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NCI CANCERLIT® Search: Hereditary Melanoma - June 2002
National Cancer Institute®
Last Modified: June 1, 2002
- Re: DNA repair, dysplastic nevi, and sunlight sensitivity in the development of cutaneous malignant melanoma.
- Quantitative nested real-time RT-PCR specific for tyrosinase transcripts to quantitate minimal residual disease.
- Emerging concepts and technologies in melanoma research.
- Rarity of CDK4 germline mutations in familial melanoma.
- Differentially expressed genes identified in human melanoma cell lines with different metastatic behaviour using high density oligonucleotide
- Histological, immunological and molecular features of a nasal mucosa primary melanoma associated with nasal melanosis.
- Transient resistance to B16F10 melanoma growth and metastasis in CD43-/- mice.
- CIT: identification of differentially expressed clusters of genes from microarray data.
- Multiple primary melanoma revisited.
- Assessment of genomic instability in breast cancer and uveal melanoma by random amplified polymorphic DNA analysis.
- Acridine-modified, clamp-forming antisense oligonucleotides synergize with cisplatin to inhibit c-Myc expression and B16-F0 tumor progression.
- Cytokine gene transfection for autologous and allogeneic melanoma vaccines.
- IL-11 is a potent anti-melanoma factor.
- Improving the retroviral vector (RV) systems for immunotherapy of cancer.
- Tumor immunity in mice immunized with fibroblasts transfected with tumor DNA.
- Humoral responses to melanoma vaccine, genetically modified with interleukin 6 and soluble interleukin 6 receptor.
- Flow and video-imaging cytometry--usefulness of DNA ploidy measurements in diagnosis of malignant melanoma.
- The novel tumour suppressor gene ING1 is overexpressed in human melanoma cell lines.
- Promoter methylation controls the expression of MAGE2, 3 and 4 genes in human cutaneous melanoma.
- Novel carboranes with a DNA binding unit for the treatment of cancer by boron neutron capture therapy.
- The XAGE family of cancer/testis-associated genes: alignment and expression profile in normal tissues, melanoma lesions and Ewing's
- Photobiology and genetics of malignant melanoma.
- Clinical implications of cytogenetic abnormalities in melanoma.
- Effective gene transfer to human melanomas via integrin-targeted adenoviral vectors.
- Decreased expression of Ku70/Ku80 proteins in malignant melanomas of the oral cavity.
- Development of cutaneous amelanotic melanoma in the absence of a functional tyrosinase.
- Combined HSV-TK/GCV and secondary lymphoid tissue chemokine gene therapy inhibits tumor growth and elicits potent antitumor CTL response in
- Molecular determinants of human uveal melanoma invasion and metastasis.
- [Of mice and humans. Updates on susceptibility and tumor suppression of malignant melanoma]
- Human brain tumor cell culture characterization after immunostimulatory gene transfer.
- Structural consequences of tumor-derived mutations in p16INK4a probed by limited proteolysis.
Table of Contents
1
UI - 12011229
AU - Pedeux R; Boniol M; Autier P; Dore JF
TI -
Re: DNA repair, dysplastic nevi, and sunlight sensitivity in the
development of cutaneous malignant melanoma.
SO - J Natl Cancer Inst 2002 May 15;94(10):772-3; discussion 773-4
2
UI - 11814456
AU - Max N; Wolf K; Thiel E; Keilholz U
TI -
Quantitative nested real-time RT-PCR specific for tyrosinase transcripts
to quantitate minimal residual disease.
SO - Clin Chim Acta 2002 Mar;317(1-2):39-46
AD - Department of Medicine III, University Hospital Benjamin Franklin, Free
University Berlin, Hindenburgdamm 30, 12200, Berlin, Germany.
BACKGROUND: Quantification of tumor markers expressed by
occult-circulating tumor cells may be of prognostic value in a variety
of neoplasms and disease stages. Here, we report on a quantitative
nested real-time polymerase chain reaction (PCR) assay to quantify rare
transcripts using the Light Cycler system. Tyrosinase mRNA, only
expressed by melanocytes and melanoma cells, was used as the model tumor
marker. METHODS: For the establishment and sensitivity testing of this
novel real-time PCR assay, 10 ml EDTA blood from healthy volunteers was
spiked with 10(1)-10(5) MKR cells (the melanoma cell line). Following
RNA extraction and cDNA synthesis, nested and single round PCRs were
performed. Subsequently, 35 blood samples of 22 melanoma patients were
analyzed. RESULTS: Nested PCRs provided quantitative data with a
quantitative range of five orders of magnitude of tyrosinase mRNA
equivalent to 1-10(4) MKR cells/ml of blood. Nested PCR with 35
pre-amplification cycles displayed the quantitative data for nine
tyrosinase transcript-positive samples out of 35 blood samples, whereas
nested PCR with 20 pre-amplification cycles or single round PCR were
less sensitive. CONCLUSIONS: These experiments indicate that nested PCR,
which is much more sensitive than single round PCR, is a useful tool
even for the quantification of rare transcripts-a result with important
implications for the study of minimal residual disease (MRD) in melanoma
as well as in other malignancies.
3
UI - 11828252
AU - Herlyn M
TI -
Emerging concepts and technologies in melanoma research.
SO - Melanoma Res 2002 Feb;12(1):3-8
AD - The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
herlynm@wistar.upenn.edu
Melanoma research has made great advances in recent years. Particularly
in the field of immunology, melanoma researchers have opened new avenues
for basic and translational cancer research overall. Emerging research
areas such as molecular epidemiology promise to develop a similar
leadership role. On the other hand, research in biology, genetics or
experimental therapy of melanoma has remained confined to few
laboratories and entire research areas are not covered due to lack of
researchers and resources. New developments in defining stem cells in
skin and bone marrow enable us to develop new concepts for melanoma
development and progression. New technologies allow rapid progress but
they require close cooperation between laboratories. The field has to
better bridge experimental with clinical research and increase
communication. Corroboration with advocacy groups should activate the
public for increased awareness and funding.
4
UI - 11828258
AU - Goldstein AM; Chidambaram A; Halpern A; Holly EA; Guerry IV D; Sagebiel
TI -
R; Elder DE; Tucker MA
Rarity of CDK4 germline mutations in familial melanoma.
SO - Melanoma Res 2002 Feb;12(1):51-5
AD - Genetic Epidemiology Branch, Division of Cancer Epidemiology and
Genetics, National Cancer Institute, Bethesda, Maryland, USA.
goldstea@exchange.nih.gov
To date, two genes have been implicated in melanoma pathogenesis. The
first, CDKN2A, is a tumour suppressor gene with germline mutations
detected in 20% of melanoma-prone families. The second, CDK4, is an
oncogene with co-segregating germline mutations detected in only three
kindreds worldwide. We examined 16 American melanoma-prone families for
mutations in all coding exons of CDK4 and screened additional members of
two previously reported families with the Arg24Cys germline CDK4
mutation to evaluate the penetrance of the mutation. No new CDK4
mutations were identified. In the two Arg24Cys families, the penetrance
was estimated to be 63%. Overall, 12 out of 12 invasive melanoma
patients, none out of one in situ melanoma patient, five out of 13
dysplastic naevi patients, two out of 15 unaffected family members, and
none out of 10 spouses carried the Arg24Cys mutation. Dysplastic naevi
did not strongly co-segregate with the Arg24Cys mutation. Thus the
phenotype observed in melanoma-prone CDK4 families appears to be more
complex than just the CDK4 mutation. Both genetic and environmental
factors are likely to contribute to the occurrence of melanoma and
dysplastic naevi in these families. In summary, although CDK4 is a
melanoma susceptibility gene, it plays a minor role in hereditary
melanoma.
5
UI - 11828259
AU - de Wit NJ; Burtscher HJ; Weidle UH; Ruiter DJ; van Muijen GN
TI -
Differentially expressed genes identified in human melanoma cell lines
with different metastatic behaviour using high density oligonucleotide
arrays.
SO - Melanoma Res 2002 Feb;12(1):57-69
AD - Department of Pathology, University Medical Centre St Radboud, PO Box
9101, 6500 HB Nijmegen, The Netherlands. n.dewit@pathol.azn.nl
The increasing incidence of melanoma and the lack of effective
treatment, with the exception of tumour excision before the onset of the
metastatic phase, make it important to identify genes that may function
as new molecular markers for diagnosis and/or prognosis or as new
targets for therapy. Recently, a new technique using high density
oligonucleotide arrays has been developed to simultaneously screen for
the expression of thousands of genes. We used this technique to compare
the mRNA expression patterns of two human melanoma cell lines with
different metastatic behaviour. Eight differentially expressed genes,
namely apolipoprotein CII, tyrosinase-related protein 1, transforming
growth factor-beta superfamily, subtilisin-like protein, elongation
factor 1 alpha2, alpha2-macroglobulin, human cell division cycle 10 and
serine/threonine protein kinase (DYRK1A), were selected to validate the
array results by Northern blotting and reverse transcription-polymerase
chain reaction (RT-PCR). Furthermore, a reliable correlation between
differential expression of these genes in the melanoma cell lines and in
fresh lesions of melanocytic tumour progression was demonstrated by
RT-PCR analysis. Altogether, our data indicate that high density
oligonucleotide arrays are a valuable and reliable tool to screen for
differentially expressed genes, and that our study may be considered a
basic step in the characterization of genes that are involved in the
(malignant) progression of melanoma.
6
UI - 11828261
AU - Hofbauer GF; Boni R; Simmen D; Mihic D; Nestle FO; Burg G; Dummer R
TI -
Histological, immunological and molecular features of a nasal mucosa
primary melanoma associated with nasal melanosis.
SO - Melanoma Res 2002 Feb;12(1):77-82
AD - Department of Dermatology, Head and Neck Surgery, University Hospital,
Gloriastrasse 31, 8091 Zurich, Switzerland.
Nasal mucosa melanoma is a rare entity that may occur together with
nasal melanosis. The histological and immunological features and loss of
heterozygosity analysis of such lesions have not been reported to date.
In the study presented here short-term cell cultures were established
from the patient's melanoma and subsequent relapses. Histology,
immunohistochemistry, reverse transcription-polymerase chain reaction
enzyme-linked immunosorbent assay, human leukocyte antigen analysis,
microdissection with subsequent polymerase chain reaction for analysis
of loss of heterozygosity were used to characterize the tumour and other
cells. Melanoma of the nasal cavity was found, with a surrounding
proliferation of atypical melanocytes corresponding to nasal melanosis.
Immunoreactivity was found for S-100, gp100, tyrosinase and MelanA
protein. Loss of heterozygosity for a p16-flanking marker was found in
the tumour and the melanotic cells. Short-term cell cultures expressed
tyrosinase and MUC18 at the mRNA level and intercellular adhesion
molecule-1 (ICAM-1) and interleukin-12 receptor at the protein level.
This is the first time short-term cell cultures have been established
and analysed from such a tumour. Melanoma-associated antigens were
identified within the tumour. The melanoma and the melanotic cells
showed loss of heterozygosity for the p16 gene, which is implicated in
melanoma development. This points to a common origin in tumorigenesis.
Pathways of tumour escape, such as expression of CD54 and
interleukin-10, were observed. The clinical, immunological and molecular
features suggest that nasal melanosis should be followed closely.
7
UI - 11828253
AU - Fuzii HT; Travassos LR
TI -
Transient resistance to B16F10 melanoma growth and metastasis in CD43-/-
mice.
SO - Melanoma Res 2002 Feb;12(1):9-16
AD - Unidade de Oncologia Experimental, Departamento de Microbiologia,
Imunologia e Parasitologia, Universidade Federal de Sao Paulo, Brazil.
CD43, the major transmembrane sialoglycoprotein of neutrophils,
monocytes, T lymphocytes and platelets, is highly glycosylated and its
high sialic acid content contributes to the strongly negative charge of
cells. In this study the role of CD43 in melanoma development was
addressed using CD43 -/- mice (null mutated for the corresponding gene
or knockout [KO]). Growth of B16F10 melanoma was retarded in the KO mice
compared with the wild-type CD43+/+ control (WT). A marked difference in
lung colonization and other metastatic foci was observed in the KO and
WT mice up to 15 days after intravenous injection of tumour cells. The
initial resistance of KO mice was reversed with time, and in the long
term there was no difference in the survival rate of the two animal
groups. Transient resistance was attributed to increased adhesion of
thrombin-activated platelets and leukocytes to melanoma and endothelial
cells in KO mice. In the KO mice tumour emboli were found in the central
portion of the lung more than at the lung periphery immediately after
intravenous injection, in contrast to the WT mice. Activation of
melanoma adhesion receptors by thrombin or TRAP stimulated lung
colonization in WT but not KO mice. Therefore, the correlation of tumour
embolism and metastasis in short-term experiments depends on the nature
and stability of interactions between the tumour and the
blood/endothelial cells of the host.
8
UI - 11836234
AU - Rhodes DR; Miller JC; Haab BB; Furge KA
TI -
CIT: identification of differentially expressed clusters of genes from
microarray data.
SO - Bioinformatics 2002 Jan;18(1):205-6
AD - Laboratory of DNA and Protein Microarray Technology, Van Andel Research
Institute, Grand Rapids, MI 49053, USA.
Cluster Identification Tool (CIT) is a microarray analysis program that
identifies differentially expressed genes. Following division of
experimental samples based on a parameter of interest, CIT uses a
statistical discrimination metric and permutation analysis to identify
clusters of genes or individual genes that best differentiate between
the experimental groups. CIT integrates with the freely available
CLUSTER and TREEVIEW programs to form a more complete microarray
analysis package.
9
UI - 12001124
AU - Blackwood MA; Holmes R; Synnestvedt M; Young M; George C; Yang H; Elder
TI -
DE; Schuchter LM; Guerry D; Ganguly A
Multiple primary melanoma revisited.
SO - Cancer 2002 Apr 15;94(8):2248-55
AD - Department of Medicine, Hematology-Oncology Division, University of
Pennsylvania, Philadelphia, Pennsylvania 19104-6145, USA.
BACKGROUND: Incidence of cutaneous melanoma continues to increase in the
Caucasian population worldwide. Approximately 5% of melanoma patients
develop additional primary melanoma. This rate is significantly higher
than the estimated lifetime risk of an individual for developing the
disease (1.4%). These features suggest that a genetic predisposition may
underlie multiple primary melanomas (MPMs). Prior studies had identified
CDKN2A mutations in a few MPM individuals. The objectives of this study
were to determine the frequency of family history of melanoma in MPM
cases, to characterize other clinical features including history of
other cancer, and to determine the association with functional CDKN2A
mutations. METHODS: This study used a case series design. All living
patients who had been seen in the Pigmented Lesion Clinic at the
University of Pennsylvania and who had more than one primary invasive
malignant melanoma or an invasive primary followed by an in situ
melanoma were eligible for participation. RESULTS: Individuals with MPM
frequently had a family history of melanoma, dysplastic nevi (DN),
and/or another cancer including basal cell carcinoma (BCC), and squamous
cell carcinoma breast cancer, and a personal history of DN, and basal
cell carcinoma. Germline mutations in CDKN2A gene were identified in 8
of 96 MPM cases (8.3%, 95% confidence interval, 6.7-9.9%). CONCLUSIONS:
These data indicate that the presence of MPM is associated with a modest
incidence of a family history of melanoma, DN, or BCC and a small
association with CDKN2A mutations. Therefore, in addition to the MPM
index case, other family members can benefit from screening and regular
surveillance for melanoma, DN, and BCC. Copyright 2002 American Cancer
Society.
10
UI - 11979433
AU - Papadopoulos S; Benter T; Anastassiou G; Pape M; Gerhard S; Bornfeld N;
TI -
Ludwig WD; Dorken B
Assessment of genomic instability in breast cancer and uveal melanoma by
random amplified polymorphic DNA analysis.
SO - Int J Cancer 2002 May 10;99(2):193-200
AD - Department of Obstetrics and Gynecology, Free University of Berlin,
Berlin, Germany.
Some types of cancer have been associated with abnormal DNA
fingerprinting. We used random amplified polymorphic DNA (RAPD) to
generate fingerprints that detect genomic alterations in human breast
cancer. Primers were designed by choosing sequences involved in the
development of DNA mutations. Seventeen primers in 44 different
combinations were used to screen a total of 6 breast cancer DNA/normal
DNA pairs and 6 uveal melanoma DNA/normal DNA pairs. Forty-five percent
of these combinations reliably detected quantitative differences in the
breast cancer pairs, while only 18% of these combinations detected
differences in the uveal melanoma pairs. Fourteen (32%) and 12 (27%)
primers generated a smear or did not produce any band patterns in the
first and second cases, respectively. Taking into account the ability of
RAPD to screen the whole genome, our results suggest that the genomic
damage in breast cancer is significantly higher than in uveal melanoma.
Our study confirms other reports that the molecular karyotypes produced
with random priming, called amplotypes, are very useful for assessing
genomic damage in cancer. Copyright 2002 Wiley-Liss, Inc.
11
UI - 12034846
AU - Stewart DA; Xu X; Thomas SD; Miller DM
TI -
Acridine-modified, clamp-forming antisense oligonucleotides synergize
with cisplatin to inhibit c-Myc expression and B16-F0 tumor progression.
SO - Nucleic Acids Res 2002 Jun 1;30(11):2565-74
AD - Department of Biochemistry and Molecular Genetics, University of Alabama
at Birmingham, Birmingham, AL 35294, USA.
The c-myc protooncogene plays a key role in the abnormal growth
regulation of melanoma cells. We have targeted three polypurine
sequences within the mouse myc mRNA with acridine-modified,
clamp-forming antisense oligonucleotides (AS ODNs) in an effort to
inhibit growth of murine melanoma cells. These ODNs are unique in that
they hybridize to the target mRNA by both Watson-Crick and Hoogsteen
hydrogen bond interactions, forming a triple-stranded structure. At a
concentration of 3 microM E1C, E2C and E3C inhibit B16-F0 proliferation
by 76, 66 and 78%, respectively. Both immunofluorescent staining and
western blot analysis corroborate a proportional reduction in c-Myc
expression by all three ODNs. There were clear distinctions in the
ability of these ODNs to inhibit tumor progression in C57BL/6 mice as a
function of Myc expression. There was no synergy demonstrated between
ODN E1C with cisplatin (DDP), which inhibited tumor growth by 77% alone
and 82% in combination. Although E2C inhibited growth by 54%, its effect
was decreased to 32% with DDP, when compared with controls. E3C, on the
other hand, demonstrated a synergistic effect with DDP, inhibiting
growth by 72% in combination, but only by 1% as a single agent.
Immunofluorescence analysis of tumors for each group revealed a
concomitant reduction in c-Myc expression in tumors from mice treated
with the most active clamp ODN alone (E1C) or clamp ODN + DDP (E1C/E3C +
DDP). Western blot analysis confirmed this decrease in target protein
expression. Our results document the growth-inhibitory activity of two
myc-targeting antisense clamp ODNs; E1C, which has activity as a single
agent, and E3C, which has in vivo synergy with DDP pretreatment. These
data confirm the antiproliferative effects of these novel ODNs and
document an interesting synergy with the chemotherapeutic agent DDP.
12
UI - 11774594
AU - Todryk S; Birchall L; Erlich R; Halanek N; Orleans-Lindsay JK; Dalgleish
TI -
A
Cytokine gene transfection for autologous and allogeneic melanoma
vaccines.
SO - Adv Exp Med Biol 2001;495():365-8
AD - Tumour Immunology Group, Institute for Immunology, Department of
Biology, National University of Ireland, Maynooth, Ireland.
13
UI - 11774596
AU - Dams-Kozlowska H; Izycki D; Mackiewicz A
TI -
IL-11 is a potent anti-melanoma factor.
SO - Adv Exp Med Biol 2001;495():373-7
AD - Department of Cancer Immunology, Academy of Medicine, GreatPoland Cancer
Center, Poznan, Poland.
14
UI - 11774599
AU - Grabarczyk P; Gryska K; Wysocki PJ; Izycki D; Mackiewicz A
TI -
Improving the retroviral vector (RV) systems for immunotherapy of
cancer.
SO - Adv Exp Med Biol 2001;495():389-92
AD - Department of Cancer Immunology, University School of Medical Sciences,
GreatPoland Cancer Center, Poznan, Poland.
15
UI - 11774600
AU - de Zoeten EF; Li D; Cohen EP
TI -
Tumor immunity in mice immunized with fibroblasts transfected with tumor
DNA.
SO - Adv Exp Med Biol 2001;495():393-401
AD - Department of Microbiology and Immunology, University of Illinois,
Chicago, Illinois 60612, USA.
16
UI - 11774603
AU - Nawrocki S; Laciak M; Izycki D; Gryska K; Wysocki PJ; Grabarczyk P;
TI -
Karczewska A; Kaczmarek A; Murawa P; Malicki J; Rose-John S; Mackiewicz
A
Humoral responses to melanoma vaccine, genetically modified with
interleukin 6 and soluble interleukin 6 receptor.
SO - Adv Exp Med Biol 2001;495():411-8
AD - GreatPoland Cancer Centre, Garbary 15, Poznan, Poland.
17
UI - 11774606
AU - Skowronek J; Karas Z; Krenz RM; Warchol JB
TI -
Flow and video-imaging cytometry--usefulness of DNA ploidy measurements
in diagnosis of malignant melanoma.
SO - Adv Exp Med Biol 2001;495():435-8
AD - Department of Radiotherapy, GreatPoland Cancer Center, Poznan, Poland.
18
UI - 11966686
AU - Campos EI; Cheung KJ Jr; Murray A; Li S; Li G
TI -
The novel tumour suppressor gene ING1 is overexpressed in human melanoma
cell lines.
SO - Br J Dermatol 2002 Apr;146(4):574-80
AD - Department of Medicine, Division of Dermatology, Vancouver Hospital and
Health Sciences Centre, University of British Columbia, Vancouver, BC,
Canada.
BACKGROUND: Epidemiological evidence indicates that exposure to
ultraviolet (UV) radiation is directly linked to the increase of both
incidence and mortality of melanoma. However, the genetic changes caused
by UV radiation that lead to melanoma formation remain poorly
understood. Recently, a potential tumour suppressor gene ING1 (inhibitor
of growth 1) was shown to inhibit cell growth and induce apoptosis in
the presence of p53. We have demonstrated that the expression of ING1 is
induced after UV irradiation and that ING1 enhances the repair of
UV-damaged DNA. OBJECTIVES: To investigate if ING1 plays a role in
melanoma formation. METHODS: We examined p33ING1 expression levels in 14
melanoma cell lines. RESULTS: We found that p33ING1 is overexpressed at
both mRNA and protein levels in melanoma cell lines compared with normal
melanocytes. Single-strand conformation polymorphism (SSCP) analysis
showed band shifting in two melanoma cell lines. DNA sequencing
confirmed that there were nucleotide alterations in the ING1 gene in
Sk-mel-24 and Sk-mel-110 cell lines. Two silent nucleotide alterations
in exon 1a were detected in Sk-mel-110. In Sk-mel-24, the A-->G
nucleotide alteration at codon 260 resulted in an amino acid change from
Asn to Ser, while seven other nucleotide alterations were silent. To
determine if the silent nucleotide alterations in these two melanoma
cell lines were due to polymorphism, SSCP analysis of ING1 gene was
performed in 25 healthy volunteers. No band shift was observed in the
SSCP analysis, suggesting that the nucleotide alterations in the
melanoma cell lines are unlikely to be due to polymorphism. CONCLUSIONS:
Taken together, our data demonstrate that ING1 is overexpressed, but
infrequently mutated, in melanoma cell lines.
19
UI - 11924907
AU - Sigalotti L; Coral S; Nardi G; Spessotto A; Cortini E; Cattarossi I;
TI -
Colizzi F; Altomonte M; Maio M
Promoter methylation controls the expression of MAGE2, 3 and 4 genes in
human cutaneous melanoma.
SO - J Immunother 2002 Jan-Feb;25(1):16-26
AD - Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Istituto
di Ricovero e Cura a Carattere Scientifico, Aviano, Italy.
Cancer-testis antigens expressed by different-histotype transformed
cells are suitable targets for tumor immunotherapy. However, their
heterogeneous expression in neoplastic lesions limits the eligibility of
patients for cancer-testis antigen-directed vaccination, and low levels
of cancer-testis antigens' expression may impair immune recognition of
malignant cells. Because of the primary clinical relevance of
cancer-testis antigens' expression in neoplastic tissues, 68 unrelated
or sequential metastatic lesions from 56 patients were used to
characterize the molecular mechanisms regulating the presence and levels
of expression of different cancer-testis antigens of the MAGE family
(i.e., MAGE2, 3 and 4) in cutaneous melanoma. Polymerase chain
reaction-based methylation analyses showed that methylation status of
specific cytosine-guanine dinucleotides in the promoters of investigated
cancer-testis antigens correlated with their heterogeneous expression
within unrelated metastatic melanoma lesions, and with their homogeneous
expression among sequential metastases from three patients with
melanoma. Unlike methylated promoters, unmethylated promoters of MAGE2,
3 and 4 genes drove the expression of reporter gene-enhanced green
fluorescent protein after transient transfection of cancer-testis
antigen-positive Mel 142 melanoma cells. Furthermore, de novo expression
of MAGE3 gene induced by the treatment of Mel 195 melanoma cells with
the DNA hypomethylating agent 5-aza-2'-deoxycytidine was associated with
a 6%-12% demethylation of selected cytosine-guanine dinucleotides in its
promoter. Finally, 5-aza-2'-deoxycytidine induced a 16-fold increase of
MAGE3 expression in Mel 313 melanoma cells expressing constitutively low
levels of the antigen, but did not affect that of Mel 275 melanoma cells
expressing high baseline levels of MAGE3. Overall, these findings
identify promoter methylation as a shared mechanism directly regulating
the expression of therapeutic cancer-testis antigens in metastatic
melanomas, and foresee the clinical use of 5-aza-2'-deoxycytidine to
design new chemoimmunotherapeutic strategies in patients with melanoma.
20
UI - 11921401
AU - Tietze LF; Griesbach U; Bothe U; Nakamura H; Yamamoto Y
TI -
Novel carboranes with a DNA binding unit for the treatment of cancer by
boron neutron capture therapy.
SO - Chembiochem 2002 Mar 1;3(2-3):219-25
AD - Institut fur Organische, Chemie Georg-August-Universitat Gottingen,
Tammannstrasse 2, 37077 Gottingen, Germany. ltietze@gwdg.de
The synthesis and biological evaluation of two ortho-carborane
derivatives which contain a 5,6,7-trimethoxyindole (TMI) unit for use in
boron neutron capture therapy is described. The TMI moiety is known to
be the DNA-binding part of the highly potent anticancer agent
duocarmycin A. The ortho-carborane derivatives were prepared from amino
alkynes which were bound to a protected TMI carboxylic acid. Addition of
decaborane(14) to the alkyne triple bond with subsequent removal of the
tert-butoxycarbonyl (Boc) and benzyl protecting groups gave the desired
product. Boron uptake from the ortho-carborane derivatives into B-16
melanoma cells was higher and faster than that observed with
L-p-boronophenylalanine (BPA), which is in use in the clinic.
21
UI - 11992404
AU - Zendman AJ; Van Kraats AA; Weidle UH; Ruiter DJ; Van Muijen GN
TI -
The XAGE family of cancer/testis-associated genes: alignment and
expression profile in normal tissues, melanoma lesions and Ewing's
sarcoma.
SO - Int J Cancer 2002 May 20;99(3):361-9
AD - Department of Pathology, University Medical Center St. Radboud,
Nijmegen, The Netherlands. H.Zendeman@pathol.azn.nl
The existence of XAGE genes was first reported after database homology
searches for PAGE-like sequences identified 3 XAGE EST clusters. One of
these clusters, XAGE-1, has in later studies been identified as a
cancer/testis-associated gene. Here, we report the expression profiles
of all 3 reported XAGE genes, as well as several splice variants of
XAGE-1, in normal human tissues, Ewing's sarcoma and melanocytic tumors.
We also provide the genetic structure of the corresponding genes.
Moreover, by searching the databases for XAGE homologues, we identified
3 additional GAGE-like genes. RT-PCR studies showed frequent expression
in melanoma metastases and Ewing's sarcoma for 2 XAGE-1-derived
transcripts. XAGE-2 was expressed at lower frequency in these tissues,
while XAGE-3 was seen only in normal placenta. Due to a frameshift, the
largest XAGE-1 putative protein is far less homologous to GAGE-like
proteins than the other XAGEs. Interestingly, all GAGE-like genes
contain a large secondary open reading frame, coding for putative
proteins homologues to the XAGE-1 primary protein. The XAGE family of
cancer/testis-associated genes is located on chromosome Xp11.21-Xp11.22.
The data outline a superfamily of GAGE-like cancer/testis antigens,
consisting of at least 19 genes. Copyright 2002 Wiley-Liss, Inc.
22
UI - 11966726
AU - Ortonne JP
TI -
Photobiology and genetics of malignant melanoma.
SO - Br J Dermatol 2002 Apr;146 Suppl 61():11-6
AD - CHU Nice, Service de Dermatologie, Hopital l'Archet 2, BP 3079, 06202
Nice cedex, France. ortonne@unice.fr
The current state of knowledge of melanoma genetics is reviewed.
Mutations in the tumour suppressor gene CDKN2A and in the oncogenes
N-ras and H-ras seem to play the most important roles in the development
and progression of malignant melanoma. Experimental studies to determine
the role of ultraviolet (UV) light in the induction of melanoma have
been hampered by a lack of suitable animal models. The commonly used
laboratory animals are not susceptible to the induction of melanoma upon
exposure to UV radiation (UVR) alone. Recent observations with four
different animals have suggested, however, that UVR may be involved in
the induction of melanoma. The most recent model consists of human skin
grafted onto immunodeficient mice. To date, using this model, only the
combination of UVB (280-320 nm) exposure and topical promoter treatment
has led to the development of malignant melanoma. The wavelength
dependency of the induction of melanoma has been established in the fish
model Xiphophorus. The application of such an action spectrum to humans
looks possible.
23
UI - 8977549
AU - Nelson MA; Thompson FH; Emerson J; Aickin M; Adair L; Trent JM; Leong
TI -
SP; Taetle R
Clinical implications of cytogenetic abnormalities in melanoma.
SO - Surg Clin North Am 1996 Dec;76(6):1257-71
AD - Department of Pathology, Arizona Cancer Center, University of Arizona,
Tucson, USA.
Unlike leukemia, in which specific reciprocal translocations are
frequently observed, melanomas involve complex recurring chromosome
anomalies. Analysis of the constituted genome of melanoma patients
should identify cancer susceptibility genes and at-risk individuals in
families with a history of melanoma. The first of these genes to be
cloned is the cell cycle regulatory protein inhibitor--the p16 gene--
and a second gene locus for melanoma predisposition has been linked to
the chromosome 1p36 band region. Detection of the most common somatic
genetic alterations in melanoma enhances our understanding of molecular
mechanisms of melanoma development and may lead to genetic markers in
melanoma. Some alterations may be used to identify interesting
subpopulations. Others may be of prognostic value when they are
considered in tandem with clinical data.
24
UI - 11916485
AU - Nakamura T; Sato K; Hamada H
TI -
Effective gene transfer to human melanomas via integrin-targeted
adenoviral vectors.
SO - Hum Gene Ther 2002 Mar 20;13(5):613-26
AD - Department of Molecular Medicine, Sapporo Medical University, S1 W17,
Chuo-ku, Sapporo 060-8556, Japan.
The utility of recombinant adenoviral vectors (Adv) for gene therapy is
limited by their low transduction efficiency and lack of specificity for
target cells. The low transduction efficiency is often recognized as due
to deficiency of the primary adenoviral receptor, the
coxsackievirus-adenovirus receptor (CAR). In this paper, studies of CAR
levels on human melanoma cell lines confirmed that low transduction
efficiency was closely related to deficiency of the adenoviral receptor.
To achieve CAR-independent gene transfer via Adv, we modified viral
tropism via genetic alteration of the adenovirus type 5 (Ad5) fiber
protein. Insertion of an Arg-Gly-Asp (RGD)-containing peptide in the HI
loop of the fiber knob domain allowed the virus to use an alternative
receptor, the integrin receptor, during the cell entry process. With
this modified vector (Adv-F/RGD) transduction was increased 5- to
96-fold relative to a vector containing wild-type fiber (Adv-F/wt) in
five human melanoma cells expressing integrins of the alpha(v)beta(3),
alpha(v)beta(5) class, which are recognized by the RGD peptide motif. In
contrast, no significant difference in transduction efficiency between
Adv-F/RGD and Adv-F/wt was observed in 293 cells, which show high-level
expression of CAR. In this study, we attempted to apply Adv-F/RGD for
gene therapy for malignant melanoma. At the same multiplicity of
infection, melanoma cells infected with Adv-F/RGD carrying human
interleukin 2 (AxCAhIL2-F/RGD) produced a higher level of cytokine than
cells infected with AxCAhIL2-F/wt. Treatment by intratumoral injection
of AxCAhIL2-F/RGD was more effective than intratumoral injection of
AxCAhIL2-F/wt in regressing tumors in a melanoma xenograft model. These
data suggest that integrin-targeted adenoviral vectors may be a powerful
tool in gene therapy for CAR-deficient melanomas.
25
UI - 12017286
AU - Korabiowska M; Tscherny M; Grohmann U; Honig JF; Bartkowski SB;
TI -
Cordon-Cardo C; Brinck U
Decreased expression of Ku70/Ku80 proteins in malignant melanomas of the
oral cavity.
SO - Anticancer Res 2002 Jan-Feb;22(1A):193-6
AD - Department of Cytopathology, University of Gottingen, Germany.
Ku70/80 are genes responsible for the repairing of DNA double-strand
breaks and they function as a regulatory subunit of the DNA-dependent
protein kinase. Their expression has not yet been investigated in
malignant melanomas of the oral cavity. These tumours are characterized
by very poor prognosis and etiology independent of UV-radiation. We
investigated 29 malignant melanomas of the oral cavity for the
expression of Ku70/80 proteins. Ku70 expression was preserved in 21 out
of 29 tumours and the percentage of Ku70-positive cells did not exceed
76%. Ku80 was found in 19 out of 29 tumours and the percentage of
Ku80-positive cells peaked at 62%. Correlations between Ku70 and Ku80
expression were lost (p>0.05). We conclude that decreased Ku70/80
expression in malignant melanomas of the oral cavity and loss of
correlation between these markers may influence progression of oral
melanomas.
26
UI - 11775059
AU - Cohen-Solal KA; Reuhl KR; Ryan KB; Roberts KG; Chen S
TI -
Development of cutaneous amelanotic melanoma in the absence of a
functional tyrosinase.
SO - Pigment Cell Res 2001 Dec;14(6):466-74
AD - Department of Chemical Biology, College of Pharmacy, Rutgers, the State
University of New Jersey, Piscataway 08854, USA.
Lack of characteristic pigmentation and a wide range of clinical
presentations account for the diagnostic challenge associated with
amelanotic malignant melanoma. Experimental studies of this important
human cancer have been hampered by the lack of an appropriate animal
model. We previously described a transgenic mouse line (TG-3) that
spontaneously develops pigmented cutaneous melanoma. F1 crosses were
generated with TG-3 and several albino strains, and backcrosses were
then made with the albinos. In the present report, we describe the
restricted development and characterization of cutaneous amelanotic
melanoma in these albino transgenic backcrosses. The incidence and
behavior of melanoma in these mice were monitored. A high incidence
(80-100%) of spontaneous amelanotic melanoma was observed in albino
transgenic mice derived from backcrosses with A, AKR, FVB, and SJL
strains. The lowest incidence (30%) was obtained in BALB/c-derived
crosses. No tumors were observed in non-transgenic mice.
Immunohistochemical and western blot analyses using antibodies against
three melanocyte-specific markers of the tyrosinase family of proteins
confirmed that the tumors were composed of amelanotic melanocytes.
Furthermore, the presence of numerous premelanosomes observed by
electron microscopy further supported the melanocytic origin of these
tumors. Previous in vitro studies on human melanoma have suggested that
cutaneous amelanotic melanoma was evolving from preexisting pigmented
cutaneous melanoma. However, our results indicate that it can occur
directly, as evidenced by the appearance of cutaneous amelanotic
melanoma in the tyrosinase-deficient albino mice. These mice represent a
potentially valuable model for studying the mechanistic, diagnostic, and
therapeutic features of this highly malignant neoplasm.
27
UI - 12014627
AU - Warren P; Song W; Holle E; Holmes L; Wei Y; Li J; Wagner T; Yu X
TI -
Combined HSV-TK/GCV and secondary lymphoid tissue chemokine gene therapy
inhibits tumor growth and elicits potent antitumor CTL response in
tumor-bearing mice.
SO - Anticancer Res 2002 Mar-Apr;22(2A):599-604
AD - Oncology Research Institute, Greenville Hospital System, SC 29605, USA.
Suicide gene therapy in combination with pro-drugs represents an
attractive approach to the treatment of cancer. Unfortunately this
approach is limited by difficulty in targeting all tumor cells,
especially those at the distant metastases associated with the most
complex tumors. For this reason, attempts to stimulate global anti-tumor
immune responses at the sites of effective suicide
gene/pro-drug-mediated tumor cell destruction are appealing. Here we
show that, by including a gene coding for secreted secondary lymphoid
tissue chemokine (SLC) along with the herpes simplex virus thymide
kinase (HSV-TK) gene in a bicistronic vector for anti-tumor gene therapy
in conjunction with the pro-drug ganciclovir (GCV), we are able to
mediate a greatly enhanced anti-tumor effect in the murine B16 melanoma
tumor model. The data presented suggests that this enhanced antitumor
effect is the result of a strong induced CTL immune response resulting
from the recruitment of immune cells to the site of HSV-TK/GCV-induced
tumor destruction by the potent chemokine SLC.
28
UI - 12067204
AU - Seftor EA; Meltzer PS; Kirschmann DA; Pe'er J; Maniotis AJ; Trent JM;
TI -
Folberg R; Hendrix MJ
Molecular determinants of human uveal melanoma invasion and metastasis.
SO - Clin Exp Metastasis 2002;19(3):233-46
AD - Department of Anatomy and Cell Biology, College of Medicine and The
Holden Comprehensive Cancer Center, University of Iowa, Iowa City
52242-1109, USA.
The molecular analysis of cancer has benefited tremendously from the
sequencing of the human genome integrated with the science of
bioinformatics. Microarray analysis technology has the potential to
classify tumors based on the differential expression of genes. In the
current study, a collaborative, multidisciplinary approach was utilized
to study the molecular determinants of human uveal melanoma invasion and
metastasis. Uveal melanoma is considered the most common primary
intraocular cancer in adults, resulting in the death of approximately
50% of patients affected. Unfortunately, at the time of diagnosis, many
patients already harbor microscopic metastases, thus underscoring a
critical need to identify prognostic markers indicative of metastatic
potential. The investigative strategy consisted of isolating highly
invasive vs. poorly invasive uveal melanoma cells from a heterogeneous
tumor derived from cells that had metastasized from the eye to the
liver. The heterogeneous tissue explant MUM-2 led to the derivation of
two clonal cell lines: MUM-2B and MUM-2C. Further morphological and
functional analyses revealed that the MUM-2B cells were epithelioid,
interconverted (expressing mesenchymal and epithelial phenotypes) highly
invasive, and demonstrated vasculogenic mimicry. The MUM-2C cells were
spindle-like, expressed only a vimentin mesenchymal phenotype, poorly
invasive, and were incapable of vasculogenic mimicry. The molecular
analysis of the MUM-2B vs. the MUM-2C clones resulted in the
differential expression of 210 known genes. Overall, the molecular
signature of the MUM-2B cells resembled that of multiple
phenotypes--similar to a pluripotent, embryonic-like genotype.
Validation of select genes that were upregulated and down-regulated was
conducted by semiquantitative RT-PCR measurement. This study provides a
molecular profile that will hopefully lead to the development of new
molecular targets for therapeutic intervention and possible diagnostic
markers to predict the clinical outcome of patients with uveal melanoma.
29
UI - 11968172
AU - Anonymous
TI -
[Of mice and humans. Updates on susceptibility and tumor suppression of
malignant melanoma]
SO - Hautarzt 2002 Jan;53(1):88-9
30
UI - 11950413
AU - Parney IF; Farr-Jones MA; Koshal A; Chang LJ; Petruk KC
TI -
Human brain tumor cell culture characterization after immunostimulatory
gene transfer.
SO - Neurosurgery 2002 May;50(5):1094-102
AD - Division of Neurosurgery, Department of Surgery, University of Alberta,
Edmonton, Alberta, Canada. ifparney@v-wave.com
OBJECTIVE: Immunogene therapy is a novel cancer treatment strategy based
on vaccination with irradiated autologous tumor cells transduced with
immunostimulatory genes. To characterize such cells before clinical
applications, we studied a human glioma cell line (D54 MG) and early
passage human glioma (Ed147.BT, Ed149.BT) and melanoma (Ed141.MEL)
cultures after immunostimulatory gene transfer. METHODS:
Granulocyte-macrophage colony-stimulating factor (GM-CSF),
interleukin-12 (IL-12), and B7-2 genes were retrovirally transferred to
tumor cells. Gene expression before and after irradiation (200 Gy) was
assessed by enzyme-linked immunosorbent assay (GM-CSF, IL-12) and flow
cytometry (B7-2). Viability and clonogenicity were determined via trypan
blue staining before and after irradiation. Growth rates were determined
by serial cell counts. RESULTS: GM-CSF expression was high in
GM-CSF-transduced (10.36-162.10 ng/10(6) cells/d preirradiation and
10.22-122.02 ng/10(6) cells/d postirradiation) but lower in
B7-2/GM-CSF-transduced cultures (1.41-2.90 ng/10(6) cells/d
preirradiation, 1.96-5.02 ng/10(6) cells/d postirradiation). IL-12
expression also was lower (1.30-2.10 ng/10(6) cells/d preirradiation,
0.47-1.70 ng/10(6) cells/d postirradiation). B7-2 expression was high
(one- to two-logarithm increase in fluorescence) and unaffected by
radiation. Postirradiation viability was initially high (94.20 +/-
8.46%, Day 1) but decreased rapidly (28.13 +/- 4.64%, Day 10). No
cultures demonstrated evidence of clonogenicity (i.e., cell division)
after 200-Gy irradiation. Growth rates were similar in wild-type and
gene-transduced Ed141.MEL, Ed147.BT, and Ed149.BT. However, D54MG-IL-12
growth was slower than that of wild-type D54MG. CONCLUSION: GM-CSF,
IL-12, and B7-2 genes can be transferred to human glioma and melanoma
cell cultures efficiently by use of our retroviral vectors. Irradiation
(200 Gy) does not significantly alter therapeutic gene expression.
Irradiated cells remain viable for several days but cannot undergo
further cell division. Early passage culture growth rates are not
altered by therapeutic gene expression but are decreased by IL-12 in an
immortalized cell line (D54MG). These results suggest that it is
feasible to create vaccines with irradiated, autologous, genetically
modified brain tumor cells.
31
UI - 12009890
AU - Zhang B; Peng ZY
TI -
Structural consequences of tumor-derived mutations in p16INK4a probed by
limited proteolysis.
SO - Biochemistry 2002 May 21;41(20):6293-302
AD - Department of Biochemistry, University of Connecticut Health Center, 263
Farmington Avenue, Farmington, Connecticut 06032, USA.
The cyclin-dependent kinase inhibitor p16(INK4a) (hereafter p16)
functions as a multiple tumor suppressor. Mutations in p16, which are
distributed throughout the entire protein, have been identified in a
variety of human cancers and cancer-derived cell lines. It is unclear
how tumor-derived mutations disrupt the structure and function of p16,
especially since many of these mutations are located far away from the
cyclin-dependent kinase binding site. In this study, we investigated the
effect of two tumor-derived mutations, P81L and V126D, on the structure
of p16 by limited proteolysis. The proteolytic products were
characterized by gel electrophoresis, HPLC, and mass spectrometry. Our
results show that the N-terminal half of p16 is significantly more
sensitive to proteolysis in both tumor-derived mutant proteins than in
the wild type, suggesting that this region is particularly unstable.
Interestingly, the N-terminal half of p16 contains many residues that
are important for cyclin-dependent kinase binding. Thus, our results
provide a structural mechanism by which tumor-derived mutations
inactivate the function of p16 and suggest that stabilization of the
N-terminal region could be a useful strategy for future therapeutic
development.
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