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Tumorigenicity of human HT1080 fibrosarcoma X normal fibroblast hybrids: chromosome dosage dependency.

The tumorigenic capacity of hybrids formed by fusion of the highly tumorigenic HT1080 human fibrosarcoma cell line with nontumorigenic normal fibroblasts was examined. The HT1080 also contains an activated N-ras oncogene. Near-tetraploid hybrids which contained an approximately complete chromosomal complement from both parental cells were nontumorigenic when 1 X 10(7) cells were injected s.c. into athymic (nude) mice, whereas the parental HT1080 cells produced tumors in 100% of the animals with no latency period following injection of 2 X 10(6) cells. Tumorigenic variants were obtained from these hybrids which had lost only a few chromosomes compared to cells from the nontumorigenic mass cultures. In addition, several near-hexaploid hybrids were obtained which contained approximately a double chromosomal complement from the HT1080 parental line and a single chromosomal complement from the normal fibroblasts. All of these near-hexaploid hybrids produce tumors in 100% of nude mice with no latency period. Our results indicate that tumorigenicity of these particular human malignant cells of mesenchymal origin can be suppressed when fused with normal diploid fibroblasts. In addition, the results suggest that tumorigenicity in this system is chromosomal dosage dependent, since a diploid chromosomal complement from normal fibroblasts is capable of suppressing the tumorigenicity of a near-diploid but not a near-tetraploid chromosomal complement from the tumorigenic HT1080 parent. Finally, the loss of chromosome 1 (the chromosome to which the N-ras oncogene has been assigned) as well as chromosome 4 was correlated with the reappearance of tumorigenicity in the rare variant populations from otherwise nontumorigenic near-tetraploid hybrid cultures. Our results also suggest the possibility that tumorigenicity in these hybrids may be a gene dosage effect involving the number of activated N-ras genes in the hybrids compared to the gene(s) controlling the suppression of the activated N-ras genes.

Cell Fusion↗

Chemical carcinogen-induced transplantable fibrosarcomas in histocompatible chickens. II. Effect of age and thymectomy on tumor incidence.

The incidence of primary fibrosarcoma 2-4 months after im injection of 7,12-dimethylbenz[a]anthracene (DMBA) was studied in normal, neonatally thymectomized and bursectomized SC (B2/B2) chickens. The tumor incidence was not significantly increased in thymectomized chickens inoculated at 1 week of age, but thymectomized animals inoculated at 4 weeks of age developed a higher incidence of tumors than did controls. Bursectomy did not affect tumor induction. Whereas thymectomy and bursectomy clearly reduced T- and B-cell immune responses, respectively, neither the carcinogen nor the presence of tumor had a detectable effect on the immune response. The effect of varying the age of chickens at the time of carcinogen injection was also studied. DMBA injected into chickens at 8-12 weeks of age produced a significantly lower incidence of tumors than did a similar dose of DMBA injected into chickens at 1-4 weeks of age. Thus DMBA-induced tumors in the chicken may present an interesting model for studies on immune surveillance.

9,10-Dimethyl-1,2-benzanthracene↗

Derivation of transplantable 7,12-dimethylbenz[a]anthracene-induced chicken fibrosarcoma lines: differences in metastasizing properties and organ specificity.

Several transplantable 7,12-dimethylbenz[a]anthracene-induced SC chicken fibrosarcoma (CHCT-NYU) lines were studied for their ability to grow in internal organs after iv injection (artificial metastases) into 1- to 3-week-old chickens. Some tumor lines were recently derived, whereas others were studied after many serial subcutaneous transplantations. STriking similarities as well as differences were found between tumor lines' ability to grow in various organs. Artificial metastases were seen primarily in the stomach, pancreas, lungs, heart, and muscle, and occasionally also in the kidneys and in the liver. Agammaglobulinemic recipients showed more extensive organ involvement than normal recipients of the same age. Whole-body gamma-irradation also enhanced the incidence of artificial metastases, particularly in lungs. Antibody from the serum of a primary tumor-bearing host reduced the growth of the corresponding tumor in many organs. The metastatic pattern of line CHCT-NYU4 was a relatively stable property, since there was little difference in the internal localization of these tumor cells studied before and after 15 serial subcutaneous transplants. However, intravenous transplantation of tumor cells from line CHCT-NYU4 taken from the liver, lungs, and pancreas of a single recipient established sublines with changes in organ specificity. After a few such serial transplants of liver-derived tumor, a line was derived that grew virtually in the liver alone. A subline with preference for growth in lungs was also obtained, but its ability to grow in the pancreas persisted. A pancreas-derived tumor line also grew in the liver and lungs. Subcutaneous transplants of tissue fragments of the lung-derived tumor line caused the appearance of spontaneous metastases in lungs. The incidence of spontaneous metastases with the lung-derived line was much greater than that with the liver-derived line or with the original CHCT-NYU4 line.

9,10-Dimethyl-1,2-benzanthracene↗

Isolation and preliminary characterization of an Adriamycin-resistant murine fibrosarcoma cell line.

A variant cell line (UV-2237-ADMR) resistant to the anthracycline antibiotic Adriamycin (Doxorubicin) was selected in vitro from the murine UV-2237 fibrosarcoma tumor cell line. Resistance to Adriamycin proved to be a stable characteristic of the UV-2237-ADMR line, whether the line was grown in vivo or in vitro. The UV-2237-ADMR line also exhibited increased resistance to N-trifluoroacetyladriamycin-24-valerate, daunorubicin, actinomycin D, amsacrine, mitomycin C, vinblastine, and vincristine but not to bleomycin. Cell-cell hybridization studies showed that the Adriamycin resistance is an incompletely dominant trait. Uptake and efflux studies with [14C]Adriamycin indicated that the resistance exhibited by the UV-2237-ADMR line was due to both reduced uptake of the drug and an increased active efflux.

Animals↗

Effect of hyperglycemia on thermochemotherapy of a spontaneous murine fibrosarcoma.

The effect of hyperglycemia on the cytotoxic effect of a chemotherapeutic agent was studied at elevated temperature. The seventh generation of a spontaneous C3Hf/Sed mouse fibrosarcoma, FSa-II, was transplanted into the footpads of the same strain of mice. Hyperthermia was given by immersing animal feet into a water bath where 41.5 +/- 0.1 degrees (range) was maintained by a constant temperature circulator. Cyclophosphamide (CY), an alkylating agent, was selected as a test agent. Single i.p. doses of glucose and of CY were given 60 and 30 min before the initiation of hyperthermia. Tumor response was assayed by determining the median tumor growth time (time required for one-half of the treated tumors to reach 1000 cu mm), and the dose-response curve was obtained. Hyperthermia enhanced tumor response to CY. The enhancement was greater when a glucose dose of 10 mg/g was administered before CY and heat treatments. The enhancement ratio, calculated as a ratio of the tumor growth time following CY (200 mg/kg) with heat or with glucose and heat to that following CY alone, was 1.31 or 2.86, respectively. Glucose given at ambient temperature did not enhance the effect of CY. A dose-response curve obtained for a glucose dose with fixed CY (200 mg/kg) and heat (90 min at 41.5 degrees) doses demonstrated that a significant enhancement was obtained following a glucose dose as low as 2 mg/g, suggesting that the glucose enhancement could be safely achieved for human cancer treatment.

Animals↗

The radiosensitivity of a murine fibrosarcoma as measured by three cell survival assays.

The radiation sensitivity of a weakly immunogenic spontaneous fibrosarcoma of the C3Hf/Sed mouse (designated FSa-II) was assessed by three in vivo cell survival methods: end-point dilution (TD50) assay, lung colony (LC) assay, and agar diffusion chamber (ADC) assay. The hypoxic fraction of this tumour was also determined by the ADC method. Although there was a good agreement of the cell survival data between the ADC and LC methods, the TD50 method yielded a considerably less steep cell survival curve. Beneficial aspects and limitations of each assay are discussed. In addition, the use of the ADC method for the growth of xenogeneic cell lines and a preliminary experiment with human tumour cells in non-immunosuppressed hosts suggest that this method may be a valuable adjunct for studying the growth and therapeutic responses of human tumour cells.

Agar↗

[Primary mandibular condyle tumors. Osteomas, chondroma, fibrosarcoma, giant cell tumor (author's transl)].

Six out of 11 cases of primary condylar tumors treated in the Department of stomatology and Maxillofacial Surgery were analyzed. They included 3 patients with osteomas, and one case each of fibrosarcoma, chondroma, and multinucleated giant cell tumor. Typical signs were lateral displacement of the mandible (2 cases), reduction in the buccal opening (3 cases), and pain (3 cases) and swelling (3 cases) in the pretragal region. Swelling is never observed with osteomas, which develop antero-internally. The presence of the tumors was confirmed by radiological examination in all cases. Usual treatment is condylectomy, by means of C. Hosxés approach, confirmation of diagnosis requiring pathological examinations.

Adolescent↗

Low-dose cyclophosphamide inhibition of transplantable fibrosarcoma growth by augmentation of the host immune response.

Preinjection of a low dose of cyclophosphamide (Cy) (500 microgram/mouse) either delayed or inhibited tumor appearance following the inoculation of transplantable 3-methylcholanthrene-induced fibrosarcomas in inbred male C3H/HeJ mice. This dose of Cy decreased the spleen weight by 13% and the total spleen cell count by 23%. However, the same dose could potentiate the footpad swelling reaction (FPSR) measured against Staphylococcus aureus antigen. Splenic lymphocytes from Cy-treated animals showed increased blastogenic response against phytohemagglutinin-M and bacterial lipopolysaccharide. Thus 500 micrograms Cy/animal may have depleted suppressor cell populations leading to: a) an increase in FPSR, b) increased blastogenic transformation of lymphocytes, and c) tumor growth inhibition.

Animals↗

Receptor-dependent antiproliferative effects of corticosteroids in radiation-induced fibrosarcomas and implications for sequential therapy.

Competitive binding studies with [3H]dexamethasone and Scatchard analysis demonstrated a single class of high-affinity, low-capacity glucocorticoid receptor sites in 105,000 x g cytosols from radiation-induced fibrosarcomas. In vivo, both dexamethasone (DEX) and methylprednisolone treatments resulted in dose-dependent inhibition of tumor growth and cell proliferation. Changes in the sensitivity of the clonogenic cell population to 3 mM hydroxyurea were used to assess changes in the clonogenic cell proliferation during and after treatments with DEX or methylprednisolone. Neither methylprednisolone nor DEX given every 12 hr for three doses resulted in significant cell kill in the clonogenic fraction. However, changes in the hydroxyurea sensitivity of the clonogenic population after cessation of DEX treatments indicated G1 cell cycle progression delay with transient enrichment of S-phase clonogenic cells 24 to 48 hr after cessation of DEX treatments. The duration of the DEX-induced progression delay and the timing of maximal S-phase cellularity after DEX was directly correlated with the level of glucocorticoid receptors in the treated tumors. Using regrowth delay to assess the efficacy of kinetically directed sequential chemotherapy, the effectiveness of vincristine, given after DEX, was highly sequence dependent, with the most effective treatment interval being coincident with maximal S-phase clonogenic fraction. Other studies indicated that the effectiveness of cyclophosphamide could also be increased by time sequencing after DEX.

Animals↗

Pharmacokinetic and anti-tumor studies with the radiosensitizer misonidazole in dogs with spontaneous fibrosarcomas.

Nine dogs with spontaneous oral fibrosarcomas were given the radiosensitizer misonidazole (Ro-07-0582) In combination with orthovoltage radiotherapy. Although there appeared to be a trend toward greater disease-free survival of these animals as compared with a group of 13 dogs with similar tumors treated by orthovoltage x-rays alone, on analysis there was no significant difference. The plasma half-life and the volume of distribution of misonidazole were determined as 4.95 hours and 15.1 L/m2, respectively. In 3 dogs with evidence of misonidazole toxicosis, plasma concentrations at 4 hours after the dose exceeded 85 microgram/ml, and the areas under the concentration vs time curve for this first 10 hours were greater than 850 microgram.hr/ml.

Animals↗

Inhibition of lung metastases in mice bearing a malignant fibrosarcoma by treatment with liposomes containing human C-reactive protein.

Recent studies suggest an immune modulator role for C-reactive protein (CRP). We have tested the effect of CRP in a tumor system designed for study of metastases. Fibrosarcoma T241 was implanted on one hind foot of syngeneic C57BL/6 mice. After 17 days, the tumor-bearing feet were amputated, and i.v. therapy of liposomes containing CRP or control reagents was started. Examination of the lungs on Day 35 showed that CRP:liposome-treated animals had significantly fewer and smaller metastases as compared with those in the control groups. Moreover, 38% of the animals in the former groups were completely free of metastases as compared with 0 to 2% of the controls. Significantly, enhanced survival was also noted in the CRP liposome-treated group. CRP may have biological response modifier" function of value in cancer therapy.

Animals↗

Isolation and characterization of a multiplication-stimulating activity (MSA)-like polypeptide produced by a human fibrosarcoma cell line.

A human fibrosarcoma cell line, 8387, produces and secretes multiplication-stimulating activity (MSA)-like polypeptide growth factors, which are associated with a high molecular weight binding protein. The purification of 8387-MSA involved concentration of serum-free media conditioned by 8387 cells, dialysis, and chromatography of the acid-soluble growth-promoting activity on Bio-Gel P-100 in 1 M acetic acid and subsequently on carboxymethylcellulose. The purification was followed by a radioreceptor assay specific for MSA and an assay for growth-stimulating activity. Both activities chromatographed through the purification steps of 8387-MSA. 8387-MSA competes with 125I-labeled rat MSA for binding on rat cells with a specific activity 5 times lower than that of rat MSA and stimulates [3H]-thymidine incorporation into DNA of normal rat fibroblasts at comparable concentrations. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the MSA-competing activity co-migrated with a single band of protein that behaved heterogeneously on discpolyacrylamide gels in the presence of 6 M urea, yielding two bands associated with biological activity. 8387-MSA is a single chain polypeptide with an apparent molecular weight of 14,500.

Animals↗

Cardiac fibrosarcoma with bone metastases.

The diagnosis of a primary cardiac sarcoma with bone metastases was suspected in a previously normal patient because of the development of unremitting pulmonary edema and lytic bone lesions. Echocardiography substantiated the diagnosis, which proved at autopsy to be a primary fibrosarcoma of the heart. This represents only the third such case reported with bone metastases.

Bone Neoplasms↗

[Reoxygenation in a transplantable murine fibrosarcoma (author's transl)].

The fibrosarcoma SSK31 was irradiated under ambient or hypoxic conditions either acutely or at various intervals after a priming dose of 13 Gy. The absence of local recurrences was determined. The hypoxic fraction and the time course of reoxygenation were calculated on the basis of a comparison of the cure curves.

Animals↗

[Desmoid tumor - transformation into fibrosarcoma (author's transl)].

Report of a case of aggressive musculo-aponeurotic fibromatosis in a 14-year-old girl with transformation into fibrosarcoma, 10 years later. The tumoral mass initiated its growth in the nuchal region but finally invaded both the cervical and the right retroscapular region. Evidence for muscular, osseous and neurological invasion and destruction was found. The tumor could be controlled neither by surgery, nor by radiotherapy and chemotherapy. This case report is studied in the light of cases reported in the literature.

Adolescent↗