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PubMed1991

Incidence and management of secondary malignancies in patients with retinoblastoma and Ewing's sarcoma.

Childhood cancer survivors at highest risk of developing a secondary malignancy are those with hereditary retinoblastoma. The majority of such secondary cancers will be sarcomas, most commonly of bone. One-third of these occur outside a typical radiation field, commonly in an extremity. Bone sarcoma is also the most commonly reported secondary cancer to develop among survivors of Ewing's sarcoma. In this group, radiation doses greater than 60 Gy as well as alkylating agent chemotherapy have been identified as contributors to the increased risk. The prognosis for patients with a secondary sarcoma has been poor, with few cures reported to date. However, an aggressive, combined modality approach, including radical resection, postoperative radiation, and adjuvant chemotherapy, may improve the survival rate.

Adolescent↗
PubMed1990

Molecular cloning of an amino acid-regulated mRNA (amino acid starvation-induced) in rat hepatoma cells.

Using the combination of a subtracted library and differential hybridization, a 409-base pair cDNA was identified that corresponds to a mRNA that is induced 2-3-fold when rat Fao hepatoma cells are subjected to amino acid starvation for 12 h. While this mRNA species was induced during starvation, others such as beta-actin, Cu-Zn superoxide dismutase, glyceraldehyde-3-P, and histone H4 were decreased in abundance to 25-50% of their original levels. The induction of the amino acid starvation-induced (ASI) mRNA was repressed when starved cells were returned to a medium supplemented with amino acids. Tissue distribution analysis showed the ASI mRNA, approximately 650 base pairs in length, to be present in every rat tissue tested. The cDNA clone has been sequenced and appears to correspond to the 3'-most end of the mRNA. The cDNA sequence includes the poly(A) tail, two potential polyadenylation signal sequences, and an open reading frame that we presume to be a portion of the coding sequence. The ASI cDNA will be used to investigate the molecular mechanisms for amino acid-dependent regulation of protein expression by mammalian cells.

Amino Acid Sequence↗
PubMed1988

Genetic evidence for progressive selection and overgrowth of primary tumors by metastatic cell subpopulations.

We have exploited random insertions of transfected DNA as unique clonotypic markers to follow cell lineages during primary and metastatic tumor growth of a mouse mammary adenocarcinoma, SP1. Southern analysis was undertaken of primary solid tumors and metastases obtained after injection of a pooled population of individual SP1 transfectants, or reconstituted mixtures of genetically marked metastatic and unmarked nonmetastatic cells. Here we provide evidence for the reproducible selection and eventual overgrowth of primary tumors by genotypically distinct metastatic clones, thereby illustrating that late-state, advanced primary tumors can evolve to become biologically similar, or even identical, to distant metastases. The selective growth advantage of metastatic cells within primary tumors was shown to occur despite the fact that tumors generated by both metastatic and nonmetastatic SP1 cell populations grew at comparable growth rates when injected and analyzed separately. The extent of the local growth advantage manifested by individual metastatic clones varied considerably, from 5- to 50-fold. Clonal overgrowth was also observed whether the tumor cells were injected ectopically, or orthotopically (i.e., into the mammary fat). This type of experimental approach should provide new insights into the dynamics of tumor progression and metastasis, the lineage relationship of primary tumors to metastases, the influence of clonal interactions on tumor behavior, and the physiological changes which are causative of malignant disease.

Adenocarcinoma↗
PubMed1995

DNA topoisomerase II alpha expression is associated with alkylating agent resistance.

Increased expression of DNA topoisomerase II alpha has been associated with resistance to certain DNA-damaging alkylating agents, but no causal relationship or mechanism has been established. To investigate this observation, we developed a model of topoisomerase II overexpression by transfecting a full-length Chinese hamster ovary topoisomerase II alpha into EMT6 mouse mammary carcinoma. Topoisomerase II alpha-transfected cell lines demonstrated continued topoisomerase II alpha mRNA and protein expression, which were undetectable in vector-only lines, in stationary phase (G0-G1). The topoisomerase II transfectants were approximately 5-10-fold resistant to the alkylating agents cisplatin and mechlorethamine. Upon release from G0-G1, the topoisomerase II transfectants demonstrated more rapid thymidine incorporation and shorter cell-doubling times than control cells. Purified topoisomerase II and nuclear extracts with topoisomerase II-decatenating activity bound to cisplatin-treated DNA with significantly greater affinity than to untreated DNA in a cisplatin concentration-dependent manner. These observations suggest that expression of topoisomerase II alpha may have a role in cellular resistance to antineoplastic alkylating agents. The mechanism for this may involve increased binding of topoisomerase II alpha to alkylating agent-damaged DNA.

Animals↗
PubMed1996

Evidence for the involvement of the Wnt 2 gene in human colorectal cancer.

Colorectal cancer (CRC) is one of the most frequent cancers in humans. It develops via a multistage process involving alterations of both protooncogenes and tumor suppressor genes. In the present report we determined the level of expression of several Wnt genes in CRC by RT-PCR and direct sequencing. While Wnt-1 was not detectably expressed in any colonic tissues, Wnt-5a gene was efficiently expressed both in nontumorous as well as in colonic tumor tissues. In contrast, the Wnt-2 gene, which was expressed at low levels in normal colon, exhibited overexpression in all tumor tissue samples at the different Dukes' stages of CRC progression, including premalignant polyps and liver metastases. Overexpression of the Wnt-2 gene occurred also in other digestive neoplasms such as gastric and esophageal carcinomas, as well as in diverticulitis associated with stenosis or pseudo-tumor.

Base Sequence↗
PubMed1996

Repair Defect in p21 WAF1/CIP1 -/- human cancer cells.

p53 induction and cell cycle arrest occur following DNA damage, possibly to allow repair prior to replication. p21WAF1/CIP1, a cyclin-cyclin-dependent kinase inhibitor and proliferating cell nuclear antigen-interacting protein, is induced by p53 and mediates the cell cycle arrest. To investigate a role for p21 in DNA repair in vivo, we studied the expression of in vitro damaged reporter DNA transfected into p21 +/+ or -/- HCT116 human colon cancer cells. Introduction of UV-damaged or cisplatinum-damaged cytomegalovirus-driven beta-galactosidase reporter DNA into tumor cells revealed a significant decrease (2-5-fold) in reporter expression in p21 -/- versus +/+ cells. In the absence of DNA damage, there was a significant increase (2-3-fold) in the number of 6-TG-resistant colonies derived from p21 -/- versus +/+ cells. Reintroduction of wild-type p21, but not a p21 C-terminal truncation mutant which lacks the proliferating cell nuclear antigen interaction domain, stimulated (2-3-fold) the repair capacity of the p21-deficient cells. We conclude that p21 deficiency is associated with a defect in DNA repair, which could lead to an increased sensitivity of tumor cells to DNA damage.

Cell Cycle↗
PubMed1996

Cisplatin.

Explore the source record for details and available documents.

Animals↗
PubMed1996

[Resistance to antineoplastic treatments: mechanisms, clinical value].

Drug resistance is a major obstacle to successful chemotherapy for cancer. When it occurs, resistance to a wide range of agents is noted. Factors that rule this resistance can be defined as pharmacologic and cellular. Pharmacologic factors are those that prevent an adequate degree of tumor cell exposure and include considerations of dose and schedule of drugs. Cellular factors are those that imply the tumor cell itself and it is probable that multiple mechanisms co-exists: 1) the drug transport across the tumor cell membrane and the duration of the drug exposure, 2) the drug metabolism (activation, inactivation), 3) the cellular targets and the DNA repair processes. The pleiotropic multidrug resistance (mdr, mrp, lrp), alterations of a target enzyme (topoisomerase II, protein kinase C, glutathione S transferase, O6 alkylguanine-DNA alkyltransferase) and the protein modifications (heat shock protein, metallothioneins) are the principal mechanisms involved. Several methods have been established for the determination of the presence of these drug resistance mechanisms but variations in the results are observed with the different methods used. Therefore, the value and the relative importance of these mechanisms in human tumor resistance is not yet established. In the mean-time, strategies to prevent and to overcome this resistance are developed.

Antineoplastic Agents↗
PubMed1992

Could cancer be a physiological phenomenon rather than a pathological misfortune?

The hypothesis presented here is that cancer is not a phenomenon where the normal functions of the human body break down (like diabetes mellitus or renal failure) but rather a well planned and well coordinated physiological response (similar to the inflammatory response). 'Cancer initiating genes' are presumed neoplastic DNA sequences involved in sensing genome deterioration, consequently enhancing preservation. This genetic trait, different from the concept of oncogenes, actively triggers the neoplastic transformation once genome deterioration is sensed. This self destructive, altruistic phenomenon, obviously devastating to the organism, is nevertheless shown to be a possible mechanism of natural selection. The survival advantage of cancer initiation is discussed using both the concepts of group selection and gene selection. Natural selection, the driving force of evolution, is believed to operate solely on the basis of phenotype differences among individuals. In this paper cancer is hypothesized to be a mechanism that directly scrutinizes the gene contents of the individual, therefore representing natural selection based on genotype differences.

DNA, Neoplasm↗