Pegylated liposome-encapsulated doxorubicin and cisplatin enhance the effect of radiotherapy in a tumor xenograft model.

Concomitant chemotherapy and radiotherapy (CCRT) has recently been shown to improve treatment outcome in a range of solid tumors. Pegylated liposomes have the potential to target drugs directly to tumors and may increase the efficacy and reduce the toxicity of CCRT by selectively delivering radiosensitizing agents to tumor, as opposed to normal, tissues. In these studies, we have assessed CCRT using pegylated liposome encapsulated doxorubicin (PLED) and pegylated liposome encapsulated cisplatin (PLEC) against KB head and neck cancer xenograft tumors in nude mice. The addition of low-dose (2 mg/kg) PLED (P < 0.001) and PLEC (P < 0.001) significantly increased the effect of 4.5 Gy, but not 9 Gy, single-fraction radiotherapy (SFRT). Both PLED and PLEC were significantly more effective than their unencapsulated counterparts in increasing the effect of SFRT. In addition, PLED (P < 0.001) and PLEC (P < 0.05) significantly increased the effect of fractionated radiotherapy (9 Gy in 3 fractions) in two different dosing schedules (2 mg/kg single dose or three sequential doses of 0.67 mg/kg). Unencapsulated diethylenetriaminepentaacetic acid and pegylated liposomal diethylenetriaminepentaacetic acid were used as controls to test the effect of the liposome vehicle and showed no interaction with 4.5 Gy or 9 Gy SFRT (P > 0.1). CCRT was well-tolerated, with no evidence of increased local or systemic toxicity, as compared with radiotherapy alone. This study is the first to demonstrate the value of pegylated liposomes as vehicles for the delivery of radiosensitizing drugs in CCRT strategies.

Pegylated liposomes have potential as vehicles for intratumoral and subcutaneous drug delivery.

The potential value of intratumoral or s.c. injections of pegylated liposomes as locoregionally targeted therapy of tumors and their draining lymph nodes was assessed in nude mice as part of an ongoing program aimed at developing pegylated liposomal radiosensitizers for the treatment of head and neck cancers. Animals received (111)In-labeled diethylenetriaminepentaacetic acid (DTPA), either encapsulated in pegylated liposomes (IDLPL) or in the unencapsulated form ((111)In-DTPA), as intratumoral or s.c. injections, and the local retention, locoregional nodal drainage, and systemic biodistribution were measured. After intratumoral injections, IDLPL were effectively retained in the tumor with an area under the curve (AUC) between 1 and 96 h of 2,574.4% injected dose per gram hours (%ID/g x h). The corresponding value for (111)In-DTPA was 204.4%ID/g x h. Accumulation of IDLPL was seen in ipsilateral lymph nodes. The maximal ipsilateral:contralateral node ratios were 8:1 (2.2 versus 0.27%ID/g) for inguinal nodes at 24 h and 19:1 (2.5 versus 0.13%ID/g) for axillary nodes at 48 h. Unencapsulated (111)In-DTPA showed no evidence of accumulation in locoregional nodes. After s.c. injection, IDLPL were cleared slowly from the injection site with an AUC between 1 and 192 h of 24,051.1%ID/g x h. Unencapsulated (111)In-DTPA was cleared rapidly with an AUC between 1 and 192 h of 46.4%ID/g x h. Again, significant levels of IDLPL were detected in the ipsilateral locoregional nodes, with ipsilateral:contralateral ratios of 121:1 (57.9 versus 0.48%ID/g) at 24 h (inguinal nodes) and 17:1 (5.2 versus 0.3%ID/g) at 72 h (axillary nodes). There was no retention of unencapsulated (111)In-DTPA in the draining nodes. Locoregional administration of pegylated liposomal radiosensitizers may be a useful approach for targeted therapy of head and neck tumors and their nodal metastases.

The effect of irradiation on the biodistribution of radiolabeled pegylated liposomes.

PURPOSE: The effect of total-body irradiation (TBI) on the biodistribution and pharmacokinetics of (111)In-DTPA-labeled pegylated liposomes (IDLPL) was evaluated in tumor-bearing nude mice as part of an ongoing effort to develop liposome-targeted radiosensitizers. METHODS AND MATERIALS: Mice received TBI (2 Gy or 5 Gy) according to two protocols: (1) to test the effect of radiation delivered 30 min before liposome injection on the time course of IDLPL biodistribution to tumor and normal tissues over 96 h; (2) to test the effect of radiation at times ranging from 72 h to 1 h before liposome injection on tumor and normal tissue uptake of IDLPL at 24 h. Tumor and tissue/organ levels of liposome uptake were measured by dissection and quantitation in a gamma counter. RESULTS: For most tissues (tumor, liver, kidney, lung, skin, heart, and central nervous system), irradiation did not alter IDLPL biodistribution. Splenic uptake appeared to be increased by TBI, but further analysis revealed that this effect was due to reduced splenic weight in irradiated mice. IDLPL uptake was increased in the small intestine, stomach, musculoskeletal system, female reproductive tract, and adrenal glands in irradiated mice. CONCLUSION: These findings suggest that concomitant administration of liposomal radiosensitizers during radical radiotherapy is likely to be safe. However, caution should be exercised in situations in which significant volumes of small intestine or hemopoietic tissue will be irradiated.

Use of monoclonal antibodies for the diagnosis and treatment of bladder cancer.

Although the management of cancer by exploiting properties distinguishing neoplastic and normal cells has always been an attractive concept, it was the development of hybridoma technology and the resulting tumor-associated monoclonal antibodies (MAbs) that offered new prospects for this strategy. Twenty years later, some of the applications of MAbs in oncology are now part of the everyday diagnosis and treatment, while others are the subject of intensive investigation. We reviewed the current applications of MAbs in the diagnosis and treatment of bladder cancer and attempted to put the issue into perspective, with particular presentation of their therapeutic potential.

Paclitaxel and gemcitabine vs. paclitaxel and pegylated liposomal doxorubicin in advanced non-nasopharyngeal head and neck cancer. An efficacy and cost analysis randomized study conducted by the Hellenic Cooperative Oncology Group.

BACKGROUND: The prognosis of patients with recurrent and/or metastatic head and neck cancer (HNC) is poor. Median survival of these patients following chemotherapy is in the range of 6 to 9 months. In the present randomized phase III trial we compared two new combinations containing new drugs with proven activity in phase II studies with patients with HNC. PATIENTS AND METHODS: From November 1999 until November 2004, 166 eligible patients with HNC were enrolled in the study. They were treated with paclitaxel 175 mg/m(2) on day 1 and gemcitabine 1000 mg/m(2) on days 1 and 8 every 3 weeks (group A, 85 patients) or with paclitaxel, as in group A, and pegylated liposomal doxorubicin 40 mg/m(2) on day 1 every 4 weeks (group B, 81 patients). RESULTS: There was no significant difference in response rate (20% versus 29%, P = 0.21), time to disease progression (median; 4.4 months versus 6.0 months, P = 0.09) and survival (median; 8.6 months versus 11.05 months, P = 0.25). Both regimens were generally well tolerated. The most frequently reported side effect, apart from alopecia, was neutropenia. Overall, there was no significant difference in severe toxicity between the two treatment arms. CONCLUSIONS: The present study could not demonstrate a survival benefit with either regimen. Both treatments were well tolerated. Randomized studies comparing each of the two regimens with standard chemotherapy are warranted.

Biodistribution and pharmacokinetics of 111In-DTPA-labelled pegylated liposomes in a human tumour xenograft model: implications for novel targeting strategies.

The biodistribution and pharmacokinetics of 111In-DTPA-labelled pegylated liposomes in tumour-bearing nude mice was studied to examine possible applications of pegylated liposome-targeted anti-cancer therapies. Nude mice received an intravenous injection of 100 microl of 111In-DTPA-labelled pegylated liposomes, containing 0.37-0.74 MBq of activity. The t1/2alpha and t1/2beta of 111In-DTPA-labelled pegylated liposomes were 1.1 and 10.3 h, respectively. Tumour uptake was maximal at 24 h at 5.5 +/- 3.0% ID g(-1). Significant reticuloendothelial system uptake was demonstrated with 19.3 +/- 2.8 and 18.8 +/- 4.2% ID g(-1) at 24 h in the liver and spleen, respectively. Other sites of appreciable deposition were the kidney, skin, female reproductive tract and to a lesser extent the gastrointestinal tract. There was no indication of cumulative deposition of pegylated liposomes in the lung, central nervous system, musculoskeletal system, heart or adrenal glands. In contrast, the t1/2alpha and t1/2beta of unencapsulated 111In-DTPA were 5 min and 1.1 h, respectively, with no evidence of accumulation in tumour or normal tissues. Incubation of 111In-DTPA-labelled pegylated liposomes in human serum for up to 10 days confirmed that they are very stable, with only minor leakage of their contents. The potential applications of pegylated liposomes in the arena of targeted therapy of solid cancers are discussed.

Influence of tumour size on uptake of(111)ln-DTPA-labelled pegylated liposomes in a human tumour xenograft model.

The relationship between tumour size and uptake of(111)In-DTPA-labelled pegylated liposomes has been examined in a human head and neck cancer xenograft model in nude mice. The mean tumour uptake of(111)In-labelled pegylated liposomes at 24 hours was 7.2 +/- 6.6% ID/g. Liposome uptake for tumours < 0.1 g, 0.1-1.0 g and > 1.0 g was 15.1 +/- 10.8, 5.9 +/- 2.2 and 3.0 +/- 1.3% ID/g, respectively. An inverse correlation between tumour weight and liposome uptake was observed by both Spearman's rank correlation test (r(s)= - 0.573, P< 0.001) and Pearson's correlation coefficient (r(s)= - 0.555, P< 0.001). For 18 tumours with macroscopic central necrosis, the ratio of uptake in the tumour rim relative to the necrotic tumour core was 11.2 +/- 6.4. Measurement of tumour vascular volume for tumours of various sizes revealed an inverse correlation between tumour weight and tumour vascular volume (Spearman's rank correlation test, r(s)= - 0.598, P< 0.001), consistent with poor or heterogeneous vascularization of larger tumours. These data have important implications for the clinical application of pegylated liposome targeted strategies for solid cancers which are discussed in detail.

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

5-Iodo-2'-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', 5'-O-dipalmitoyl-5-iodo-2'-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(-1) 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.