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Melanoma, Parkinson’s disease and levodopa:causal or spurious link? A review of the literatureRoberto Zanettia, Dora Loriab and Stefano Rossoa Since the early 1970s, a number of case reports have correlation between social class and melanoma risk; (5) suggested that levodopa therapy for Parkinson’s disease the relationship between the risk of Parkinson’s disease increases the risk of cutaneous malignant melanoma. As and the risk of melanoma may be due to a common genetic yet, no formal epidemiological study has been conducted profile or it can be attributed to a confounding role of social to verify this hypothesis. To elucidate the relationship class, associated with both melanoma and Parkinson’s between levodopa and the risk of cutaneous malignant disease possibly through an inverse relationship with melanoma, a systematic literature search using tobacco smoking. Melanoma Res 16:201–206 computerized bibliographic databases was done. This review presents the case history evidence for and againstthe hypothesis of a causal association, and explores possible epidemiological, genetic, social, biochemical and Keywords: causality, levodopa, melanoma, Parkinson’s disease, smoking toxicological factors that may increase the risk of melanoma in Parkinson’s disease patients. All the case aPiedmont Cancer Registry, Center for Oncology, Turin, Italy and bInstitute of reports in the literature were considered. We concluded Oncology AH Roffo, Buenos Aires, Argentina that (1) there is no epidemiological or experimentalevidence of a causal role of levodopa in increasing the risk Correspondence and requests for reprints to Roberto Zanetti, MD, PhD, of melanoma incidence or progression; (2) there is good Piedmont Cancer Registry, CPO-Centre for Oncology Prevention, Via SanFrancesco da Paola, 31, 10123 Torino, Italy evidence of an excess risk of melanoma in patients with Tel: + 39 011 6333870; fax: + 39 011 6333861; e-mail: roberto.zanetti@cpo.it Parkinson’s disease; (3) there is good evidence of aprotective effect of tobacco smoking on the risk for Received 9 June 2005 Accepted 24 February 2006 Parkinson’s disease; (4) there is good evidence of positive association with melanoma risk, and the toxicology of Levodopa treatment for Parkinson’s disease (PD) was levodopa with respect to melanocytic cells. In addition, introduced at the end of the 1960s. In 1972, Skibba et al.
the review presents possible explanations for the associa- [1] described a case of skin melanoma in a patient with tion between PD, levodopa and CMM, and questions PD. Since then, numerous case reports of a similar nature whether this association is causal or produced by other No formal epidemiological study of the hypothesis that levodopa therapy increases the risk of melanoma devel- opment has, however, been undertaken. A cohort study in As indicated above, the first case mentioned in the Danish PD patients [2] found a consistent increase of literature was reported by Skibba et al. [1] in 1972. The melanomas. Common steps in the metabolic pathways of patient, a 50-year-old man already affected by PD, was levodopa and melanin synthesis also suggest potential for diagnosed with melanoma in the left scapular area before interaction, although this has not been confirmed levodopa treatment. This was treated with surgical experimentally. Despite the paucity of data, the prescrib- removal and a skin transplant; there was no evidence of ing information of levodopa drug includes a warning of a metastasis. In September 1971, the patient started possible increased risk of occurrence or progression of levodopa treatment. In January of the following year, melanoma during treatment, and recommends a prudent some pigmented nodules were removed from the approach to use in PD patients with a previous history of transplant area, with a diagnosis of recurring melanoma.
Levodopa treatment was interrupted at the end ofJanuary 1972.
The present review examines what is relevant to theassociation between levodopa and melanoma: the case Further cases were reported in the literature and report studies on melanomas during levodopa treatment, summarized by Lieberman and Shupack [3]. The authors the epidemiology and aetiology of cutaneous malignant presented the highest dosages of levodopa but not the melanoma (CMM), the aetiology of PD and the length of treatment, which varied from a few weeks to Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
several months. The data show that, in four of the five bibliography and the 50 participants mentioned by the cases, melanoma actually preceded levodopa treatment author come from an unpublished source (files of a by 2–88 months. One death occurred as a result of rapid levodopa manufacturer), thereby making a strict compar- clinical evolution (6 months between bleeding of a ison impossible. We believe that, independently of their naevus and death from diffuse metastasis) and two cases exhaustiveness, the case reports mentioned by Pfu in which melanoma had not recurred following treatment.
and Przybilla [18] and quoted in the present review In another case, recurrence is not documented.
represent the majority of this type of investigation.
Subsequently, another report linking the occurrence of superficial spreading melanoma without metastasis with The incidence of melanoma is well documented by the levodopa in a PD patient is considered to be questionable world network of cancer registries. Since the early 1960s, because levodopa treatment was not actually started the incidence has shown the fastest increase among owing to the presence of the melanoma [4].
tumours, matched only recently by prostate cancer. Datafrom the Surveillance, Epidemiology and End Results The final case report published in this period (1970s) programme showed that the increase of CMM incidence was presented by Sober and Wick [5]. In this case, a in North America was particularly high in men, reaching a 48-year-old man was diagnosed with melanoma 6 years level of more than 40 cases per 100 000 in several areas in after the onset of PD and the beginning of levodopa 1999 [21]. In European men (1993–1997), CMM treatment. One year after the melanoma diagnosis, the incidence was as high as 17 cases per 100 000 in patient had not had a recurrence or metastasis.
Switzerland, 10 in Denmark, nine in the Netherlandsand more than seven in Finland, England and Scotland; The state-of-the-art at this point is well summarized in rates were slightly lower in women. Rates in southern the letters exchanged in JAMA in 1979 by Fermaglich and Europe were lower still, but with a consistent increase Delaney [4] on one side and Sober and Wick [5] on the compared with earlier data: doubling in Spain from other. Fermaglich and Delaney [4] stated that the 2.2 in 1983–1987 to four cases per 100 000 in the period available evidence suggests a risk of melanoma progres- 1993–1997, for example, and increasing by about 30% in sion associated with the use of levodopa, and they Italy in the same period, from five to seven cases per recommend its proscription, suggesting bromocriptine as 100 000 [22]. In fact, mortality in developed countries an alternative treatment. In contrast, Sober and Wick [5] showed increasing trends only till the end of the 1980s, regard the evidence (including experimental results) as when it stabilized or started to decline slightly. At insufficient. Nevertheless, they agree upon a cautious present, mortality rates are 2.8 and 1.3 in men and approach until there is clear epidemiological evidence on women in North America, 1.6 and 1.2 in Europe, and five Further case reports were published in the 1980s and Knowledge of the aetiology of melanoma derives 1990s and in more recent years. As in the first group of substantially from good case–control studies conducted case reports, the melanoma sometimes followed and from the 1980s onwards in America [23–27], Australia sometimes preceded levodopa treatment [6–19].
[28,29] and Europe [30–33]. These studies show that theaetiology consists of complex interactions between It must be noted that some of these case reports are genetic characteristics (i.e. skin phenotype), social and ‘negative’ in terms of a link between levodopa and environmental factors (e.g. exposure to sunlight).
melanoma. For example, the paper by Weiner et al. [15]presented nine melanoma cases in levodopa-treated PD All the indicators of pale complexion and sensitivity to patients; in only one case did the melanoma recur.
sunlight are associated with a 2–4-fold increased risk of Woofter and Manyam [16] described the case of a man melanoma. Moreover, specific population subgroups with who died at the age of 97 years, after having taken 4.3 kg a collection of risk factors, such as people with red hair, of levodopa in the 15 years following the melanoma blue eyes, a tendency to sunburn, and with a large number of freckles and naevi have observed relative risksup to 10 times that of the population average. Number of The case reports included above, with the exception of sunburns and age at first sunburn can be considered as those of Wobbes and Bonenkamp [19], are also reported intermediate indicators of skin sensibility and sun ¨tzner and Przybilla [18] in their 1997 review of the literature. In 2000, Siple et al. [20] found 34 case reportson Medline within 1999, and counted a total of melanoma and sun exposure were observed early on in were, however, not completely listed in the article’s the research on this topic. First, there is a protective Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Melanoma, Parkinson’s disease and levodopa Zanetti et al.
effect of persistent tanning from chronic sun exposure, Kessler and Diamond [47] published a second large-scale observed in cohorts of outdoor workers [31,32]. Second, case–control study in 1971 analysing 468 cases (and as there is an increasing risk of melanoma with higher social many controls) with a valid interview. Less strong class. Factors such as opportunities for intermittent sun protective effects of smoking than those in the study exposure on holidays, during seaside sojourns and water by Nefzger et al. [46] were found (RR: 0.66). The sports are (even more so in the past) positively related to proportion of smokers in the control group was somewhat an increase of melanoma risk and to social class.
lower than that of the general population (contrary to thatin the study by Nefzger et al. [46] in which it was slightlyhigher), and this can explain the differences between the Aetiological epidemiology of Parkinson’s disease and association with melanoma riskNotwithstanding Subsequently, several other studies were conducted, epidemiological studies, the aetiology of PD remains which differed in design, quality and scale. In general, substantially unknown. Studies have focused on different however, investigators came to the conclusion that factors and have been of varying size and quality [34–39].
tobacco smoking or tobacco-related cancers were inver-sely related to PD. Morens et al. [40] provide a complete Reviews have been conducted by Morens et al. [40], review of 34 studies published up to 1995.
Tanner and Ben-Shlomo [41] and Fiala et al. [42].
More recent case–control studies in PD patients clearly confirmed the decreased risk in smokers [48,49].
concerns the protective effect of tobacco smoking.
Epidemiological The most important study with respect to melanoma risk relationship, and the hypothesis is supported by a is a cohort study conducted in Denmark between 1977 credible biological mechanism. Consequently, the rela- and 1999 in which data from 14 088 patients with a PD tionship between tobacco smoking and risk of PD is diagnosis were linked with the Danish Cancer Registry examined in depth in this review because, in our opinion, incidence files [2]. Apart from strongly confirming the it also explains the apparent association between PD and deficit in tobacco-related cancers, this study found a clear excess of cutaneous melanoma risk (RR 1.95; confidenceinterval: 1.4–2.6). This excess of melanoma risk could be The first formal evidence of an inverse relationship explained by the inverse relationship between tobacco between tobacco smoking and PD risk is derived from smoking and social class, especially in men, whereas the Dorn’s study on American war veterans [43]. Smoking risk of melanoma is positively correlated with this habits of a large cohort of American war veterans were variable. If tobacco smoking protects against PD, PD established through a mailed questionnaire and revealed a patients would tend to belong to a higher social class and net mortality deficit (mortality ratio 0.36) from PD in smokers compared with nonsmokers. When presentingthis highly surprising result, the authors excluded two Biochemical relationship between levodopa possible artefacts, namely that PD symptoms lead to cessation of smoking and that PD might be obscured as a It is well known that pigmented neurons, containing cause of death in death certificates by other concurrent neuromelanin and high amounts of iron, are typically lost causes associated with tobacco. The same negative in PD. In contrast, neurons that survive are free of relationship was also noted in other large studies on neuromelanin and contain low amounts of iron [50].
tobacco consumption, specifically those by Doll and Peto[44] on British medical doctors and by Hammond [45] on One of the important functions of cutaneous melanin is one million Americans. Indeed, the final results of Doll its role in the determination of phenotypic appearance.
and Peto [44] confirmed the protective effect of tobacco More than 80 genetic loci that regulate mammalian pigmentation are known, and a summary of the biochem-ical control of melanogenesis has been published [51].
A case–control study was later carried out by Nefzger et al.
[46], with 198 cases and 198 controls being analysed.
The fact that levodopa is an intermediate in the A protective effect was found for tobacco consumption biosynthesis of melanins necessitates investigation of [relative risk (RR) 0.33–0.44] and the data showed a good the suggested link between levodopa and malignancies consistency for the different modalities and durations of arising from melanocytic cells. The biochemical pathway exposure to tobacco. Of note, the patients’ education responsible for the production of several pigments in levels and job titles were found to be higher than those of mammalian melanocytes is quite well established [52] Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
melanoma should not be regarded as a contraindication toantiparkinsonian therapy.
DiscussionBy definition, case reports are descriptive and not demonstrative or conclusive. When they signal a possible association that implies a risk, this should lead to thedesign and performance of adequate formal studies totest the hypothesis. In the case of levodopa and melanoma, this has not happened and, over the last 30 years, even more case reports have monotonouslyappeared. Even assuming, however, that there is no Mechanism of formation of phaeomelanins and eumelanins. Common increased melanoma risk following levodopa treatment, steps in the metabolic pathway of levodopa and melanins.
the real number of cases of random association betweenlevodopa and melanoma would have been enormouslyhigher than the few dozens identified by case reports,given the growing incidence of melanoma in the general In-vitro studiesIt has been shown that levodopa, an amino acid that is not population and the growing PD prevalence that is treated normally found in cellular proteins, is incorporated into with levodopa. This argument has already been expressed different cell lines and melanoma cells [53]. When the by Sober and Wick [60] in their letter in 1979, and toxicity of levodopa on melanoma cells was discovered, it repeated by Rampen [61] in his letter in 1998.
led to the consideration of its therapeutic potential. It hasbeen shown that levodopa blocks cell proliferation in all Moreover, some case reports are spurious and even phases of the cell cycle [54]. Clement et al. [55] advised contradictory. This is the case with those publications caution when extrapolating results of culture assays to reporting melanoma before the beginning of levodopa treatment and those in which melanoma did not progressover the course of treatment. Nevertheless, the falseimpression of an association persists and a further case report in a similar vein was published in 2002 [19].
In animalsA few earlier studies investigate the effect of levodopa onexperimental tumours. In one, levodopa at high dosage While the evidence for a role of levodopa in increasing the enhanced the survival time of animals bearing melanoma risk of melanoma or its progression is completely and mammary carcinoma but did not have any effect on inconsistent, as also discussed by Fiala et al. [42] in their review of a long series of published case reports, there isgood evidence of a positive association between melano-ma incidence and PD. This evidence is mainly based on Other antitumour assays demonstrate that levodopa and the results of the Danish PD cohort study [2], in which dopamine, the principal levodopa catabolite, are capable the association between PD and melanoma is very high of prolonging the survival of mice [57].
(standardized incidence ratio: 2.35) within the first yearafter PD diagnosis and decreases in subsequent periods, implying that the association is not due to PD treatment, Melanocytes have a ‘nonvital’ role in adult humans, so but to some pre-existing causal or confounding factor.
potential toxicity to normal melanocytes is not a serious A causal relationship would mean that a common factor problem. The possibility of using these agents to act could cause both the destruction of substantia nigra selectively on cells with mature phenotypes (like neurons and the neoplastic transformation of cutaneous melanoma cells), in combination with other neoplastic melanocytes, rather than that PD could directly cause drugs, appears interesting. More details can be found in a CMM or vice versa. A common genetic pattern could be review by Wick [58]. In 1991, Gurney et al. [59] responsible for both diseases and so explain their attempted to treat malignant melanoma with high association. Or, alternatively, the association may be due concentrations of levodopa but, in the 17 metastatic to a third external factor associated with both PD and melanoma patients given oral levodopa/carbidopa, no CMM. At least one such factor exists, and that is social clinical response was shown. Nevertheless, no patient in class. Indeed, there is good evidence that this is this study experienced an increase in tumour growth positively associated with melanoma, probably through a following treatment. According to the authors, while greater recreational sun exposure habit among the levodopa/carbidopa may be regarded as an ineffective wealthier participants. Similarly, there are direct ele- treatment for metastatic melanoma, a previous history of ments (in the study by Nefzger et al. [46] for instance) of Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Melanoma, Parkinson’s disease and levodopa Zanetti et al.
a positive association between social class and PD. Above Bernstein JE, Medenica M, Soltani K, Solomon A, Lorincz AL. Levodopa all, however, there is the weight of the following administration and multiple primary cutaneous melanomas. Arch Dermatol1980; 116:1041–1044.
combination: an inverse association between tobacco Rosin MA, Braun M III. Malignant melanoma and levodopa. Cutis 1984; and PD, an inverse association between tobacco and social class, and thus a direct positive association between Kochar AS. Development of malignant melanoma after levodopa therapy fordisease. Report of a case and review of the literature. Am J Med 1985; PD and social class. The magnitude of each of these associations (with OR between 1.5 and 2.5 each) Przybilla B, Schwab U, Landthaler M, Braun-Falco O. Development of two adequately explains the PD–melanoma association ob- malignant melanomas during administration of levodopa. Acta DermatolVenereol 1985; 65:556–557.
served in the Danish cohort [2]. It must be highlighted Rampen FH. Levodopa and melanoma: three cases and review of literature.
that this sequence of reasoning about causality remains J Neurol Neurosurg Psychiatry 1985; 48:585–588.
true, independently of whether each factor is a causal or a Sandyk R. Accelerated growth of malignant melanoma by levodopa inParkinson’s disease and role of the pineal gland [letter]. Int J Neurosci confounding one. Some of them are more likely to be confounding factors (e.g. social class); others are more Haider SA, Thaller VT. Lid melanoma and parkinsonism. Br J Ophthalmol likely to be truly causal factors (recreational sun exposure Merello M, Esteguy M, Perazzo F, Leiguarda R. Impaired levodopa response as a risk factor for melanoma, and nicotine as a protective in Parkinson’s disease during melanoma therapy. Clin Neuropharmacol Weiner WJ, Singer C, Sanchez-Ramos JR, Goldenberg JN. Levodopa,melanoma, and Parkinson’s disease. Neurology 1993; 43:674–677.
Woofter MJ, Manyam BV. Safety of long-term levodopa therapy in malignant No evidence exists of a causal role of levodopa in melanoma. Clin Neuropharmacol 1994; 17:315–319.
Kleinhans M, Schmid-Grendelmeier P, Burg G. Levodopa and malignant increasing the risk of melanoma or accelerating its growth.
melanoma: case report and review of the literature. A contribution to causal The early association observed can be interpreted as relationship between levodopa and the development of malignant casual, and subsequent associations published are no melanoma. Hautarzt 1996; 47:432–437.
Pfu¨tzner W, Przybilla B. Malignant melanoma and levodopa: is there a more than anecdotal, and even then less frequent than relationship? Two new cases and a review of the literature. J Am Acad would be expected on the ground of no additional risk.
Dermatol 1997; 37(2 Pt 2):332–336.
Wobbes T, Bonenkamp JJ. Melanoma while using levodopa due toParkinson’s disease: causal association unlikely. Ned Tijdschr Geneeskd No evidence exists of a carcinogenic effect of levodopa in experimental models: results are negative in culture cells, Siple JF, Schneider DC, Wanlass WA, Rosenblatt BK. Levodopa in rodents and in humans. Levodopa has been tested as therapy and the risk of malignant melanoma. Ann Pharmacother 2000;34:382–385.
an antineoplastic drug, without showing any appreciable Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, et al., effect either in slowing or spreading and accelerating editors. SEER Cancer Statistics Review, 1973–1999, National Cancer Institute. 2002; Bethesda, Maryland, http://seer.cancer.gov/csr/1973_1999/.
Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB, editors Cancer Good evidence, mainly based on the statistically powerful incidence in five continents. Vol VIII. Lyon: IARC Scientific Publications;2003; No 155, IARC.
Danish cohort study, suggests that the incidence of Lew RA, Sober AJ, Cook N, Marvell R, Fitzpatrick TB. Sun exposure habits in melanoma is doubled in people affected by PD. Strong patients with cutaneous melanoma: a case control study. J Dermatol Surg evidence exists of a protective effect of tobacco smoking Elwood JM, Whitehead SM, Davison J, Stewart M, Galt M. Malignant against the risk of PD; the effect is attributable to a role melanoma in England: risks associated with naevi, freckles, social class, hair of nicotine in the substantia nigra. As a consequence, the colour and sunburn. Int J Epidemiol 1990; 19:801–810.
association between melanoma and PD can be inter- Holly EA, Kelly JW, Shpall SN, Chiu SH. Number of melanocytic nevi as amajor risk factor for malignant melanoma. J Am Acad Dermatol 1987; preted as noncausal, if a common genetic pattern increases the risk of both, or confused by social class, Dubin N, Moeseson M, Pasternack BS. Sun exposure and malignant which is positively related to both (in the case of PD, via melanoma among susceptible individuals. Environ Health Perspect 1989;81:139–151.
Loria D, Matos E. Risk factors for cutaneous melanoma: a case control studyin Argentina. Int J Dermatol 2001; 40:108–114.
Green A, Siskind V, Bain C, Alexander J. Sunburn and malignant melanoma.
Skibba JL, Pinckley J, Gilbert EF, Johnson RO. Multiple primary melanoma Holman CDJ, Armstrong BK, Heenan PJ. Relationship of cutaneous following administration of levodopa. Arch Pathol Lab Med 1972; 93: malignant melanoma to individual sunlight-exposure habits. J Natl Cancer Olsen JH, Friis S, Frederiksen K, McLaughlin JK, Mellemkjaer L, Moller H.
MacKie RM, Aitchison T. Severe sunburn and subsequent risk of primary Atypical cancer pattern in patients with Parkinson’s disease. Br J Cancer cutaneous malignant melanoma in Scotland. Br J Cancer 1982; 46: Lieberman AN, Shupack JL. Levodopa and melanoma. Neurology 1974; Tucker MA, Stone BJ, Jensen OM. The Danish case control study of cutaneous malignant melanoma II. Importance of UV-light exposure. Int J Fermaglich J, Delaney MP. Melanoma and Parkinson’s disease. Neurology Zanetti R, Rosso S, Faggiano F, Roffino R, Colonna S, Martina G. A case Sober AJ, Wick MM. Levodopa therapy and malignant melanoma. JAMA control study of melanoma of the skin in the province of Torino, Italy. Rev Epide´miol Sante´ Publique 1988; 36:309–317.
Botteri A, Nordstro¨m PO. Samband mellan levodopa-behandling och Elwood JM, Whitehead SM, Davison J, Stewart M, Galt M. Malignant maligna tumo¨rer. (Connection between levodopa therapy and malignant melanoma in England: risks associated with naevi, freckles, social class, hair tumors) [in Swedish]. La¨kartidningen 1979; 76:316–317.
colour and sunburn. Int J Epidemiol 1990; 19:801–810.
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Kessler II. Parkinson’s disease in epidemiologic perspective. In: Kessler II, Diamond EL. Epidemiologic studies of Parkinson’s disease.
Schoenberg BS, editor. Neurological epidemiology: principles and Smoking and Parkinson’s disease: a survey and explanatory hypothesis.
applications. New York: Raven Press; 1978. pp. 355–383.
Duvoisin RC, Eldridge R, Williams A. A twin study of Parkinson’s disease.
Gorell JM, Rybicki BA, Johnson CC, Peterson EL. Smoking and Parkinson’s disease: a dose–response relationship. Neurology 1999; 52: Marttila RJ, Rinne UK. Arteriosclerosis, heredity, and some previous infections in the aetiology of Parkinson’s disease: a case control study.
Checkoway H, Powers K, Smith-Weller T, Franklin GM, Longstreth WT Jr, Clin Neurol Neurosurg 1976; 79:45–46.
Swanson PD. Parkinson’s disease risks associated with cigarette smoking, Stern M, Dulaney E, Gruber SB, Golbe L, Bergen M, Hurtig H, et al. The alcohol consumption, and caffeine intake. Am J Epidemiol 2002; 155: epidemiology of Parkinson’s disease: a case control study of young-onset and old-onset patients. Arch Neurol 1991; 48:903–907.
Hirsch EC. Biochemistry of Parkinson’s disease with special reference to Ward CD, Duvoisin RC, Ince SE, Nutt JD, Eldridge R, Calne DB. Parkinson’s dopaminergic systems. Mol Neurobiol 1994; 9:135–142.
disease in 65 pairs of twins and in a set of quadruplets. Neurology 1983; Hearing V. Biochemical control of melanogenesis and melanosomal organization. J Invest Dermatol Symp Proc 1999; 4:24–28.
Ward CD, Duvoisin RC, Ince SE, Nutt JD, Eldridge R, Calne DB, et al.
Prota G. Melanins and melanogenesis. San Diego: Academic Press; 1992.
Parkinson’s disease in twins. Adv Neurol 1984; 40:341–344.
Wick MM, Byers L, Frei E III. L-dopa: selective toxicity for melanoma cells in Morens DM, Grandinetti A, Reed D, White LR, Ross GW. Cigarette smoking and protection from Parkinson’s disease: false association or aetiologic Kable EP, Favier D, Parson PG. Sensitivity of human melanoma cells to clue? Neurology 1995; 45:1041–1051.
L-dopa and DL-buthionine (S,R)-sulfoximine. Cancer Res 1989; 49: Tanner CM, Ben-Shlomo Y. Epidemiology of Parkinson’s disease. Adv Clement MV, Long LH, Ramalingam J, Halliwell B. The cytotoxicity of Fiala KH, Whetteckey J, Manyam BV. Malignant melanoma and levodopa in dopamine may be an artefact of cell culture. J Neurochem 2002; 81: Parkinson’s disease: causality or coincidence? Parkinsonism Relat Disord Shohat B, Kott E, Bornstein B. The effect of L-dopa, noradrenaline and Kahn HA. The Dorn study of smoking and mortality among US veterans: adrenaline on P-388 mouse leukaemia, B-16 mouse melanoma and E0771 a report on eight and one-half years of observation. Epidemiological mammary carcinoma. Experimentia 1975; 31:110–111.
approaches to the study of cancer and other chronic diseases. Natl Cancer Maat B. Pigment hyperplasia of epidermis following feeding of L-dopa to Inst Monogr (Washington GPO) 1966; 19:100–125.
elderly rats. J Natl Cancer Inst 1977; 58:1433–1436.
Doll R, Peto R. Mortality in relation to smoking: 20 years’ observations on Wick MM. An experimental approach to the chemotherapy of melanoma.
male British doctors. BMJ 1976; 2:1525–1536.
Hammond EC. Smoking in relation to the death rates of one million men and Gurney H, Coates A, Kefford R. The use of L-dopa and carbidopa women. Epidemiological approaches to the study of cancer and other in metastatic malignant melanoma. J Invest Dermatol 1991; 96: chronic diseases. Natl Cancer Inst Monogr (Washington GPO) 1966; Sober AJ, Wick MM. Levodopa and melanoma. JAMA 1979; 241:883.
Nefzger MD, Quadfasel FA, Karl VC. A retrospective study of smoking in Rampen F. Melanoma and levodopa. J Am Acad Dermatol 1998; 38 Parkinson’s disease. Am J Epidemiol 1968; 88:149–158.
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