Antitumour effects of indomethacin alone and in combination with radiotherapy: role of inhibition of tumour angiogenesis.
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Animals↗
Biomedical subjects
L Milas
Publications and source records attributed to L Milas.
Chemo-radiotherapy: radiosensitizing nucleoside analogues (review).
The available knowledge on potential radiosensitizing nucleoside analogues with special focus on fludarabine and gemcitabine is reviewed. These analogues are prodrugs whose active triphosphate forms inhibit various enzymes involved in DNA synthesis and repair. Several properties of these analogues support their use as radiosensitizers. As repair inhibitors, they have the potential to increase the amount of residual DNA and chromosome damage after irradiation, and as DNA synthesis inhibitors, they specifically target the S-phase cell component and could thus overcome the detrimental effect of tumor clonogen repopulation during fractionated irradiation. Also, through their cytotoxic effect, these analogues could increase tumor cell loss, facilitating tumor reoxygenation, and thus obviate tumor hypoxia's inhibitory effect on radioresponse. Induction of DNA damage in all phases of the cell cycle by irradiation could create DNA sites for drug incorporation, possibly inducing an apoptotic response in cells outside of S-phase. Experimental data addressing these hypotheses are reviewed and updates on ongoing clinical trials combining fludarabine or gemcitabine and irradiation are given.
Antineoplastic Combined Chemotherapy Protocols↗
A role for T lymphocytes in the antitumour action of systemic C. parvum.
The frequency of tumours arising from s.c. injection of a syngeneic chemically-induced fibrosarcoma (Fsa) was not influenced by systemic administration of C. parvum (day + 3) except when doses less than the TD50 were injected. Then the number of takes was increased. The tumour normally grows progressively however regression was frequent in intact mice treated with C. parvum. Tumour regression did not occur in T cell-depleted mice treated in the same way. Splenic T cell-enriched populations of cells taken from Fsa-bearing C. parvum-treated mice caused tumour regression when adoptively transferred to Fsa-bearing T cell-depleted mice. Although this assay measures systemic rather than intratumoral T cell activity, it is proposed that C. parvum-induced regression of the fibrosarcoma is to a large extent due to enhanced T cell reactivity.
Animals↗
In vivo transfer of antitumor activity by peritoneal exudate cells from mice treated with C. parvum.
We have investigated whether peritoneal exudate cells (PEC) from C. parvum (CP) treated (C3Hf/Bu mice could transfer in vivo the resistance against a syngeneic fibrosarcoma (FSa). Inhibition of tumour development and prolongation of survival of recipients were observed when CP-activated PEC were admixed with FSa cells before their intraperitoneal (ip) or subcutaneous (sc) injections into normal mice. The antitumour activity increased with the increase of the ratio of effector to target cells. Heat killed CP-PEC were unable to transfer the resistance. Also, pretreatment of recipients with 600 rads whole body irradiation (WBI) substantially reduced the efficacy of CP-PEC. Reconstitution of WBI mice with mixed normal spleen and lymph node cells, or spleen cells alone, or bone marrow cells did not restore the antitumor activity of transferred CP-PEC. In fact, reconstituted mice showed a further reduction of transferred antitumor resistance. CP-PEC activity was also inhibited in sc transfer experiments when normal PEC, spleen cells, T-cells or even fetal fibroblasts were admixed with tumor cells and CP-PEC. Possible reasons for the failure of WBI recipients to be fully protected by transferred CP-PEC are discussed.
Animals↗
Effects of C. parvum on radiation response of murine tumors.
The effects of intravenous C. parvum (CP) on the efficacy of fractionated gamma-irradiation in treating a fairly immunogenic fibrosarcoma (FSa) and a weakly immunogenic mammary carcinoma (MDAH-MCa-4) were studied in C3Hf/Bu mice. Tumors were 8 mm in diameter at the start of irradiation. The FSa was exposed to 500 and the MDAH-MCa-4 to 750 rads daily for 3.6 or 10 days. The administration of 0.25 mg CP varied from 4 days before to 14 days after the start of irradiation. CP greatly augmented radiocurability of FSa, especially when applied before irradiation. The effect was evidenced by the increase in the cure rate, and, in mice not cured, by the tumor growth retardation, reduction of pulmonary metastasis incidence and prolongation in survival of mice. This effect of i.v. CP on FSa radiocurability was not further increased by intralesional CP, or by systemic injections of vitamin A or the hypoxic tumor cell radiosensitizer Ro-07-0582. CP was less effective in augmenting radiation response of the MDAH-MCa-4. Here, CP slowed the growth of irradiated tumors and prolonged the survival of mice.
Animals↗
Increased sensitivity of C. parvum treated mice to ionizing whole body irradiation.
We have investigated whether C. parvum (CP)-induced stimulation of hematopoiesis affects the survival of mice exposed to the whole body irradiation (WBI). C3Hf/Bu mice treated with CP exhibit an increased hematopoietic colony forming activity in their spleens and blood, but not in their bone marrow, as determined by the exogenous spleen colony assay. Also, CP-treated C3Hf/Bu as well as CBA mice show an increase in their endogenous colonies. This increased hematopoietic activity caused by CP treatment did not protect mice from the consequences of the WBI ranging from 650 to 950 rads. In fact, more mice died if they had been treated with CP. A decrease in the number of erythrocytes was more pronounced in mice treated with CP and irradiation than in those given irradiation alone.
Animals↗
Relation of apoptosis to cancer therapy.
Apoptosis, or programmed cell death, is a mode of cell death characterized by distinctive biochemical and morphological features that include endonuclease activation, chromatin condensation and margination, and cellular shrinkage and fragmentation. Its role is homeostatic regulation essential in the maintenance of renewable tissues; the process is controlled by the interaction of genes and tissue-specific hormones or growth factors. A number of apoptosis-regulating genes have recently been discovered including bc1-2, c-myc, and p53. Recent experimental evidence suggests that apoptosis plays an important role in regulation of tumor growth and tumor response to various forms of cancer therapy, including radiotherapy and chemotherapy. Apoptosis develops rapidly, within hours, after cytotoxic treatments and is dose dependent. The apoptotic response correlates well with the antitumor efficacy of radiation and chemotherapy, which makes it a candidate predictor of tumor treatment response. Tumors vary in their apoptotic response to cytotoxic agents, with carcinomas being more responsive than sarcomas. In addition to this intertumor heterogeneity, there is also significant intratumor heterogeneity in apoptosis induction, consistent with the idea that the propensity for apoptosis is genetically regulated. Regulating apoptosis might be an effective way to improve tumor therapy; therapeutic gain would be achieved by increasing apoptotic response of tumors or by inhibiting apoptotic response of normal tissues.
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Cytotoxic treatments and tumor oxygenation.
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