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At least 505 records · Page 28Linked to original sources
PubMed1999

GR-891: a novel 5-fluorouracil acyclonucleoside prodrug for differentiation therapy in rhabdomyosarcoma cells.

Differentiation therapy provides an alternative treatment of cancer that overcomes the undesirable effects of classical chemotherapy, i.e. cytotoxicity and resistance to drugs. This new approach to cancer therapy focuses on the development of specific agents designed to selectively engage the process of terminal differentiation, leading to the elimination of tumorigenic cells and recovery of normal cell homeostasis. A series of new anti-cancer pyrimidine acyclonucleoside-like compounds were designed and synthesized by structural modifications of 5-fluorouracil, a drug which causes considerable cell toxicity and morbidity, and we evaluated their applicability for differentiation therapy in human rhabdomyosarcoma cells. We tested the pyrimidine derivative GR-891, (RS)-1-[[3-(2-hydroxyethoxy)-1-isopropoxy]propyl]-5-fluorouracil, an active drug which shows low toxicity in vivo and releases acrolein which is an aldehyde with anti-tumour activity. Both GR-891 and 5-fluorouracil caused time- and dose-dependent growth inhibition in vitro; however, GR-891 showed no cytotoxicity at low doses (22.5 micromol l(-1) and 45 micromol l(-1)) and induced terminal myogenic differentiation in RD cells (a rhabdomyosarcoma cell line) treated for 6 days. Changes in morphological features and in protein organization indicated re-entry in the pathway of muscular maturation. Moreover, GR-891 increased adhesion capability mediated by the expression of fibronectin, and did not induce overexpression of P-glycoprotein, the mdr1 gene product, implicated in multidrug resistance. New acyclonucleoside-like compounds such as GR-891 have important potential advantages over 5-fluorouracil because of their lower toxicity and their ability to induce myogenic differentiation in rhabdomyosarcoma cells. Our results suggest that this drug may be useful for differentiation therapy in this type of tumour.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Expression and parental imprinting of the H19 gene in human rhabdomyosarcoma.

The expression of Insulin-like Growth Factor 2 (IGF-2) and H19, two genes located on human chromosome 11p15 and provided with cell growth modulating activity, is regulated by parental imprinting, in that the activity of their alleles is dependent on the parental origin. Parental bias in the genetic alterations of chromosome 11p15 observed in several pediatric cancers suggests the involvement of imprinted genes in tumor development. We have previously reported that the number of functional IGF-2 alleles is frequently increased in rhabdomyosarcoma (RMS), as a consequence of either relaxation of imprinting (LOI) or gene duplication. Here we show that the expression of the H19 gene is significantly suppressed with respect to normal muscle tissue in 13 out of 15 rhabdomyosarcomas with embryonal histology (ERMS) and in three out of 11 rhabdomyosarcomas classified as alveolar subtype (ARMS). Since a growth-inhibitory activity has been found associated with the H19 gene, the extinction of its expression can contribute to RMS development. Parental imprinting of the H19 gene was found conserved in all informative RMSs, including those whose ICF-2 imprinting was relaxed, indicating that LOI is a gene-specific event. Seven ERMSs and one ARMS displaying low H19 RNA levels showed an underrepresentation of the expressed allele in their genotype. This result is consistent with the paternal imprinting of the H19 gene and with the preferential loss of the maternal 11p15 alleles in these neoplasms. Low H19 expression was also found in four out of eight RMSs retaining the heterozygosity at 11p15, but showing IGF-2 LOI. These findings suggest that the genetic and epigenetic alterations affecting chromosome 11p15 in a high number of RMSs cause deregulation of more than one imprinted gene, possibly affecting tumor growth, including the extinction of H19 expression and an increase in the number of active IGF-2 alleles.

Alleles↗
PubMedDate not supplied

Congenital primary cutaneous rhabdomyosarcoma in a neonate.

We report a case of congenital primary cutaneous rhabdomyosarcoma, solid alveolar type, presenting as a solitary skin lesion on the right upper lip of a 2-week-old infant boy. Rhabdomyosarcoma originates from the embryonic mesenchyme precursor of striated muscle. Histologically it belongs to the group of "small round cell tumors." Its myogenic origin is ascertained by immunohistochemical studies positive for myogenin, muscle-specific actin, desmin, and myoglobin. Malignancy in the neonatal period is uncommon and the clinical management presents considerable challenges. Congenital alveolar rhabdomyosarcoma is a highly malignant tumor with no record of long-term survivors. Treatment options include chemotherapy, excision, and radiotherapy. This infant's tumor was responsive to chemotherapy and surgery and he was free of disease at the 6-month follow-up.

Humans↗
PubMed2000

Molecular features of a human rhabdomyosarcoma cell line with spontaneous metastatic progression.

A novel human cell line was established from a primary botryoid rhabdomyosarcoma. Reverse transcription polymerase chain reaction investigations of this cell line, called RUCH-2, demonstrated expression of the regulatory factors PAX3, Myf3 and Myf5. After 3.5 months in culture, cells underwent a crisis after which Myf3 and Myf5 could no longer be detected, whereas PAX3 expression remained constant over the entire period. Karyotype analysis revealed breakpoints in regions similar to previously described alterations in primary rhabdomyosarcoma tumour samples. Interestingly, cells progressed to a metastatic phenotype, as observed by enhanced invasiveness in vitro and tumour growth in nude mice in vivo. On the molecular level, microarray analysis before and after progression identified extensive changes in the composition of the extracellular matrix. As expected, down-regulation of tissue inhibitors of metalloproteinases and up-regulation of matrix metalloproteinases were observed. Extensive down-regulation of several death receptors of the tumour necrosis factor family suggests that these cells might have an altered response to appropriate apoptotic stimuli. The RUCH-2 cell line represents a cellular model to study multistep tumorigenesis in human rhabdomyosarcoma, allowing molecular comparison of tumorigenic versus metastatic cancer cells.

Animals↗
PubMed2000

Characterization and modulation of drug resistance of human paediatric rhabdomyosarcoma cell lines.

The role of multidrug resistance (MDR) and p53 functional status in the treatment of paediatric rhabdomyosarcoma is unclear. We have characterized a panel of seven human rhabdomyosarcoma cell lines for MDR and p53 phenotype. None of the cell lines had P-glycoprotein (P-gp) or multidrug resistance-related protein (MRP) detectable by Western blotting, whereas immunohistochemistry suggested that very low levels of MDR proteins may be present in some of the lines. RT-PCR studies indicated that mdr-1, mrp-1 and Irp mRNA was present in 5/7, 7/7 and 5/7 lines respectively. The function of p53 is compromised in six of the lines, either through mutation of the p53 gene or by overexpression of mdm-2. The sensitivity of many of the cell lines to vincristine could be modulated above 2-fold and as high as 16-fold using two modulating agents, PSC833 and VX710 (with VX710 being a significantly more potent modulator of the rhabdomyosarcoma lines). PSC833 also increased vincristine accumulation in all of the lines from 1.2- to 2.2-fold. These results suggest that some of these cell lines have low levels of multidrug resistance. The level of MDR proteins is very low and therefore difficult to detect, but may be sufficient to confer low-level, but clinically relevant, resistance to some cytotoxic agents, especially vincristine. These cell lines will therefore provide a suitable model to test new strategies in treatment and for further understanding relationships between protein expression and drug resistance.

Antineoplastic Agents, Phytogenic↗
PubMed2001

High levels of the MDM2 oncogene in paediatric rhabdomyosarcoma cell lines may confer multidrug resistance.

The MDM2 protein is known to be overexpressed in some sarcomas including rhabdomyosarcoma. However, the extent to which the MDM2 protein influences sensitivity to chemotherapeutic drugs is unclear. We have analysed this further using stable transfection of the mdm2 gene into 4 well-characterised human paediatric rhabdomyosarcoma cell lines. Transfection with the mdm2 gene resulted in increased levels of the MDM2 protein in all the cell lines. In 2 of the lines, SCMC and RD, the mdm2 gene caused between 2-fold and 61-fold increase in resistance to vincristine, etoposide and doxorubicin but not to cisplatin. In these lines there was an increase in expression of the mdr-1 gene which encodes P-glycoprotein, but not the mrp1 gene which encodes the multidrug resistance protein (MRP). The resistance was reversible using the MDR modulator PSC833, confirming the presence of P-glycoprotein. We conclude that MDM2 overexpression may be a mechanism by which multidrug resistance is regulated in some rhabdomyosarcomas.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Insulin-like growth factor binding protein-6 and CCI-779, an ester analogue of rapamycin, additively inhibit rhabdomyosarcoma growth.

Rhabdomyosarcomas secrete high levels of insulin-like growth factor-II, suggesting this autocrine growth factor plays a major role in the unregulated growth of this childhood cancer. Treatment of Rh30 rhabdomyosarcoma cells with insulin-like growth factor binding protein-6 (IGFBP-6; 1000 ng/ml), which binds insulin-like growth factor-II with high affinity, inhibited growth in vitro (p < 0.001). Co-incubation of cells with rapamycin (1.56 ng/ml), an inhibitor of p70 S6 kinase, and IGFBP-6 (200 ng/ml) resulted in a significant reduction in Rh30 cell number compared to rapamycin or IGFBP-6 alone (p < 0.05 for both). Co-treatment of Rh30 cells with CCI-779 (5 and 50 ng/ml), an ester analogue of rapamycin, and IGFBP-6 (200 or 1000 ng/ml) also inhibited growth in vitro relative to CCI-779 alone (p < 0.01 and p < 0.001, respectively). In a nude mouse model, xenografts of Rh30 cells transfected with a recombinant vector encoding IGFBP-6 (phBP6-E3) showed delayed growth relative to vector control xenografts (27 days vs. 19 days to reach an average tumour volume of 0.5 cm (3); p < 0.001). Treatment with CCI-779 (10 mg/kg) of mice inoculated with vector control xenografts, also delayed growth (to 31 days; p = 0.0055) relative to untreated mice with vector control xenografts. Co-treatment with CCI-779 (10 mg/kg) reduced phBP6-E3 transfected xenograft growth even further (to 45 days) compared to vector control xenografts (p < 0.001, day 33). CCI-779 thus acts additively with IGFBP-6 to reduce rhabdomyosarcoma growth both in vitro and in vivo.

Animals↗
PubMed2005

[Primary pulmonary rhabdomyosarcoma as a rare differential diagnosis of small cell lung cancer].

Primary pulmonary rhabdomyosarcoma is a rare entity and the histological differential diagnosis can be difficult. We report on a 43-year old female patient, smoker (25 pack-years), in whom a large solitary brain metastasis was diagnosed and enucleated. Histological examination revealed a typical small cell carcinoma and histological examination of biopsies obtained from a tumor in the left upper lobe of the lung was compatible with a small cell carcinoma. Despite chemotherapy there was a progressive tumor growth. Bronchial biopsies again showed a small cell tumor, although immunohistochemistry proved it to be a pleomorphic rhabdomyosarcoma. Due to the progressive tumor growth with necrosis and superinfection and a lack of further metastases lobectomy of the left upper lobe was performed, complicated by postoperative pleural empyema, limiting the possibilities of adjuvant therapy. Early relapse occurred with pleural, pulmonary, chest wall and spinal metastases. Laminectomy and extirpation of the spinal metastases, local radiotherapy and chemotherapy with iphosphamide and doxorubicine led to partial remission and clinical improvement for few months only. The patient died from metastatic primary rhabdomyosarcoma of the lung. This rare tumor mimicked small cell lung cancer. Appraisal of the atypical clinical course and a close dialogue between pathologists and clinicians enabled the correct diagnosis.

Adult↗
PubMed1998

[Rhabdomyosarcoma in the area of the head-neck. A synopsis of some cases, therapeutic possibilities and prognoses].

BACKGROUND: Soft tissue sarcoma represent approximately 7% of all neoplasms in children up to 14 years. The most common type (approx. 50%) among them is the rhabdomyosarcoma (RMS). Within the head and neck, which accounts for approx. 35% of all RMS, the tumor can be found ubiquitiously. Preferred localizations are the orbita, the paranasal sinuses, and the soft tissue of cheek and neck. The prognosis of RMS was formerly poor but has markedly improved since defined multimodal therapy was established in the Seventies (for example the Intergroup Rhabdomyosarcoma Study, IRS, in 1972; the International Society of Paediatric Oncology, SIOP, in 1975, or the German "Cooperative Weichteil-Sarkom-Studien", CWS, in 1981). The therapy of choice for RMS, according to the CWS, is chemotherapy because very often a good remission of the tumor is achieved. The main role of surgery is first to obtain biopsy specimens for histological diagnosis, and second aim is the complete resection of the primary and resectable metastases, for example by a neck dissection. Severe mutilation by radical surgery, especially in childhood, should be avoided in favor of multidrug chemotherapy and radiation in the interest of patient well-being. PATIENTS: Our retrospective study shows the treatment and results of 11 patients with a rhabdomyosarcoma of the head and neck within 25 years (1972-1997). RESULTS: Five of the 11 patients, who were treated in the years 1972-77, died (average 13 months, range 3-72 months). Five of the six patients, who were treated since 1991, have survived to date, one had a relapse of the tumor. Four special cases of patients are discussed in greater detail. CONCLUSION: Although the achieved mean survival time is encouraging nowadays (a 5-year survival rate of approx. 70% for all RMS is described) fatal cases are typical for this malignancy. Early diagnosis, localization, histological subtype, and prompt initiation of adequate treatment is decisive for a successful outcome.

Adolescent↗
PubMed2000

Orbital abscess masquerading as a rhabdomyosarcoma.

Although orbital cellulitis is the most common cause of acute-onset proptosis with inflammatory signs in a child, the clinician should always be alert to the possibility of rhabdomyosarcoma. We describe an unusual presentation of acute-onset nonaxial proptosis of the left orbit without sinus disease or systemic toxicity in a 6-year-old boy. Our clinical differential diagnosis included orbital cellulitis, metastatic disease, capillary haemangioma, lymphangioma with cyst, ruptured dermoid cyst, and orbital rhabdomyosarcoma. Only after orbital biopsy and subsequent microbiologic confirmation were obtained was a diagnosis of chronic orbital abscess tenable. Features in our patient included paucity of symptoms and signs of inflammation. This case illustrates the difficulty in differentiating a chronic orbital infection from orbital rhabdomyosarcoma on the basis of clinical, laboratory, and orbital imaging findings. Possible causes of this unusual presentation are discussed.

Abscess↗
PubMed1996

Microsatellite instability in childhood rhabdomyosarcoma is locus specific and correlates with fractional allelic loss.

Replication errors (RERs) were initially identified in hereditary nonpolyposis colon cancer and other tumors of Lynch syndrome II. Mutations in genes involved in mismatch repair give rise to a mutator phenotype, resulting in RERs. The mutator phenotype is thought to predispose to malignant transformation. Here we show that in the embryonal form of childhood rhabdomyosarcoma, RERs also occur, but in contrast to hereditary nonpolyposis colon cancer, only a subset of the microsatellite loci analyzed show RERs. The occurrence of RERs is strongly correlated with increased fractional allelic loss (P < 0.001), suggesting that the occurrence of RERs is a secondary phenomenon in rhabdomyosarcoma. Coincidental loss of genes involved in mismatch repair, possibly due to their proximity to tumor suppressor genes involved in tumor progression of embryonal form of childhood rhabdomyosarcoma, could explain the observed phenomenon.

Alleles↗
PubMed2006

Cutaneous embryonal rhabdomyosarcoma presenting as a nodule on cheek; a case report and review of literature.

We report a case of primary cutaneous rhabdomyosarcoma, solid embryonal type, presenting as a rapidly enlarging nodule on the right cheek of a 7-year-old boy. This lesion had begun as a pea-sized nodule 8 months previously, and, with suspected abscess, had been incised. It recurred 2 months later; at that time, incisional biopsy was consistent with malignant round cell tumor. Wide local excision of the tumor was then completed. Subsequent immunohistochemical staining with desmin and myoglobin confirmed embryonal rhabdomyosarcoma. The patient underwent radiation therapy followed by chemotherapy and continues to be disease free at 14 months after his wide local excision. Rhabdomyosarcoma presenting as a dermal nodule is rare. It usually presents as an asymptomatic papule without distinctive clinical features and therefore may result in delayed diagnosis unless a biopsy is performed.

Cheek↗
PubMedDate not supplied

Rhabdomyosarcoma metastasizing as a malignant ectomesenchymoma.

Rhabdomyosarcoma is a common childhood malignancy that may occasionally occur as a component of a mixed mesenchymal tumor, e.g., a triton tumor or malignant ectomesenchymoma. A case is reported of a 13-year-old boy who had resection of a paratesticular embryonal rhabdomyosarcoma with subsequent radiation and chemotherapy. Two years later, a retroperitoneal metastasis was resected. Histology showed a mixture of rhabdomyoblasts, ganglion cells, and a third population of cells with combined features of these two distinct cell types. Electron microscopy confirmed the presence of rhabdomyoblasts with characteristic bundles of myofilaments and Z-band material, and ganglion cells with prominent nuclei and nucleoli, rough endoplasmic reticulum, dense core granules, filaments, and tubules. Notably, the third cell population showed features of both rhabdomyoblasts and ganglion cells. Immunohistochemistry confirmed the mixed population of rhabdomyoblasts (positive for vimentin, desmin, negative for S-100, NSE), ganglion cells (positive for S-100 and NSE, negative for vimentin and desmin), and the third population expressing all test antigens. The features of this metastatic lesion are those of a malignant ectomesenchymoma with combined rhabdomyosarcoma and ganglioneuroma components. It is postulated that this lesion results from biphenotypic expression of tumor cells that previously expressed only rhabdomyoblastic differentiation. The role of prior chemotherapy and radiotherapy in this particular case is unclear.

Adolescent↗
PubMed2000

Blueberry muffin rash as a presentation of alveolar cell rhabdomyosarcoma in a neonate.

Soft tissue sarcomas of childhood continue to present problems with pathologic diagnosis, staging and treatment. Rhabdomyosarcoma, the most common soft tissue sarcoma, represents 4-8% of all malignant solid tumours in children. We report a case of congenital alveolar rhabdomyosarcoma who presented with "blueberry muffin"-like rash. A full-term female infant was noted at birth to have multiple skin lesions resembling blueberry muffin rash and an abdominal mass in the left iliac fossa, which appeared to be fixed to the posterior abdominal wall. There was no enlargement of liver and spleen, but her para-aortic lymph nodes were enlarged. Biopsy from the mass confirmed the diagnosis of alveolar cell rhabdomyosarcoma. Molecular investigation for the t (2:13) translocation was negative. The infant received chemotherapy but died within 1 mo of diagnosis.

Biopsy↗
PubMed2003

Regression of refractory rhabdomyosarcoma after allogeneic stem-cell transplantation.

A 17-year-old girl developed refractory rhabdomyosarcoma. An allogeneic peripheral-blood stem-cell transplant was performed after a myeloablative regimen. Although rapid disease progression had resolved transiently, after the start of high-dose chemotherapy, re-progression was apparently observed from day 14. However, delayed tumor regression occurred on day 30, shortly after the reduction of immunosuppressants. She achieved a partial remission. The second tumor regression provides suggestive clinical evidence that graft-versus-tumor effect may occur against rhabdomyosarcoma. Although further investigation is required, allogeneic stem-cell transplantation could provide a new therapeutic option for refractory rhabdomyosarcoma.

Adolescent↗
PubMedDate not supplied

Neurofibromatosis 1 associated with embryonal rhabdomyosarcoma of the urinary bladder.

A 10-month-old boy presented with a 6-week history of abdominal pain. The pain was due to a large, stage IV embryonal rhabdomyosarcoma of the urinary bladder. The rhabdomyosarcoma was found in association with neurofibromatosis 1 (NF1) manifesting multiple café au lait spots and bowing of the right calf. The diagnosis of NF1 had not been made before presentation. This case report is intended to heighten the awareness of the manifestations of NF1 and the possibility of developing a nonneuroectodermal tumor as a concomitant of NF1, and to emphasize the importance of timely diagnosis and treatment of such an NF1-associated malignancy. Reports of the epidemiologic evidence for rhabdomyosarcoma in children with NF1 are reviewed.

Humans↗
PubMed1984

Systemic rhabdomyosarcoma with diffuse bone marrow involvement. Case report of an unusual presentation.

Rhabdomyosarcoma presenting as a systemic disease is rare. This report concerns a 12-year-old girl who came to medical attention for what was thought to be a hematologic malignancy. Diffuse lytic bone lesions and large primitive cells in the bone marrow exhibiting erythrophagocytosis supported this diagnosis. During the course of the disease, a soft tissue mass in the region of the left ankle was removed and was a typical alveolar rhabdomyosarcoma. Retrospective review of the marrow, including electron microscopy, demonstrated that the primitive marrow cells were probably rhabdomyoblasts as well. The clinical course was a rapid downhill one in which lytic bone lesions and hypercalcemia were prominent. Although rhabdomyosarcoma eventually may disseminate, initial widespread disease without a clinically apparent primary can be a diagnostic dilemma. This clinical presentation, in combination with the recognized aggressiveness of the alveolar histologic subtype, identifies a rare subgroup of patients with rapidly fatal disease.

Ankle↗
PubMed1998

Inhibition of spontaneous formation of lung tumors and rhabdomyosarcomas in A/J mice by black and green tea.

We investigated the effects of black tea (BT) and green tea (GT) infusion on the spontaneous formation of lung tumors and rhabdomyosarcomas in A/J mice. Female A/J mice, 6 weeks of age, were allocated into five groups (50 per group) and were given the following as the sole source of drinking fluid: (i) deionized water (control group), (ii) 0.5% BT, (iii) 1% BT, (iv) 2% BT and (v) 1% GT. After 60 weeks, the mice were killed by decapitation. Lung tumor incidence, multiplicity and volume were significantly lower in the 2% BT group as compared with the controls (27 versus 52%, 0.33 versus 0.72 tumors/mouse and 4.27 versus 38.3 mm3, respectively). The 1% GT group had significantly lower lung tumor multiplicity (0.41/mouse), while the 1% BT group had significantly decreased tumor volume (7.17 mm3). Rhabdomyosarcomas were found in 34% of the mice in the control group, and both the 1 and 2% BT groups had significantly lower incidences at 13 and 14%, respectively. The mice in the 2% BT group weighed 16% less than those in the control group, although they consumed more food than the control group. The other tea-consuming groups also weighed less than the control group (7.8-11%) while consuming more food and fluid. In a separate experiment, similar carcinogenesis inhibition was also observed in female A/J mice that were given 0.6% and then 0.3% instant black tea for 52 weeks. These results demonstrate the inhibitory activity of BT against the spontaneous formation of lung tumors and rhabdomyosarcomas in mice.

Animals↗