Targeted radiosensitisation by pegylated liposome-encapsulated 3′, 5′-O-dipalmitoyl 5-iodo-2′-deoxyuridine in a head and neck cancer xenograft model

Abstract

5-Iodo-20 -deoxyuridine (IUdR) is an effective radiosensitiser but its clinical development has been limited by toxicity. Prolonged intravenous infusions of IUdR are necessary for optimal tumour uptake but cause dose-limiting myelosuppression. The lack of selective tumour uptake can lead to radiosensitisation of adjacent normal tissues and enhanced local radiation toxicity. Liposomal IUdR delivery offers selective targeting of tumour tissues and avoidance of local and systemic toxicity. In these studies, we report the development of a pegylated liposome containing a lipophilic IUdR derivative (3 0 , 5 0 -O-dipalmitoyl-5-iodo-2 0 -deoxyuridine) for use in a head and neck cancer xenograft model. Initial studies confirmed the ability of IUdR to sensitise two head and neck cancer cell lines to single fractions of radiotherapy (SFRT) and this effect was seen to correlate with the thymidine replacement index in KB cells. In vivo delivery of single doses of either unencapsulated IUdR or pegylated liposomal IUdR (PLIUdR) to nude mice bearing KB xenograft tumours did not enhance the effect of SFRT delivered 16 h later. When PLIUdR was delivered by a protracted administration schedule to a dose of 48 mg kg À1 over 7 days, it enhanced the effect of both 4.5 Gy SFRT and fractionated radiotherapy. PLIUdR was at least as effective as unencapsulated IUdR delivered by multiple intravenous injections or continuous subcutaneous infusion. Immunohistochemistry with a specific anti-IUdR monoclonal antibody confirmed greater levels of tumour staining in tumours from animals treated with PLIUdR compared with those treated with unencapsulated IUdR.

Dependence of Cell Survival on Iododeoxyuridine Concentration in 35-keV Photon-Activated Auger Electron Radiotherapy

“…Deutsch et al (8) showed improved median survival of rats with brain gliosarcoma after receiving 24 Gy in three fractions with IUdR + 4-MV x-rays (30.5 days), as compared to IUdR (21.5 days) or 4-MV x-rays (19.5 days) alone. Harrington et al (9) showed improvement in time to volume tripling of KB xenographs in mice receiving five fractions at 3 Gy/fraction using pegylated liposomal IUdR (PLIUdR) + 137 Cs gamma rays (34 days), as compared to PLIUdR (9 days) or 137 Cs gamma rays (19 days) alone. By contrast, Rousseau et al (10) showed no significant difference in median survival of rats with F98 glioma that received 15 Gy in one fraction when using IUdR + 50 keV photons (46 days) and 50 keV photons alone (44 days).…”

Enhanced Cancer Therapy by Combining Radiation and Chemical Effects Mediated by Nanocarriers

“…The time and administration rate of the liposomes before radiotherapy appeared to influence the therapeutic outcome as demonstrated by Zhang et al . and Harrington et al . This effect was proposed to be related to the mechanism of drug radiosensitization and was therefore expected to differ per chemotherapeutic.…”

Intracerebral delivery of 5-iodo-2′-deoxyuridine in combination with synchrotron stereotactic radiation for the therapy of the F98 glioma

“…Mairs et al (2000) have shown that a single injection of 0.37 MBq of 125 I-IUdR in 10 mL labelled only 6% of tumor cells in C6 glioma-bearing rats whereas similar amounts of 125 I-IUdR released from polymer or infused continuously via an osmotic pump labelled 22% and 34% of tumor cells, respectively. Using a xenograft model for a head and neck cancer, Harrington et al (2004) obtained their best results with pegylated liposome-encapsulated IUdR administered over seven days.…”

“…However, even with a 22% ILS, 10% of the animals survived for > 65 d. There are few studies dealing with i.c. tumor treated with stable IUdR in combination with irradiation (Deutsch et al, 1989(Deutsch et al, , 1990Harrington et al, 2004;Kinsella et al, 1987Kinsella et al, , 1998Williams et al, 1997;Mairs et al, 2000). Deutsch et al (1990) reported on the efficacy of IUdR as a radiosensitizer when administered into the cerebral spinal fluid of the lateral ventricles of 9 L gliosarcoma-bearing rats.…”