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PubMed1988

Intermediate filament proteins and actin isoforms as markers for soft tissue tumor differentiation and origin. II. Rhabdomyosarcomas.

A series of 15 rhabdomyosarcomas was examined by light microscopy, transmission electron microscopy, two-dimensional gel electrophoresis (2D-GE) and indirect immunofluorescence, the latter using monoclonal or affinity-purified polyclonal antibodies to desmin, vimentin, alpha-smooth muscle and alpha-sarcomeric (alpha-sr) actins. By light microscopy, the authors diagnosed 1 botrioid, 1 alveolar, and 7 embryonal rhabdomyosarcomas, 4 pleomorphic spindle cell sarcomas, and 2 spindle cell sarcomas, one nondistinct, the other with a hemangiopericytomatous pattern. By transmission electron microscopy, 13 neoplasms disclosed rhabdomyoblastic differentiation; the remaining 2, myogenic differentiation. By immunofluorescence microscopy, all neoplasms expressed vimentin and alpha-sr actin, 12 expressed, in addition, desmin, and 1 expressed alpha-smooth muscle actin. Among the 11 neoplasms studied by means of 2D-GE, 7 demonstrated an alpha-actin spot, while 4 showed only beta and gamma spots. One tumor disclosed, in addition to alpha, beta, and gamma spots, a spot with a molecular weight corresponding to actin, but more acidic than alpha-actins. This study demonstrates that alpha-sr actin antibody represents a valuable marker for the diagnosis of rhabdomyosarcoma, because it was present in all neoplasms, including the one negative for desmin. This antibody further allowed the recognition of pleomorphic variants and morphologically atypical forms of rhabdomyosarcomas. The presence of alpha-smooth muscle actin in 1 case of rhabdomyosarcoma suggests that this actin isoform may be expressed during skeletal muscle differentiation.

Actins↗
PubMed1987

Alveolar rhabdomyosarcoma of the larynx: case report and literature review.

We report the 11th well-documented case of laryngeal rhabdomyosarcoma and only the second of laryngeal alveolar rhabdomyosarcoma. The optimum treatment of head and neck rhabdomyosarcoma has not yet been defined, but it appears that the ideal should consist of an aggressive multimodality approach. This includes surgical extirpation if it can be done without major morbidity, postoperative radiotherapy with a margin around known and suspected disease, and multiagent chemotherapy. Unlike most sarcomas, rhabdomyosarcoma (especially alveolar rhabdomyosarcoma) spreads by way of the lymphatic system as well as the blood stream. Inclusion of the draining lymphatics in the radiation field must be given strong consideration.

Combined Modality Therapy↗
PubMed1987

Myoglobin, desmin and vimentin in ultrastructurally proven rhabdomyomas and rhabdomyosarcomas. An immunohistochemical study utilizing a series of monoclonal and polyclonal antibodies.

The present study is an immunohistochemical analysis utilizing a series of mono- and polyclonal antibodies to myoglobin, desmin and vimentin in smooth and striated control muscle tissues, 7 alveolar and 7 embryonal rhabdomyosarcomas and 1 adult and 1 fetal rhabdomyoma with ultrastructurally proven rhabdomyoblastic differentiation in all the tumors. Formaldehyde-fixed and paraffin-embedded tissue was used for the immunohistochemical analysis of all the tumors, while ethanol fixation was also used for the analysis of the control tissues. The staining for myoglobin with the poly- and monoclonal antibody used was positive in both formaldehyde- and ethanol-fixed skeletal and cardiac control muscle. Trypsin treatment abolished the positive staining when the monoclonal antibody was used. Both the striated and smooth control muscle tissues were positively stained by the antidesmin antibodies. The influence of the fixative that was used and the trypsin treatment depended on the antibody used and the type and origin of the muscle tissue. All the tumors were positively stained with the polyclonal antimyoglobin and 8/14 rhabdomyosarcomas and the 2 rhabdomyomas were positively stained with the monoclonal antimyoglobin. All the tumors were positively stained with the polyclonal and 3 of the 5 monoclonal antidesmin antibodies used. Well-differentiated tumor cells were usually positively stained for both myoglobin and desmin. There were small, poorly differentiated tumor cells in the rhabdomyosarcomas and the fetal rhabdomyoma which were positively stained for desmin, whereas very few or no such cells were positively stained for myoglobin. A varying number of mostly small, poorly differentiated tumor cells were positively stained for vimentin in 12 of 14 rhabdomyosarcomas and in the fetal rhabdomyoma. The study showed that one of the monoclonal antidesmin antibodies produced the most consistent result with a positive staining in all cases. The monoclonal antimyoglobin antibody, which is a specific marker of rhabdomyoblastic differentiation, is also considered to be of value, although it did not produce positivity in all cases. It remains to be shown whether desmin can help in the diagnosis of poorly or undifferentiated rhabdomyosarcomas without light- or electron-microscopic evidence of rhabdomyoblastic differentiation.

Adolescent↗
PubMed1985

[Rhabdomyosarcoma in childhood. I. Histologic structure].

Histological structure of rhabdomyosarcoma was studied in a group of 37 children. The classification was: embryonal rhabdomyosarcoma in 28 cases, alveolar rhabdomyosarcoma in 9 cases. 5 cases showed an ambivalent structure. The diagnosis of rhabdomyosarcoma is based on cytology: various rhabdomyoblasts are to be identified as well as distinguished from similar cells. The structural point of view is helpful but diagnostic only in typical cases of sarcoma botryoides and alveolar rhabdomyosarcoma. Undifferentiated cells maturating into rhabdomyoblasts combined with numerous polymorphic cells were found consecutive investigations of individual cases.

Adolescent↗
PubMed1985

[Rhabdomyosarcoma in childhood. II. Ultrastructure].

The diagnosis of rhabdomyosarcoma was established or proved by electron microscopy in two thirds of 21 cases. Histological classification was not adequate or formulated as "undifferentiated sarcoma" in half the cases. Electron microscopy did not succeed in one third of cases and rhabdomyosarcoma was classified according to simultaneous or successive study. Undifferentiated tumour cells resembled myoblastema cells of the 5th-6th gestation weeks. Differentiation of myoblasts and myotubes corresponded to the muscle development of the 7th-16th weeks. Immature cells showed features of fibroblasts and myofibroblasts in most cases of embryonal rhabdomyosarcoma. Alveolar rhabdomyosarcomas were characterized by exclusive myoblastic differentiation. Different cellular sources were discussed in rhabdomyosarcomas with differentiation into one cell type or into various mesenchymal cells.

Child↗
PubMed1984

Enolase isozymes as markers for differential diagnosis of neuroblastoma, rhabdomyosarcoma, and Wilms' tumor.

Enolase isozymes (alpha, beta and gamma enolases) in the extracts of pediatric tumors (neuroblastoma, ganglioneuroblastoma, rhabdomyosarcoma and Wilms' tumor) were determined by means of enzyme immunoassay systems. All tumor tissues examined contained alpha enolase at high levels (2070-19100 ng/mg protein). The beta and gamma enolases were present at high levels particularly in rhabdomyosarcoma (886 +/- 750 ng/mg protein) and (ganglio)neuroblastoma (2060 +/- 890 ng/mg protein), respectively. Immunohistochemical studies confirmed these results. Serum levels of these enolase isozymes were also determined in pediatric tumor patients. Before treatment, a serum sample from a patient with rhabdomyosarcoma contained a high level of beta enolase and serum samples from patients with (ganglio)neuroblastoma contained high levels of gamma enolase. However, the levels of serum beta and gamma enolases were low in patients with Wilms' tumor. The elevated level of beta or gamma enolase in serum from rhabdomyosarcoma or (ganglio)neuroblastoma patients was markedly decreased after adequate treatment (operation, chemotherapy or radiation). The results indicated that the enolase isozymes are useful marker antigens for differential diagnosis and therapeutic monitoring of neuroblastoma and rhabdomyosarcoma.

Child↗
PubMed1980

[The cellular and tissue patterns of so-called embryonal rhabdomyosarcomas. Histological and histochemical investigations (author's transl)].

Embryonal rhabdomyosarcomas consist of two histological variants; it can be distinguished between solid embryonal rhabdomyosarcomas and botryoid sarcomas. We investigated 13 solid and 7 botryoid rhabdomyosarcomas and used 46 biopsies of 20 patients between 6 weeks and 14 years old. There were 12 male and 8 female patients. The histologic examination yielded variations of cytologic pattern and tissue structure. Besides undifferentiated sarcoma cells which constituted the majority of tumor cells and a changing amount of rhabdomyoblastic cells (but only 40% of all tumors showed cells with cytoplasmic cross striation) in 6 solid and 6 botryoid tumors some other cellular features could be observed. There were tumor cells with characteristics of lipoblasts and histiocytes, and occasionally the potency to form vascular spaces was detected, too. The histochemical examination proved the presence of glycosaminoglycans and mucoproteins. The glycosaminoglycans seemed to contain only a few sulphated groups. In agreement with a preceding electron microscopic study of botryoid sarcomas in the nasopharynx (Katenkamp et al. 1979) we stated that many so-called embryonal rhabdomyosarcomas show the basic pattern of an undifferentiated embryonal sarcoma and have some diverging cellular differentiations. Therefore, it is an open question whether the term "embryonal rhabdomyosarcoma" should be defined more precisely than usually done in the routine histological work today.

Adolescent↗
PubMed1997

Immunohistochemical detection of vinculin in human rhabdomyosarcomas.

The microfilament-associated protein vinculin is a major constituent of muscle tissue localized in costameres and Z-discs of the sarcomeric apparatus, where it is thought to play a pivotal role in the alignment of sarcomeric myofibrils and the transduction of mechanical force between the internal contractile machinery and the extracellular environment. In order to investigate whether anti-vinculin antibodies are helpful in confirming the commitment of rhabdomyosarcomas to the myogenic pathway, we studied immunohistochemically the expression pattern of vinculin in a series of 7 human rhabdomyosarcomas including those of embryonal, botryoid, and pleomorphic subtypes. Using monoclonal antibody from clone hVIN-1 by APAAP techniques on formalin-fixed, paraffin-embedded tissue, all but one tumor, which was a primitive embryonal rhabdomyosarcoma, demonstrated a significant positive vinculin staining. Vinculin expression was most prominent in differentiated tumors with a focal staining pattern showing a high degree of correlation with rhabdomyoblasts, whereas a diffuse staining was observed in areas in which small, poorly differentiated tumor cells alone were present. Since vinculin immunoreactivity could also be demonstrated in cases of leiomyosarcoma, the positive immunohistochemical detection of vinculin was not exclusively restricted to mesenchymal tumors derived from sarcomeric muscle tissue. Immunodetectable amounts of nebulin could be revealed only in two embryonal rhabdomyosarcomas. Our results suggested that the positive identification of rhabdomyosarcoma achieved by using antibodies against vinculin in addition to other known myogenic markers may be particularly useful in the differential diagnosis of anaplastic, poorly differentiated sarcomas.

Adult↗
PubMed1998

The fetal form of the acetylcholine receptor distinguishes rhabdomyosarcomas from other childhood tumors.

The fetal nicotinic acetylcholine receptor (AChR) of muscle is an oligomeric membrane protein with subunit composition alpha2betadeltagamma. After birth, the adult form, in which an epsilon-subunit replaces the gamma-subunit, predominates, and expression of the fetal form is limited to thymic myoid cells, extraocular muscles, and denervated striated muscle. We looked for expression of AChR in rhabdomyosarcomas and other childhood tumors by reverse transcription polymerase chain reaction and immunohistochemistry. mRNA for the AChR gamma-subunit was detected in all embryonal and alveolar rhabdomyosarcomas tested (n = 16) and in some tumors with a rhabdomyomatous component (n = 2) but not in other nonrhabdomyomatous tumors of childhood and adults (n = 45). The fetal form of the AChR was detected immunohistochemically in five of eight embryonal and four of eight alveolar rhabdomyosarcomas and in two Wilms' tumors with a rhabdomyomatous component but not in other tumors or in normal muscle. We conclude that reverse transcription polymerase chain reaction for AChR gamma-subunit could be useful for the diagnosis of rhabdomyosarcoma of childhood and for the detection of micrometastases and minimal residual disease. In addition, the fetal AChR protein is the first extracellular tumor marker that can distinguish rhabdomyosarcomas from nonrhabdomyomatous tumors and from normal muscle. Our findings, therefore, imply that the fetal AChR may be a target for in vivo imaging and, as AChR internalization and degradation is increased by antibody-induced cross-linking, may also provide a sensitive and specific target for immunotherapeutic strategies.

Adolescent↗
PubMed1998

Rhabdomyosarcoma presenting as a parotid gland mass in pediatric patients: fine-needle aspiration biopsy findings.

BACKGROUND: The head and neck region is one of the most common locations of rhabdomyosarcoma. Salivary gland involvement is usually secondary to advanced disease, and presentation as a primary salivary gland tumor is very rare. METHODS: Three cases of rhabdomyosarcoma presenting as parotid masses, in 2 boys (ages 3 and 7 years) and a girl (age 5 years), were retrieved from the files of 2 institutions. RESULTS: The three patients presented with parotid gland enlargement. Clinically, the enlargements appeared to be inflammatory, and they were treated unsuccessfully with antibiotics. Fine-needle aspiration biopsy (FNAB) was performed on all three patients. The cytologic features varied from one case to another; one case had features of a small round cell tumor, another was composed of a monomorphic population of spindle cells in a metachromatic stroma, and the third case was composed mostly of spindle cells with moderate cellular pleomorphism. Immunohistochemical studies performed in two of the cases confirmed the diagnosis of rhabdomyosarcoma, and ultrastructural studies were confirmatory in the other case. The patients are alive; 2 of them have had no evidence of disease after 6 and 9 years of follow-up, and the third, the most recent patient, has just finished adjuvant chemotherapy. CONCLUSIONS: With the increased use of FNAB for the evaluation of salivary gland masses in children, the authors believe that it is important to recognize the occurrence of rhabdomyosarcoma in this location. Immunohistochemical studies have proved helpful in differentiating rhabdomyosarcoma from other parotid gland tumors and can be readily done on cytologic preparations.

Biopsy, Needle↗
PubMed1998

[Standards, options and recommendations (SOR) for clinical care of rhabdomyosarcoma (RMS) and other soft tissue sarcoma in children. Federation of the French Cancer Centers. French Society of Pediatric Oncology].

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. For pediatric issues, this project is a collaboration between the FNCLCC and the French Society of Pediatric Oncology (SFOP). The main objective is the development of clinical practice guidelines to improve the quality of health care and outcomes for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop a clinical practice guideline according to the definitions of Standards, Options and Recommendations for the clinical care of rhabdomyosarcoma and other soft tissue sarcoma in children and adolescents. METHODS: Data have been identified by literature search using Medline (1985-may 1997) and experts group personal references lists. The main criteria considered were incidence, risk factors, prognostic factors and efficacy of cancer treatment. Once the guideline was defined, the document was submitted for review to 14 national and international independent reviewers, and to the medical committees of the 20 French Cancer Centres and, in particular the 4 which have expertise in pediatric cancer management, for agreement. RESULTS: The main recommendations for rhabdomyosarcoma management are: 1/ diagnosis is based on appropriate clinical and radiological findings; 2/ pathological and immunohistochemical studies are essential to confirm the diagnosis; 3/ surgery must be performed by an experienced surgeon. Surgery and radiotherapy must be as conservative as possible; 4/ therapeutic strategies for rhabdomyosarcoma depend on location and extends and are based on chemotherapy, surgery and radiotherapy. Inclusion of patients in SFOP, SIOP and IRS clinical trials is recommended; 5/ treatment of metastatic rhabdomyosarcoma is based on intensive chemotherapy, and surgery with or without radiotherapy; 6/ the management of non-rhabdomyosarcoma is based on the likelihood of sensitivity to chemotherapy; 7/ at the present time, there are no clear data on which to base guidelines for timing and duration of follow-up studies in these conditions.

Child↗
PubMed1994

The effect of age at diagnosis on outcome in rhabdomyosarcoma.

BACKGROUND: Survival for rhabdomyosarcoma appears to be more favorable in children and adolescents compared with adults. To determine the significance of age at diagnosis as a prognostic indicator in rhabdomyosarcoma, we performed a retrospective analysis of a combined pediatric and adult rhabdomyosarcoma data base. METHODS: Pertinent prognostic variables, including age, TNM stage, histopathologic subtype, anatomic site, resectability, radiation to the primary site, and dose intensity of chemotherapy, were compared in a Cox proportional hazards model with mortality as the outcome variable. RESULTS: Age at diagnosis (P = 0.0001) and local tumor invasiveness (P < 0.0001), distant parenchymal metastases (P < 0.0001), regional lymph node involvement (P = 0.0027), and histopathologic subtype (P = 0.0446) contributed information to the proportional hazards model. CONCLUSIONS: Age at diagnosis is an independent predictor of outcome in patients with rhabdomyosarcoma along with tumor invasiveness, metastases, regional lymph node involvement, and histopathologic subtype.

Adolescent↗
PubMed2004

Altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma.

Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in children. Some reports have discussed the altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma; however, variable frequencies of occurrence have been noted. In the current study, among 72 cases of rhabdomyosarcoma, the authors evaluated for the expression of p53, MDM2, p16, p21/WAF1, p27, cyclin D1, cyclin E, pRb and E2F-1 protein immunohistochemically and assessed for proliferative activities using MIB-1. We also analyzed the mutation of the p53 gene in 45 cases, the amplification of the MDM2 gene in 18 cases and the mutation of the H-ras gene in 29 cases, using formalin-fixed paraffin-embedded materials. Furthermore, we assessed the correlation between clinicopathologic factors and the results of both immunohistochemical and molecular analyses. Alveolar type affected older patients, and it had a significantly higher mitotic rate compared with the embryonal type (P=0.0226). p53 overexpression was detected in 22 (30.6%) of 72 cases, and 10 (22.2%) of 45 cases had p53 gene abnormalities. As for MDM2, its overexpression was found in nine (12.5%) of 72 cases, and three (16.7%) of 18 cases showed MDM2 amplification. A statistically significant association was observed between immunoreaction for MDM2 and p53 overexpression (P=0.0002), and p53 and MDM2 overexpression was significantly correlated with high MIB-1 labeling indices. E2F-1 labeling indices showed a significantly higher score in alveolar type compared with that seen in embryonal type (P=0.0334), but MIB-1 did not. In conclusion, our study suggests that p53 overexpression may be related to tumor progression because tumors with p53 overexpression have a high proliferative activity in the current study. Alveolar type had a significantly higher both mitotic rate and E2F-1 labeling indices when compared with the embryonal type. The current study is the first report of the correlation of E2F-1 with alveolar rhabdomyosarcoma.

Adolescent↗
PubMed1996

Rhabdomyosarcoma presumed metastatic to the orbit.

BACKGROUND: Orbital metastasis from rhabdomyosarcoma is a rare disorder with a poor prognosis for long-term survival. Only one other detailed account of this disorder has appeared in the ophthalmic literature. METHODS: The authors report the clinical features of four patients with presumed orbital metastasis from alveolar and embryonal rhabdomyosarcoma. RESULTS: The most common ophthalmic manifestations of orbital metastasis from rhabdomyosarcoma in these patients included proptosis, reduced visual acuity, orbital pain, and motility disorders. Computed tomography documented orbital masses in all of the patients. In those patients with a primary tumor of the maxillary sinus, there was no evidence of direct extension into the orbit. Despite combination chemotherapy and radiation, all four patients died of their illness within 6 months of orbital metastasis. CONCLUSIONS: Although uncommon, rhabdomyosarcoma should be considered in the differential diagnosis of metastatic tumors to the orbit in children and adults. Despite the poor prognosis, prompt diagnosis and palliative radiotherapy may improve the quality of life for these patients with terminal disease.

Adolescent↗
PubMed2001

Histology-specific expression of a DNA repair protein in pediatric rhabdomyosarcomas.

PURPOSE: DNA repair enzymes have a critical role in cellular maintenance and survival. The enzyme apurinic/apyrimidinic endonuclease/redox factor 1 (APE/ref1), a key protein in the base excision repair pathway, displays both repair and redox control. We examined the role of APE/ref1 in pediatric embryonal and alveolar rhabdomyosarcomas (ARMS). MATERIALS AND METHODS: Using an immunohistochemical method, fixed tissue from 31 newly diagnosed pediatric rhabdomyosarcomas were evaluated for expression of APE/ref1. Tissue was obtained from Indiana University and the Cooperative Human Tissue Network. RESULTS: We demonstrated high levels of expression within the localized and metastatic embryonal rhabdomyosarcomas. This contrasted with both localized and metastatic ARMS, which had low levels of APE/ref1 expression. This histology-specific difference proved to be significant (P = 0.003). Furthermore, the expression within all tumors examined was localized to the nucleus and did not differ between localized and metastatic tumors. CONCLUSIONS: We propose several hypotheses to explain this histology-specific expression of APE/ref1 in pediatric rhabdomyosarcomas. Because the majority of ARMS expressed either the PAX3/FKHR or PAX7/FKHR fusion transcript, the low level of expression may be related to the redox activity of APE/ref1. The low levels may also be related to the bioreductive activity of APE/ref 1.

Adolescent↗
PubMed1996

Retrogenic expression of the MET proto-oncogene correlates with the invasive phenotype of human rhabdomyosarcomas.

The MET oncogene encodes the receptor for HGF/Scatter Factor, known to control cell motility and invasion in epithelial cells. We report that the Met/HGF receptor, absent in differentiated adult skeletal muscles, is aberrantly expressed in clinical samples and in established cell lines of human rhadbomyosarcomas. In both the embryonal and alveolar histotypes the oncogene is overexpressed and, in some cases, amplified. The Met receptor is exposed at the cell surface and is functionally active in response to HGF/Scatter Factor. Accordingly, rhabdomyosarcoma cells exhibit an invasive phenotype in vitro in response to exogenous HGF/Scatter factor. As the factor is known to be produced by connective tissues, a paracrine stimulation of rhabdomyosarcoma invasiveness in vivo is hypothesized. Two alveolar rhabdomyosarcomas were found in co-express the ¿two-kringle' alternatively-spliced HGF/Scatter Factor variant, which has been previously shown to stimulate cell motility and matrix invasion in vitro. These cells displayed the invasive phenotype in the absence of exogenous HGF/Scatter Factor, suggesting an autocrine mechanism in vivo. These data indicate that aberrant expression of the MET proto-oncogene provides rhabdomyosarcoma cells with the same property as embryonal myoblasts to migrate into the surrounding connective tissues.

Base Sequence↗
PubMed2004

Laryngeal embryonal rhabdomyosarcoma: a case of cervical metastases 13 years after treatment and a 25-year review of existing literature.

Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood, the majority of which are of the embryonal rhabdomyosarcoma (ER) variety. Present day treatment protocols involve a combination of aggressive surgery, chemotherapy, and radiation therapy. Embryonal rhabdomyosarcoma of the larynx is rare and unlike ER of other regions exhibits excellent response to multimodality treatment without the need for extensive surgery. We report a case of cervical metastases in a 29-year-old man 13 years after treatment of his laryngeal ER. To our knowledge, this is the first reported case of late neck metastases in ER of the larynx and the second reported case of delayed presentation of recurrent disease. A 25-year review of all published reports of ER of the larynx was conducted that highlights the move toward organ preservation with the multimodality treatment protocols. Embryonal rhabdomyosarcoma of the larynx is highly responsive to combination chemoradiotherapy, allowing for excellent cure rates without the need for extensive surgery. Late relapses warrant long-term follow-up.

Adult↗
PubMed1996

Inverse expression of mdr 1 and c-myc genes in a rhabdomyosarcoma cell line resistant to actinomycin d.

Cytotoxic agents used in cancer therapy may induce differentiation in tumour cells with no proliferative potential. However, chemotherapy can also induce multidrug resistance, a formidable obstacle to the successful treatment of tumours. Both events were recently shown to occur in a rhabdomyosarcoma cell line (RD-DAC) resistant to actinomycin D, a drug of choice in the treatment of these tumours. To analyse this connection, cell line RD cultures were investigated with progressive concentrations of actinomycin D and it was shown that a minimum dose (1.2 x 10(-6) mM) of the drug was necessary to increase mdr 1 mRNA in RD-DAC. The mechanism of mdr 1 overexpression was an increase in the number of copies of the mdr 1 gene, although the mRNA levels were not correlated with mdr 1 amplification. Drug resistance mediated by mdr 1 overexpression coincided with the development of myogenic differentiation in RD-DAC and with a decrease in c-myc mRNA levels, whereas levels of N-myc mRNA showed no modulation. These findings suggest that factors implicated in cell proliferation and differentiation, such as c-myc, may be responsible for the control of genes related to the development of multidrug resistance in rhabdomyosarcomas. Modulation of these factors may determine the sensitivity of rhabdomyosarcoma cells to drugs and may play an important role in triggering the differentiation programme found in these resistant rhabdomyosarcoma cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗