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96 The Lucké renal adenocarcinoma of northern leopard frogs (Rana pipiens) was originally described by Balduin Lucké during the 1930s (Lucké, 1934a,b, 1938a). Lucké’s contribution to this era in medical history is important for several reasons. At the time, Lucké, a pathologist at the University of Pennsylvania, was treading on dangerous terrain when he suggested that the frog renal adenocarcinoma was caused by a virus—in this case, a herpesvirus (Lucké, 1952). A few years earlier, Rockefeller Institute’s Peyton Rous had identified a virus as the etiological agent of a chicken tumor. Rous was castigated by the medical establishment for daring to suggest that a cancer could be caused by a virus. It was believed then that cancers were truly spontaneous. If an agent could be identified as the cause of a malignancy, then the malignancy could not be a “true cancer.” It was not until 1966 that Rous received proper recognition of his viral oncogenesis work and was awarded a Nobel Prize (Rous, 1967). Lucké was a trailblazer in yet another way. Prior to the frog renal adenocarcinoma, no cancer had ever been linked with a herpesvirus. Lucké’s herpesvirus, now known as ranid herpesvirus-1 (RaHV-1), was subsequently shown to be the etiological agent of the cancer. It has been well established (two-thirds of a century later) that in addition to several animal cancers, a number of human malignancies are associated with herpesviruses. These human cancers include Burkitt’s lymphoma of African children, a nasopharyngeal carcinoma that afflicts males of southeast Asia, and Kaposi’s sarcoma (Haverkos, 1996; Howley et al., 1997; Schulz, 1998; McGeoch and Davison, 1999). We should remember that Lucké’s studies on a common North American anuran clearly established for the first time the validity of a herpesvirus etiology for a specific cancer. The depletion of frog populations has been a major concern of herpetologists worldwide (Houlahan et al., 2000). One of the authors of this paper (R.G.M.) has studied the cell biology of the Lucké renal adenocarcinoma since 1958. Early in these studies it became obvious that the best way to obtain frog renal adenocarcinomas for experimental studies was to study frogs in natural populations. Mature frogs were collected and palpated for lumps in the region of the mesonephros. The diagnostic procedure of frog palpation is an imperfect art, but it is sufficiently accurate to permit the identification of many frogs with malignancies. During the early years of this study, northern leopard frogs were adequately abundant to permit the examination of thousands of frogs. Later, it became obvious that frogs were less plentiful. We reported finding reduced frog abundance long before many other scientists recognized the phenomenon (McKinnell et al., 1979). In retrospect, it seems curious that an investigation into the cell biology of a frog neoplasm would lead to early recognition of depleted frog populations. Differentiation therapy—manipulating a cancer cell genome in such a way that its mitotic progeny are forced to give rise to normal cells—is a relatively new concept in the treatment of cancer (Pierce and Speers, 1988; McKinnell, 1989; Sachs, 1993). Differentiation therapy exploits the origin of cancer from aberrant stem cells. Cloning of vertebrates, which originated with the now classic study of northern leopard frogs (Briggs and King, 1952), involves the transfer of nuclei into enucleated eggs with the intent to characterize the differentiative potential of the genome under consideration. Emerging from the cloning studies of frog renal adenocarcinoma nuclei (and differentiation studies elsewhere) was the notion that the genome of cancer cells could be manipulated to undergo substantial differentiation with the formation of normal, or near normal, nuclear progeny. While this research may seem esoteric to some, it led to the development of a treatment protocol for acute promyelocytic leukemia, which is acknowledged to be the “paradigm of differentiation therapy ” (Degos et al., 1995). We can only hope that other human neoplasms will respond to the more gentle differentiation therapy in lieu of highly toxic chemotherapy—if this happens we are at least partly in debt to early studies of a frog renal adenocarcinoma. The history of the Lucké renal adenocarcinoma of northern leopard frogs is impressive in that these studies led to the notions that herpesviruses can cause cancer, that there was a problem with frog populations in the upper Midwest, and that differentiation therapy may lead to a new form of cancer treatment . It is a pleasure, therefore, to review past and present investigations of this...

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