Oral squamous cell carcinoma (SCC) is the most common cancer among males and ranks among 5 common cancers in females in India (Gupta, 1993). The high incidence of oral cancer in the Indian subcontinent is causally associated with the widespread habit of tobacco and betel quid chewing. The etiology of oral SCC in the betel-and tobacco-abused Indian population is considerably different as compared with Western populations. Betel quid chewing induces physical abrasions, which might create a mitogenic environment. In addition, chronic exposure of the oral cavity to the mutagenic constituents of betel quid may cause mutations in cellular genes. Heat shock proteins (HSP) or stress proteins are molecular chaperones that are induced by various environmental and pathophysiological stimuli (Ashburner and Bonner, 1979). Members of the 70-kDa heat shock protein (HSP70) family are involved in the regulation of cell growth and transformation. Cell-cycle-related regulation of HSP70 levels has been shown in mammalian cells, suggesting a role for this protein in the control of mammalian cell growth (Ferris et al., 1988). HSP70 binds to p53 (mutant/wild-type) tumour-suppressor protein and, consequently, regulates p53 accumulation or subcellular localization and modulates its biological effects on cells (Davidoff et al., 1992).We have previously reported that elevation in the levels of p53 and HSP70 proteins are early events in the pathogenicity of human oral cancer (Kaur et al., 1994;Kaur and Ralhan, 1995). Differential expression of HSP70 was observed during oral tumorigenesis. A significant increase in HSP70 levels was observed as the tissues progressed from normal to dysplasia and towards carcinoma (p Ͻ 0.001) (Kaur and Ralhan, 1995). Furthermore, an intriguing feature was the unusual cell-surface localization of HSP70 protein in a subset of oral premalignant and malignant lesions, suggesting that HSP70 protein may be involved in tumour immunity (Kaur et al., 1998a). Furthermore, tumours exhibiting elevated HSP70 levels showed poor prognosis (Kaur et al., 1998b). These clinical results revealed that HSP70 may be implicated in oral tumorigenesis. However, the specific role of HSP70 in the genesis of oral cancer is not known. Hence, the present study was undertaken to determine the functional significance of HSP70 in oral oncogenesis by abrogation of its expression in oral cancer cells using antisense HSP70 oligonucleotides. MATERIAL AND METHODS Synthesis and purification of oligomersThe 15-mer phosphorothiolate oligodeoxynucleotides (antisense, sense and nonsense) were synthesized using an automated model 381 Applied Biosystems (Foster City, CA) oligonucleotide synthesizer and purified by high-pressure liquid chromatography and reverse-phase chromatography. HSP70 antisense oligomer (5Ј-CGCGGCTTTGGCCAT-3Ј) was complementary to the initiation codon and 4 downstream codons of human HSP70 mRNA. The corresponding sense oligomer (5Ј-ATGGCCAAAGCCGCG-3Ј) and nonsense oligomer (5Ј-CGGGTATGCTTCGCC-3Ј) were used as controls (Wei et al., 19...
Malignant melanoma are chemoresistant tumors with poor prognosis. The aim of this study was to determine whether multimodality therapy of murine melanoma involving a combination of radiation with thermosen-sitive-liposome-encapsulated melphalan and local hyperthermia would result in enhancement of therapeutic efficacy for a more effective management of melanoma. Melphalan was entrapped in thermosensitive liposomes prepared from natural lipids: egg phosphatidyl choline, cholesterol and ethanol to show phase transition at 42 ± 0.5° C and used in combination with localized heating of B16F10 murine melanoma transplanted into the legs of C57B1/6 mice for selective drug targeting at the tumors and/or radiation for treatment of melanoma. Murine melanoma transplanted into C57B1/6 mice were subjected to bimodality treatments involving a combination of radiation, hyperthermia or melphalan. Partial tumor regression was observed in mice receiving a combination of hyperthermia and radiation (median tumor volume 427.3 mm3) or a combination of free melphalan and radiation (512.1 mm3) as compared to untreated controls (630.9 mm3). Each group consisted of 18 animals, and the results are expressed as median tumor volume ± SD. Animals receiving multimodality therapy comprising irradiation followed by injection of thermosensitive liposomal melphalan and hyperthermic treatment of the tumor-bearing leg at 42 ± 0.5°C for 1 h showed marked tumor regression in comparison with untreated controls or animals treated with a combination of radiation and hyperthermia or radiation and free-drug melphalan. Animals receiving thermoradiochemotherapy also showed prolonged survival; 70% of animals survived for more than 3 months. The study shows greater tumor cell killing, tumor growth delay and prolonged survival produced by a combination of radiation, thermosensitive-liposome-entrap-ped melphalan and hyperthermia compared with animals receiving single-modality or bimodality treatments. It is concluded that this multimodality approach will be potentially useful for more effective management of melanoma.
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