The proteasome inhibitor PS-341 in cancer therapy.

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.

Activation of heat shock transcription factor 1 to a DNA binding form during the G(1)phase of the cell cycle.

The heat shock transcription factor (HSF) genes encode proteins that bind to the heat shock elements (HSE) of stress-inducible genes. We have observed the induction of HSF1, the ubiquitous member of the HSF family from a latent cytoplasmic state to a form competent to bind HSE during early G(1)in HeLa cells in the absence of stress. The induction of DNA-binding HSF1 coincided with a burst in cellular protein synthesis in early G(1)and inhibition of this translational peak prevented the formation of DNA binding-activated HSF1.

Non-steroidal anti-inflammatory drugs inhibit the expression of cytokines and induce HSP70 in human monocytes.

Recent studies have shown that the non-steroidal anti-inflammatory drugs (NSAIDs) activate heat shock transcription factor (HSF1) from a latent cytoplasmic form to a nuclear, DNA binding state. As HSF1 can function as both an activator of heat shock genes and a repressor of non-heat shock genes such as IL1B and c- fos, we have examined the potential role of HSF1 in the effects of NSAIDs on gene expression in a human monocytic cell line THP-1. We found that two members of the NSAIDs, sodium salicylate and sulindac repress the IL1B promoter to similar degree to heat shock or HSF1 overexpression.

Optimal scheduling of interleukin 12 and chemotherapy in the murine MB-49 bladder carcinoma and B16 melanoma.

The antitumor activity of interleukin (IL)-12, a naturally occurring cytokine, has been demonstrated in several murine solid tumors. Animals bearing established B16 melanoma or MB-49 bladder carcinoma were used to study the most effective scheduling of recombinant murine IL-12 (rmIL-12), along with systemic chemotherapy. rmIL-12 (0.

Jasplakinolide: interaction with radiation and hyperthermia in human prostate carcinoma and Lewis lung carcinoma.

Purpose: Jasplakinolide is a novel natural product anticancer agent which acts by inducing overpolymerization of actin. The aim of the current study was to explore the activity of jasplakinolide with hyperthermia and radiation.

Methods: The response of human PC-3 and DU-145 prostate carcinoma cells and DU-145 xenografts and the response of the Lewis lung carcinoma to jasplakinolide were studied.

Sequence effect of irinotecan (CPT-11) and topoisomerase II inhibitors in vivo.

Unlabelled: The DNA topoisomerases I and II are the target of several clinically important antineoplastic agents which produce DNA cleavage by stabilization of the covalent DNA-protein bond with resultant cell death after DNA synthesis is attempted. Depletion of the target topoisomerase and reciprocal changes in the other occur with drug treatment.

Purpose And Methods: To develop empiric treatment regimens of combinations and sequences of agents directed against topoisomerase I (irinotecan/CPT-11) and II (etoposide and doxorubicin), in vivo studies were performed in mice bearing the EMT-6 mammary tumor to assess efficacy, host tolerance and the resultant biochemical changes in topoisomerase mRNA and protein.

Potential of the aminosterol, squalamine in combination therapy in the rat 13,762 mammary carcinoma and the murine Lewis lung carcinoma.

Squalamine, a naturally-occurring aminosterol, has demonstrated antiangiogenic activity in several experimental models. Extended treatment with other antiangiogenic agents has been shown to increase tumor oxygenation. Tumor oxygenation was measured using an Eppendorf pO2 histograph polarographic pO2 electrode system in the rat 13,762 mammary carcinoma after treatment of the tumor-bearing animals with squalamine (40 mglkg) on days 4 through 18 post tumor implantation.

Transcriptional activity of heat shock factor 1 at 37 degrees C is repressed through phosphorylation on two distinct serine residues by glycogen synthase kinase 3 and protein kinases Calpha and Czeta.

Heat shock factor 1 (HSF1) is the key transcriptional regulator of the heat shock genes that protect cells from environmental stress. However, because heat shock gene expression is deleterious to growth and development, we have examined mechanisms for HSF1 repression at growth temperatures, focusing on the role of phosphorylation. Mitogen-activated protein kinases (MAPKs) of the ERK family phosphorylate HSF1 and represses transcriptional function.

Allosteric effectors of hemoglobin as modulators of chemotherapy and radiation therapy in vitro and in vivo.

Introduction: A series of molecules designed to be allosteric effectors of hemoglobin were examined for their potential as radiation sensitizers in vitro and in vivo and for their potential as chemosensitizers in vivo as well as for their antimetastatic effect.

Results: At a concentration of 100 microM for 1 h prior to, during and for 1.5 h after radiation exposure, the allosteric effectors decreased the shoulder of the radiation survival curve of normally oxygenated EMT-6 cells and increased the slope of the radiation survival curves of hypoxic EMT-6 cells resulting in dose-modifying factors of 1.

Heat shock factor 1 represses Ras-induced transcriptional activation of the c-fos gene.

Heat shock factor 1, the critical molecular regulator of the stress response is conserved throughout eukaryotic organisms and activates the transcription of heat shock genes. We now show that heat shock factor 1 inhibits the expression of c-fos, an immediate early gene that controls responses to extracellular stimuli for growth and differentiation. Heat shock factor 1 inhibits the transcription of the c-fos gene and antagonizes the activating effects of the signal transducing protein Ras on the c-fos promoter and on the promoter of another Ras responsive gene uPA.

PEG-hemoglobin: effects on tumor oxygenation and response to chemotherapy.

Background: The study was undertaken to determine whether administration of PEG-hemoglobin could improve the oxygenation of a solid tumor prior to and after chemotherapy and to determine whether administration of PEG-hemoglobin could enhance the efficacy of chemotherapy in a solid tumor.

Materials And Methods: Rats bearing the 13762 mammary carcinoma were untreated or treated with cyclophosphamide, melphalan, taxol or cisplatin. Tumor oxygenation was determined 24 hrs.

Dynamics of tumor oxygenation, CD31 staining and transforming growth factor-beta levels after treatment with radiation or cyclophosphamide in the rat 13762 mammary carcinoma.

Purpose: Tumors are dynamic tissues that undergo marked molecular, biochemical, and physiologic changes in response to cytotoxic anticancer therapies. Understanding the changes in tumor oxygenation and transforming growth factor-beta expression may allow improved treatment regimens to be developed.

Methods And Materials: The effects of a single dose of radiation therapy (20 Gy) or a single dose of chemotherapy (cyclophosphamide, 250 mg/kg) on several molecular and physiologic parameters of the rat 13762 mammary carcinoma growing subcutaneously in female Fischer 344 rats were explored.

Sequential phosphorylation by mitogen-activated protein kinase and glycogen synthase kinase 3 represses transcriptional activation by heat shock factor-1.

Mammalian heat shock genes are regulated at the transcriptional level by heat shock factor-1 (HSF-1), a sequence-specific transcription factor. We have examined the role of serine phosphorylation of HSF-1 in the regulation of heat shock gene transcription. Our experiments show that mitogen-activated protein kinases (MAPKs) of the ERK-1 family phosphorylate HSF-1 on serine residues and repress the transcriptional activation of the heat shock protein 70B (HSP70B) promoter by HSF-1 in vivo.

Interaction of interleukin-11 with cytotoxic therapies in vitro against CEM cells and in vivo against EMT-6 murine mammary carcinoma.

Interleukin-11(rhIL-11) is a cytokine that has been shown to enhance the recovery of bone marrow and intestinal crypt cells after cytotoxic insult with radiation or anticancer drugs. The current study examined the effects of rhIL-11 on the response of CEM human lymphoblastic leukemia cells and on the EMT-6 murine mammary carcinoma in vivo to cytotoxic anticancer therapies. Exposure of CEM cells to rhIL-11 for 24 hr did not alter the cytotoxicity of melphalan or radiation, increased the cytotoxicity of CDDP (100 muM) and 4-hydroperoxycyclophosphamide (50 betaM) and decreased the cytotoxicity of 5-fluorouracil and ara-C toward the cells.

High-dose therapy/stem cell support: comparison of mice and humans.

A murine high-dose therapy/stem cell support model is described using female BALB/c mice bearing the EMT-6 mammary carcinoma. Peripheral blood cells were prepared in syngeneic donor animals mobilized by treatment with cyclophosphamide and rhG-CSF. The most effective support regimen includes administration of fluid by gavage, rhG-CSF twice per day for 12 days and peripheral blood cells administered i.

Restoration of tumor oxygenation after cytotoxic therapy by a perflubron emulsion/carbogen breathing.

Purpose: Hypoxic cells are presumed to be an obstacle to successful cancer treatment because these cells are protected from the cytotoxic effects of radiotherapy and certain anti-cancer drugs. The current study was conducted to determine the effect of cytotoxic therapy on tumor oxygenation and the effect of administration of a perfluorochemical emulsion/carbogen breathing treatment on tumor oxygenation after cytotoxic therapy.

Materials And Methods: Female Fisher 344 rats bearing 13762 mammary carcinoma cells implanted subcutaneously in a hindlimb were treated with standard therapeutic single doses of anti-tumor treatments of several types, including alkylating agents (cisplatin, melphalan, cyclophosphamide); natural products (doxorubicin, paclitaxel, etoposide); antimetabolites (fluorouracil); hypoxic cell-selective agents (mitomycin, SR-4233); and fractionated irradiation (3 Gy/day for 5 days).