Chronic irradiation of mice with ultraviolet (UV) light produces a systemic alteration of an immunologic nature. This alteration is detectable in mice long before primary skin cancers induced by UV light begin to appear. The alteration results in the failure of UV-irradiated mice to reject highly antigenic, transplanted UV-induced tumors that are rejected by unirradiated syngeneic recipients. The immunologic aspct of this systemic alteration was demonstrated by transferring lymphoid cells from UV-irradiated mice to lethally x-irradiated recipients. These recipients were unable to resist a later challenge with a syngeneic UV-induced tumor, whereas those given lymphoid cells from normal donors were resistant to tumor growth.Parabiosis of normal mice with UV-irradiated mice, followed by tumor challenge of both parabionts with a UV-induced tumor, resulted in the growth of the challenge tumors in both UV-irradiated and unirradiated mice. Splenic lymphocytes from tumor-implanted UV-treated mice were not cytotoxic in vitro against UV-induced tumors, whereas under identical conditions cells from tumor-implanted, unirradiated mice were highly cytotoxic. Our findings suggest that repeated UV irradiation can circumvent an immunologic mechanism that might otherwise destroy nascent UV-induced primary tumors that are strongly antigenic.Most skin tumors induced in mice by chronic UV irradiation are highly antigenic and can be transplanted only in immunosuppressed recipients (1). Because a high proportion of these noncross-reacting tumors are immunologically rejected upon transplantation to normal syngeneic recipients, we wished to discover how these tumors are able to arise and grow progressively in their original hosts.Our recent work suggested that chronic treatment with UV light altered the host in some way, and made it unable to eliminate these highly antigenic tumors (2). We found that long before primary tumors appeared, the UV-treated mice were unable to resist transplants of UV-induced tumors, even though such transplants were rejected by unirradiated animals. The progressive growth of these tumors in UV-treated mice was due to a systemic alteration in the animals, induced by a relatively short course of UV irradiation of the skin (3). Although this systemic alteration prevented the immunologic rejection of syngeneic UV-induced tumors, it did not affect the ability of UV-treated animals to reject skin and tumor allografts (2).In the following experiments we are continuing our attempts to characterize this UV light-induced systemic alteration. Specifically, we question whether or not the systemic alteration has an immunologic nature. MATERIALS AND METHODSMice. Specific pathogen-free mice of the inbred strain C3H/HeN(MTV-) were supplied by the Frederick Cancer Research Center Animal Production Facility. The mice were started on their regimen of UV irradiation at 6-8 weeks of age.UV Irradiation. The light source was a bank of six Westinghouse FS40 Sunlamps, which delivered an average dose rate of 2.8 J/m2 per s ov...

Exposure of mice to ultraviolet radiation results in the development of suppressor T lymphocytes in lymphoid organs, followed by the appearance of primary skin cancers. The presence or absence of these suppressor lymphocytes determines whether or not primary cancers will develop in the ultraviolet-irradiated skin. This demonstrates the importance of immunological regulatory pathways in carcinogenesis and provides an example of immunological surveillance.

We describe the synthesis and characterization of a 5′ conjugate between a 2′-O-Me phosphorothioate antisense oligonucleotide and a bivalent RGD (arginine–glycine–aspartic acid) peptide that is a high-affinity ligand for the αvβ3 integrin. We used αvβ3-positive melanoma cells transfected with a reporter comprised of the firefly luciferase gene interrupted by an abnormally spliced intron. Intranuclear delivery of a specific antisense oligonucleotide (termed 623) corrects splicing and allows luciferase expression in these cells. The RGD–623 conjugate or a cationic lipid-623 complex produced significant increases in luciferase expression, while ‘free’ 623 did not. However, the kinetics of luciferase expression was distinct; the RGD–623 conjugate produced a gradual increase followed by a gradual decline, while the cationic lipid-623 complex caused a rapid increase followed by a monotonic decline. The subcellular distribution of the oligonucleotide delivered using cationic lipids included both cytoplasmic vesicles and the nucleus, while the RGD–623 conjugate was primarily found in cytoplasmic vesicles that partially co-localized with a marker for caveolae. Both the cellular uptake and the biological effect of the RGD–623 conjugate were blocked by excess RGD peptide. These observations suggest that the bivalent RGD peptide–oligonucleotide conjugate enters cells via a process of receptor-mediated endocytosis mediated by the αvβ3 integrin.