Chromosomes in malignancy.
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Autoradiography↗
Biomedical subjects
W F Benedict
Publications and source records attributed to W F Benedict.
Expression of recessive alleles by chromosomal mechanisms in retinoblastoma.
Inheritance of a mutation at the Rb-1 locus, which has been mapped to band q14 of human chromosome 13, results in predisposition to retinoblastoma. Cloned DNA segments homologous to arbitrary loci of human chromosome 13 and which reveal polymorphic restriction endonuclease recognition sequences, have been used to look for somatic genetic events that might occur during tumorigenesis. A comparison of constitutional and tumour genotypes from several cases indicates that tumorigenesis may result from the development of homozygosity for the mutant allele at the Rb-1 locus. The homozygosity in these cases results from mitotic nondisjunction, resulting in loss of the homologous wild-type chromosome, or from a mitotic recombination event.
Alleles↗
Expression and amplification of the N-myc gene in primary retinoblastoma.
Retinoblastoma, the most common intraocular tumour of childhood, probably arises from embryonal cells and occurs in hereditary and non-hereditary forms. Recent evidence suggests that this retinoblastoma (Rb) susceptibility gene located at chromosome 13q14 is actually recessive. Knudson has proposed that the tumour is caused by two mutational events. This idea was extended by Comings, who suggested that dominantly inherited tumours may result from loss or inactivation of both alleles of regulatory or suppressor genes that, when active, prevent the expression of a structural transforming gene(s) (possibly an oncogene) normally active only during embryogenesis. Despite circumstantial evidence for this hypothesis, no activated oncogene has been identified. We now report that (1) the N-myc gene is amplified 10-200-fold in two primary retinoblastomas and a retinoblastoma cell line Y79 and (2) expression of N-myc gene is highly elevated in most of the retinoblastomas examined. This finding suggests that N-myc gene may have a primary role in the tumorigenesis of retinoblastoma.
Base Sequence↗
Immortalization of fibroblasts from two patients with hereditary retinoblastoma.
Two RB fibroblastic strains from patients with hereditary retinoblastoma (RB), namely, RB80F/250R and RB110F, were transfected with plasmid DNAs encoding SV-40 large T-antigen at passage 31 and 10, respectively, These transfected fibroblasts developed into two immortalized cell lines. RB80F/250R/ori- and RB110F/gpt. RB110F/gpt had a similar doubling time as the parental cells, whereas RB80F/250R/ori- grew more rapidly with a doubling time of 19 hours compared to the parental cells which had a doubling time of 50 hours. The RB80F/250R/ori- cell line was particularly interesting cytogenetically since no normal chromosome 13 was present, although a marker chromosome 13 was found. In contrast, two apparently normal chromosome 13s were present in RB110F/gpt cells, but these cells had a marker chromosome which involved chromosome 14 (14 p+). Both the cell lines also had an abnormal chromosome 1 (1q-). RFLP analysis using the chromosome 13 specific VNTR probe, pTH162, assigned to 13q14.1 showed that the DNA from the RB80F/250R/ori- cells contained only a 6.1kb allelic fragment whereas the DNAs from parental RB80F/250R and RB80F cultures demonstrated both the polymorphic 8.0kb and 6.1kb allelic fragments. However, the RB gene per se was normal at the DNA level. Both cell lines expressed SV-40 large T-antigen together with elevated levels of p53 protein. In addition, levels of RB protein were the same in exponentially growing nontransformed parental cell strains and their immortalized cell lines. However, at confluency the levels of RB protein were greatly reduced in nontransformed cells but not in immortalized cell lines under similar conditions. In future studies using these immortalized cell lines, we shall make an attempt to discern the role of the RB gene and other tumor suppressor genes in the regulation of normal and malignant growth.
Cell Division↗
Tissue concentrations of doxorubicin in animal models with engrafted intraocular tumours.
The role of chemotherapy in the management of retinoblastoma remains unclear. In order to evaluate the responsiveness to conventional or experimental agents, a xenograft model had been developed, where human retinoblastoma is heterotransplanted to the anterior chambers of nude mouse eyes. Because doxorubicin had been found to be ineffective in therapeutic studies utilizing the model, experiments were conducted to evaluate the concentration of the drug in tissues, including intraocular engrafted tumour. The presence of doxorubicin was demonstrated in xenograft containing mouse eyes as well as in tumours of a comparable rabbit model. Distribution in extraocular tissues was consistent with previously published data. It is concluded that failure of response to doxorubicin in the xenograft model is not explained by lack of tumour penetration by the drug.
Animals↗
The cytogenetic diagnosis of malignancy in effusions.
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Aneuploidy↗
In vitro and in vivo preclinical chemotherapy studies of human neuroblastoma.
Two human neuroblastoma cell lines, LA-N-1 and SK-N-MC growing in vitro and as subcutaneous tumors in athymic nude mice, were evaluated for their sensitivity to cyclophosphamide, doxorubicin (Adriamycin), and vincristine. In vitro, cyclophosphamide, following liver S-9 metabolic activation, and vincristine were significantly more cytotoxic to SK-N-MC than to LA-N-1 cells; doxorubicin was equally cytotoxic to both cell types. Treatment of nude mice bearing LA-N-1 and SK-N-MC tumors with cyclophosphamide and vincristine produced significant reduction (> 50%) in SK-N-MC tumor weights but not in LA-N-1 tumor weights. Doxorubicin failed to produce significant reduction in the weight of either the LA-N-1 or the SK-N-MC tumor. These sensitivities were generally similar to the clinical response of the tumors to these same agents. Such an in vitro and in vivo system using these and other neuroblastoma cell lines may provide a preclinical model for evaluating the activity of chemotherapeutic agents against human neuroblastoma.
Animals↗