Anticancer Res. 2013 Aug;33(8):3005-14.

Optimal timing in concomitant chemoradiation therapy of colorectal tumors in nude mouse treated with Cisplatin and LipoplatinTM

Thititip Tippayamontri1,2, Rami Kotb3, 4, Benoit Paquette1,2 and Léon Sanche1,2

1Department of Nuclear Medicine and Radiobiology, 2Center of Radiotherapy Research, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada 3Department of Systemic Therapy, BC Cancer Agency’s Vancouver Island Centre, Victoria, BC, Canada. 4Department of Medicine, University of British Columbia.

 

Abstract:

Background: Optimal conditions for efficient concomitant chemoradiation treatment of colorectal cancer with cisplatin still need to be better defined. In addition, intolerance of healthy tissue to cisplatin prevents the full exploitation of its radiosensitizing potential.  A liposomal formulation of cisplatin, LipoplatinTM, was proposed to overcome its toxicity. Using an animal model of colorectal cancer, we determined the platinum window of maximum radiosensitisation and synergism, defined by studying the pharmacokinetics and time-dependent intracellular distribution of cisplatin and LipoplatinTM. Materials and Methods: In nude mice bearing HCT116 human colorectal carcinoma treated with cisplatin or LipoplatinTM, the platinum accumulation in blood, serum, different normal tissues, tumor and different tumor cell compartments was measured by inductively coupled plasma mass spectrometry. Radiation treatment (15 Gy) was given 4, 24, and 48 h after drug administration and was correlated to the amount of platinum−DNA adducts in the cancer cells. The resulting tumor growth delay was reported and correlated to apoptosis analysis.

Results: The optimal treatment and highest apoptosis were observed when radiation was given at 4 h or 48 h after drug injection. These times correspond to the times of maximal platinum binding to tumor DNA. An enhancement factor (ratio of group treated by combined treatment compared to chemotherapy alone) of 13.00 was obtained with LipoplatinTM, and 4.09 for cisplatin when tumor irradiation was performed 48 h after drug administration.

Conclusion: The most efficient combination treatment of radiation with cisplatin or LipoplatinTM was observed when binding of platinum to DNA was highest. These results improve our understanding of the mechanisms of platinum-induced radiosensitization and should have significant impact on the design of more efficient treatment protocols.

Keywords: Radiotherapy, chemotherapy, concomitant therapy, colorectal cancer, cisplatin, LipoplatinTM.

 

Supplement:

The combination of chemotherapeutic drugs and radiation is now widely used in the treatment of solid tumors. Although the chemoradiation treatment with platinum (Pt) drugs has been proposed to improve patient outcome with better locoregional tumor control and/or by potentially eliminating distant metastases, the narrow therapeutic index after combined treatments is still a limiting factor. This is mainly due to severe toxicity, which excludes escalation of platinum drugs concentration in clinical practice (1). Therefore, in order to increase the efficiency of concomitant chemoradiation treatment of cancer, investigation of optimal conditions for highest radiosensitizing activity of Pt drugs, such as cisplatin, is needed, as well as the development of effective, but less toxic agents and treatment protocols.

Cisplatin is a chemotherapeutic agent, which under certain conditions can become a radiosensitizer. Cisplatin given concurrently with radiation enhanced cell death by several mechanisms, including the inhibition of radiation-induced DNA damage repair and the induction of additional damage or modification of radiation induced DNA damage (2). In recent fundamental investigations on cisplatin-DNA complexes (3), it was found that DNA damage induced by the low-energy secondary electrons, produced by ionizing radiation, was considerably increased when cisplatin was bound to DNA. This finding implies that the highest concomitant effect should be achieved, when the binding of the drug to DNA is highest. The main aim of the reported studies (4) was to verify this hypothesis (i.e., minimize tumor growth when radiation is given at the time of maximum binding of cisplatin to the DNA of cancer cells). The investigations were performed not only with cisplatin, but also with Lipoplatin, the encapsulated form of cisplatin (4).

The application of liposomes as drug carriers offers the possibility to improve their anticancer efficacy. LipoplatinTM has several therapeutic advantages: i) the anionic lipid dipalmityl phosphatidyl glycerol provides fusogenic properties, presumably acting at the level of entry of the drug through the cell membrane after reaching the target tissue, ii) the PEG polymer coating of the liposomal formulations allows the drug particles to pass undetected by the macrophages and immune-system cells so as to remain in the circulation of body fluids and tissues for long periods ii) the drug extravasates preferentially into solid tumors and metastases tissue through the altered, leaky vasculature (5).

In animal experiments, nude mice were implanted with HCT116 human colorectal xenografts. We assessed the variation of platinum concentrations in blood, in different normal tissues and in tumor tissues. The results enabled to investigate different scheduling of irradiation and evaluate the importance of cisplatin-DNA adduct levels treatment after injection of the drug. The results of combined radiation and chemotherapy treatment varied with timing of drug exposure and radiotherapy (4). Maximum antitumor treatment was achieved when either of the Pt drugs was administered 4 h or 48 h prior to radiation, which correlated to the highest level of platinum bound to the DNA (Fig.1), as predicted from fundamental studies (3).  Moreover, our in vivo data confirmed the potential role of LipoplatinTM as a radiosensitizer.

Our studies showed that the time-dependent accumulation of platinum in tumor cells and in its different cellular compartments is not linear and not completely similar to that of healthy cells (4). This opens the way to determine the best time correlation between irradiation and drug administration so as to achieve the highest concomitant anticancer effect with Pt chemotherapeutic agents. In other terms, there is a “Platinium time window” where synergism with radiotherapy, and very probably clinical benefit, is at its maximum without added toxicity. Given that most clinical Pt-based chemoradiation treatment protocols in rectal cancers or other neoplasia consist of daily fractionated radiation and intermittent chemotherapy (6), it appears clear that this window of maximal synergism is not used and most of radiation is given at times of sub-optimal or minimal synergism. There is clearly room to improve these clinical protocols in order to achieve better patient outcomes with less toxicity.

Léon Sanche-fig1

Cisplatin binding to DNA

Léon Sanche-fig2

Figure1. Timing in concomitant chemoradiation treatment. Left: Diverse sites of intrastrand and interstrand binding of cisplatin to DNA. Right: Concentration of Pt-DNA adducts in the tumoral DNA of mice bearing human colorectal cancer HCT116 xenografts, as a function of time after administration of cisplatin and LipoplatinTM. The mice were irradiated at 4, 24 and 48 h after injection of the drug.

 

References:

1)   Tannock  I.F. Treatment of cancer with radiation and drugs. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 14:3156-3174, 1996.

2)   Prestwich R.J., Shaakespeare, D. and Waters, S. The rationale for and the current role of chemoradiotherapy. Journal of Radiothrapy in Practice, 6:11-19, 2007.

3)   Zheng Y., Hunting D.J., Ayotte P. and Sanche L. Role of secondary low-energy electrons in the concomitant chemoradiation therapy of cancer. Physical Review Letters 100:198101, 2008.

4)   Tippayamontri T., Kotb R., Paquette B. and Sanche L. Efficacy of cisplatin and LipoplatinTM in combined treatment with radiation of a colorectal tumor in nude mouse. Anticancer Research, 33:3005-14, 2013.

5)  Boulikas T. and Vougiouka M. Cisplatin and platinum drugs at the molecular level (Review). Oncology Reports, 10:1663-1682, 2003.

6)   Andre, N. and Schmiegel, W. Chemoradiotherapy for colorectal cancer. Gut, 54:1194-1202, 2005.

 

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