapy has been demonstrated in several mouse xenograft models of human cancers, including colorectal (Ashkenazi et al., 1999), glioma (Roth and Weller, 1999), and breast (Walczak et al., 1999). Thus the synergetic toxicology of TRAIL in combination with traditional chemotherapy or radiotherapy attracts more and more attention.

The recombinant soluble human TRAIL mutant (DATR), recently investigated by Chengdu Diao Pharmaceutical Group Co., Ltd. (Chengdu, China), is a recombinant human 114-281 peptide of wild-type TRAIL without Pro at site 119 and Glu at site 120 (Zou et al., 2010, Zhang et al., 2011). DATR has the similar distribution, but higher concentration in tumor tissues as compared with the wild type TRAIL; furthermore, the pharmacokinetic half-life of DATR is 108 ± 12 min at the dose of 5 mg/kg (Wang et al., 2010), while the wild type TRAIL is 23 ± 6.6 min (Kelley et al., 2001). Drugs with a longer half-time will be used with lower dosage and prolonged dosing interval at the same effectiveness and thereby the side effects will be decreased. Our previous study showed that liver, renal and haematological systems might be the toxic effectors of DATR (Zou et al., 2010, Zhang et al., 2011).

The purpose of the present study was to evaluate the toxicity of DATR in combination with traditional chemotherapeutics, including irinotecan, polyene paclitaxel and oxaliplatin. This work will provide guidance to the clinical applications of DATR.

Section snippets

Chemicals

DATR and TRAIL were provided by Chengdu Diao Pharmaceutical Group Co., Ltd. (Chengdu, China) and stored at −20 °C.

Polyene paclitaxel was supplied by Shanghai PharmLab Co., Ltd. (Shanghai, China) and stored at 4 °C; irinotecan and oxaliplatin were supplied by Jiangsu Hengrui Medicine Co., Ltd. (Lianyungang, China) and stored at 4 °C.

Animals

One hundred and forty Sprague-Dawley rats (70 males and 70 females), aged 5–7 weeks, were provided by Sino-British Sippr/BK LAB Animal Co., Ltd. All rats were housed at

Results

Of all the indexes examined, only significant changes are listed or described throughout the paper.

Discussion

TRAIL has attracted great interest as a promising agent for cancer treatment (Pitti et al., 1996, Wiley et al., 1995). Previous in vivo studies showed that, like TRAIL, both DATR (unpublished) and its closely related analogue possess antitumor activity (Wiley et al., 1995).

Apart from the use of DATR as a monotherapy, combinations with traditional chemotherapeutics are potentially more valuable. An increasing number of possible rationalized TRAIL combination therapies are being tested to enhance

Conflict of interest

There is no conflict of interest.

Acknowledgments

This work was supported by grants from Chengdu Diao Pharmaceutical Group Co., Ltd. (Chengdu, China). We would like to thank Professor Yimin Dai for his excellent technical assistance with the histopathology analysis.

References (25)

  • R.W. Johnstone

    Histone-deacetylase inhibitors: novel drugs for the treatment of cancer

    Nat. Rev. Drug Discov.

    (2002)
  • S.K. Kelley et al.

    Preclinical studies to predict the disposition of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand in humans: characterization of in vivo efficacy, pharmacokinetics, and safety

    J. Pharmacol. Exp. Ther.

    (2001)
  • Cited by (2)

    • Preclinical safety assessment of antipyrine combined with lidocaine hydrochloride as ear drops

      2019, Regulatory Toxicology and Pharmacology
      Citation Excerpt :

      The parameters involved: specific gravity, pH, WBC, nitrite, protein, glucose, ketones, urobilinogen, bilirubin and occult blood. Bone marrow examination was performed by smearing onto carrier plates as described in our previous article (Zou et al., 2012). Upon dissection, the thighbones of rats were dislodged and the bone marrow was extruded onto a carrier plate, where it was smeared in a uniform fashion.

    1

    These authors contributed equally to this work.

    View full text