Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CTX, a new Xenopus Ig superfamily molecule present on some cortical thymocytes and lymphoid tumor cells, is expressed at the cell surface under six differently glycosylated isoforms as shown by two-dimensional gel analysis and by endo F glycosidase treatment. Following chemical cross-linking before immunoprecipitation, a large fraction of surface CTX forms non-covalently linked dimers at the cell surface. This finding, which is consistent with the presence of a J segment with diglycine beta bulge in the V region of the molecule, suggests that this dimer has the same conformation as a T-cell receptor (TCR) or an Ig molecule. The V8 digest patterns of the monomers and dimers are identical. While this suggests that the dimer is a homodimer of two CTX chains, it does not distinguish whether each CTX chain is encoded by the same or different gene loci. When tumor cells were added to culture wells that had been coated with the anti-CTX monoclonal antibody X71, 30-50% underwent rapid (within 30 min) morphological changes followed by growth inhibition as determined by a decrease in thymidine incorporation and by direct cell counting. No apoptosis, calcium flux or external calcium requirement was noted after cross-linking of CTX. These results suggest that CTX can function as a receptor, and that its interaction with a ligand influences the control of cell proliferation through a signalling pathway that is distinct from the TCR machinery.
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PMID:Cross-linking CTX, a novel thymocyte-specific molecule, inhibits the growth of lymphoid tumor cells in Xenopus. 918 46

The thymocyte-specific cell surface molecule CTX is a developmentally regulated type I transmembrane protein of the immunoglobulin superfamily which, in the amphibian Xenopus, is exclusively expressed by a large fraction of cortical thymocytes and by different cell lines derived from independent spontaneous thymic tumors. Antibody cross-linking of CTX in vitro inhibits the growth of tumor cells and causes morphological alterations. Cells divide abnormally, accumulate in the G2/M phase of the cell cycle, and become multinucleated. This demonstrates, for the first time, that multinucleation can be induced by specifically cross-linking a cell surface molecule.
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PMID:Antibody cross-linking of the thymocyte-specific cell surface molecule CTX causes abnormal mitosis and multinucleation of tumor cells. 928 72

Interleukin-1alpha (IL-1alpha) has potent acute antitumor activity in vivo and can enhance the efficacy of chemotherapeutic drug-mediated antitumor responses. Studies were undertaken to examine the ability of IL-1alpha to enhance the activity of cyclophosphamide (CTX) administered in combination with carboplatin. To determine the in vivo effect of IL-1alpha, CTX and/or carboplatin, mice bearing 14-day RIF-1 tumors were treated on day 0 with a concurrent i.p. injection of varying doses of CTX (5-150 mg/kg), human IL-1alpha (125 microg/kg), and carboplatin (50 mg/kg) and examined 24 h later for the surviving fraction by the in vivo excision clonogenic-tumor-cell assay. Even at the lowest doses of CTX, IL-1alpha significantly enhanced the clonogenic tumor cell kill when compared to treatment with CTX alone. When carboplatin was added to the treatment schema, significantly greater clonogenic cell killing and tumor regrowth delay were observed as compared to any agent alone or a two-drug combination (CTX/IL-1alpha or CTX/carboplatin). Significant enhancement was observed even at low doses of CTX in combination with carboplatin and IL-1alpha. The interaction between the three-drug combination was found to be synergistic as determined by the median dose effect with significant dose reduction apparent for IL-1alpha and CTX when used in this combination. These results demonstrate that IL-1alpha can synergistically enhance the antitumor efficacy of CTX and the combination of CTX and carboplatin.
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PMID:Interleukin-1alpha synergistic in vivo enhancement of cyclophosphamide- and carboplatin-mediated antitumor activity. 929 33

Cyclophosphamide (CTX) increases the antitumor effectiveness of adoptive immunotherapy in mice, and combined immunotherapy regimens are now used in some clinical trials. However, the mechanisms underlying the synergistic antitumor responses are still unclear. The purpose of this study was (a) to evaluate the antitumor response to CTX and adoptive immunotherapy in mice bearing four different syngeneic tumors (two responsive in vivo to CTX and two resistant); and (b) to define the mechanism(s) of the CTX-immunotherapy synergism. Tumor-bearing DBA/2 mice were treated with a single injection of CTX followed by an intravenous infusion of tumor-immune spleen cells. In all the four tumor models, a single CTX injection resulted in an impressive antitumor response to the subsequent injection of spleen cells from mice immunized with homologous tumor cells independently of the in vivo response to CTX alone. Detailed analysis of the antitumor mechanisms in mice transplanted with metastatic Friend leukemia cells revealed that (a) the effectiveness of this combined therapy was dependent neither on the CTX-induced reduction of tumor burden nor on CTX-induced inhibition of some putative tumor-induced suppressor cells; (b) the CTX/immune cells' regimen strongly protected the mice from subsequent injection of FLC, provided the animals were also preinoculated with inactivated homologous tumor together with the immune spleen cells; (c) CD4(+) T immune lymphocytes were the major cell type responsible for the antitumor activity; (d) the combined therapy was ineffective in mice treated with antiasialo-GM1 or anti-IFN-alpha/beta antibodies; (e) spleen and/ or bone marrow cells from CTX-treated mice produced soluble factors that assisted in proliferation of the spleen cells. Altogether, these results indicate that CTX acts via bystander effects, possibly through production of T cell growth factors occurring during the rebound events after drug administration, which may sustain the proliferation, survival, and activity of the transferred immune T lymphocytes. Thus, our findings indicate the need for reappraisal of the mechanisms underlying the synergistic effects of CTX and adoptive immunotherapy, and may provide new insights into the definition of new and more effective strategies with chemotherapy and adoptive immunotherapy for cancer patients.
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PMID:Importance of cyclophosphamide-induced bystander effect on T cells for a successful tumor eradication in response to adoptive immunotherapy in mice. 943 16

Twenty-one-day-old BALB/c mice were shaved on the back to synchronize hair growth. On day 30 or 31, when at least 90% of mice exhibited hair regrowth in the shaved area, 1,25(OH)2D3 was applied topically to the shaved area daily for 5 days. On the 6th day, cyclophosphamide (Cytoxan, CTX) was injected i.p. to induce hair loss in the shaved area. Alopecia was induced in a dose-dependent manner by CTX treatment within 1 to 2 weeks. This effect was reduced significantly if mice were pre-treated with 1,25(OH)2D3, though only slight protection was observed in female mice. Interestingly, this 1,25(OH)2D3-mediated protection against hair loss was attenuated in male mice but became more significant in female mice when they were inoculated with the EMT-6 murine mammary tumor prior to treatment. More importantly, topical treatment with 1,25(OH)2D3 alone was able to inhibit EMT-6 tumor growth in both male and female BALB/c mice. Furthermore, 1,25(OH)2D3 pre-treatment also augmented the anti-tumor effect of CTX. Our results demonstrate that topical application of 1,25(OH)2D3 can protect against CTX-induced alopecia both in tumor-free and in tumor-bearing mice in a sex-dependent manner. Moreover, 1,25(OH)2D3 was shown, either alone or in combination with CTX, to inhibit tumor growth.
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PMID:Protection against cyclophosphamide-induced alopecia and inhibition of mammary tumor growth by topical 1,25-dihydroxyvitamin D3 in mice. 946 23

To determine the most effective strategies for the treatment of postmenopausal hormone dependent breast cancer, we recently developed a model system in nude mice. In this model, estrogen receptor-positive human breast cancer cells (MCF-7) stably transfected with the aromatase gene are inoculated into ovariectomized, immunosuppressed (nude) mice. These cells synthesize sufficient estrogen from androgen substrate to stimulate their proliferation and the development of tumors. Moreover, estrogen secreted by the tumor cells maintains uterine weight comparable to that of the intact mouse. In the present study, we employed this model to investigate the effects of the aromatase inhibitor, letrozole (CGS 20267 [Femara]) on mammary tumor growth and on the uterus. We also used this model to predict the effects of combining two aromatase inhibitors, letrozole and anastrozole (Arimidex), with the antiestrogen tamoxifen (Nolvadex). Letrozole was found to be a highly potent inhibitor of tumor proliferation and more effective than tamoxifen. No stimulation of uterine growth was observed with the aromatase inhibitors. However, the combination of letrozole or anastrozole and tamoxifen was no more effective than either aromatase inhibitor alone. The agonistic effect of tamoxifen on the uterus was observed when it was given alone and when combined with the aromatase inhibitors. Furthermore, letrozole had the most potent antitumor activity when compared to other aromatase inhibitors and antiestrogens. No additional benefit was observed by combining these agents with tamoxifen over treatment with aromatase inhibitors alone.
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PMID:Preclinical studies using the intratumoral aromatase model for postmenopausal breast cancer. 955 90

The DNA repair protein O6-methylguanine-DNA methyl-transferase (MGMT) is a main determinant of resistance of cells to the cytostatic effects of O6-alkylguanine-generating alkylating agents. The purpose of our study was to assay MGMT activity in cells of lung cancers and to correlate MGMT levels with chemotherapy response to cyclophosphamide (CTX) and cisplatin (DDP). MGMT levels were determined in 14 human lung tumor xenografts. There was a wide variation of MGMT expression in these tumors, ranging from 10 to 984 fmol/mg protein. There was also a wide range in the sensitivity of the xenografts to CTX and DDP, as measured by specific growth delay. When the MGMT levels of the different xenograft lines were compared with the corresponding responses to CTX and DDP, a close correlation was found between MGMT activity and CTX (lin reg., r = -0.83, p < 0.05). The higher the MGMT activity, the less pronounced was the growth-inhibiting effect of CTX. With DDP, no such correlation was found. Our results indicate that the in vivo response of tumors to CTX is related to the level of MGMT expression.
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PMID:O6-methylguanine-DNA methyltransferase activity and sensitivity to cyclophosphamide and cisplatin in human lung tumor xenografts. 971 64

We succeeded in establishing a human myelogenous leukemia model in severe combined immunodeficient (SCID) mice by transplanting 2 x 10(7) ML-2 cells intraperitoneally (i.p.) with cyclophosphamide (CTX) pretreatment. Two months after transplantation, 9 of 10 mice developed leukemia and leukemia cells were detected in the peripheral blood (PB) and bone marrow (BM). The main findings at autopsy were peritoneal and pleural effusions and large tumor masses involving the peritoneal organs. However, successful transplantation required injection of a large number of cells. We therefore established a new cell line, ML-2S, from the PB of a mouse with ML-2 leukemia. Although only 2 x 10(6) ML-2S cells were inoculated, ML-2S induced the same pattern of leukemic dissemination reminiscent of the parent ML-2 cells. Compared to ML-2, progression of ML-2S was slow, suggesting that ML-2S is suitable as a leukemia model to study treatment. Furthermore, we confirmed that ML-2S cells are of human origin using isoenzyme analysis and also that ML-2S and ML-2 cells have the same phenotypic character by cell surface marker analysis.
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PMID:Establishment of an in vivo human myeloid leukemia model in the SCID mouse. 1021 30

Cisplatin (C) or carboplatin (CBP) plus cyclophosphamide (CTX) was until recently considered standard chemotherapy for advanced ovarian cancer (OC). Attempts to maximize platinum and its analog activity against OC include its administration directly into the peritoneal cavity. In the past we have shown that intraperitoneal (IP) CBP administration is a safe and effective treatment for OC [Polyzos et al: Proc Am Assoc Cancer Res 1990;31: 1120]. In the present study we aimed to compare the effectiveness and toxicity of CBP administration either intravenously (IV) or IP plus CTX IV. Since 1990, 90 evaluable patients with stage III OC were prospectively randomized to receive CBP 350 mg/m2 IV or IP plus CTX 600 mg/m2 IV (in both groups) every 3-4 weeks for six courses. The randomization incorporated stratification according to performance status and the amount of residual tumor (maximum diameter </=2 or >2 cm). Clinical assessment was performed with abdominal CT and serum CA-125. Responses were observed in 33/46 = 72% (95/CI 56.5-84.0) of the IV group and in 33/44 = 75% (95/CI 59.7-86.8) of the IP group with 48 and 45% clinical complete responses, respectively. Times to progression were 19 months (8-62+) for the IV group and 18 (6-72+) for the IP group. Median survivals were: 25 months (6-80+) and 26 months (6-72+), respectively. Significantly more patients in the IV group than in the IP group had grade 3 or higher leukopenia (p < 0. 01) and grade 3 thrombocytopenia (p < 0.09). Morbidity due to infectious complications in the IP group was minimal. It seems that IP CBP is equally effective to IV administration in terms of response and survival with less myelotoxicity. The favorable results on survival demonstrated in studies with IP C administration in patients with small volume disease [Alberts et al: N Engl J Med 1996;335:1950-1965] could not be repeated in the present study applying CBP in patients with variable tumor size and a relatively small number of patients. The likelihood that patients with large volume disease would benefit from a regional approach compared to systemic administration is small and this explains the inability to detect a difference between the two arms.
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PMID:A comparative study of intraperitoneal carboplatin versus intravenous carboplatin with intravenous cyclophosphamide in both arms as initial chemotherapy for stage III ovarian cancer. 1034 92

The anticancer activity of the boronic acid dipeptide proteasome inhibitor PS-341 was examined in vitro and in vivo. PS-341 was a potent cytotoxic agent toward MCF-7 human breast carcinoma cells in culture, producing an IC90 of 0.05 microM on 24 h of exposure to the drug. In the EMT-6 tumor cell survival assay, PS-341 was equally cytotoxic administered p.o. or by i.p. injection up to a dose of 2 mg/kg. PS-341 was also toxic to the bone marrow colony-forming unit-granulocyte macrophage. PS-341 increased the tumor cell killing of radiation therapy, cyclophosphamide, and cisplatin in the EMT-6/Parent tumor, but was not able to overcome the in vivo resistance of the EMT-6/CTX and EMT-6/CDDP tumors. In the tumor growth delay assay, PS-341 administered p.o. had antitumor activity against the Lewis lung carcinoma, both primary and metastatic disease. In combination, regimens with 5-fluorouracil, cisplatin, Taxol and adriamycin, PS-341 seemed to produce primarily additive tumor growth delays against the s.c. tumor and was highly effective against disease metastatic to the lungs. The proteasome is an interesting new target for cancer therapy, and the proteasome inhibitor PS-341 warrants continued investigation in cancer therapy.
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PMID:The proteasome inhibitor PS-341 in cancer therapy. 1049 43


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