Combination Of CTX Research Articles

Continuous Interleukin-2 Infusion Combined with Cyclophosphamide- Based Combination Chemotherapy in the Treatment of Hemato-Oncological Malignancies

The combination of a cyclophosphamide (CTX)-based chemotherapy regimen and interleukin-2 (IL-2) has been shown to provide synergistic effects against malignancy in animal models. We therefore conducted a phase I–II trial combining CTX-based combination chemotherapy or CTX alone with high-dose IL-2 in patients with advanced and refractory malignant disease. Fifteen patients with hemato-oncological malignancies (malignant lymphoma 8, multiple myeloma 3, solid tumor 2, leukemia 2) were enrolled in the study. Continuous high-dose IL-2 infusion was shown to be safely administered, starting as soon as recovery of white blood cell count. All patients developed rebound lymphocytosis 24–48 h after termination of IL-2 infusion. Although grade IV toxicity was observed in 5 patients (7 episodes), all side effects completely subsided. Triple chemotherapy (CTX, etoposide and Ara-C) seemed rather toxic (in this group of heavily treated patients) while CTX alone was well tolerated. Four out of 13 (31%) evaluable patients had partial response and another patient (7%) had stabilization of disease progression lasting 2–8 months. Our conclusion is that the combination of CTX and continuous infusion of IL-2 is feasible and should be investigated in patients with various malignant neoplasms.

TNFα Cooperates with the Protein Kinase A Pathway to Synergistically Increase HIV-1 LTR Transcription via Downstream TRE-like cAMP Response Elements

Activating protein-1 (AP-1) binding TPA responsive elements (TRE) are located downstream of the transcription initiation site in the U5 region of the HIV-1 long terminal repeat (LTR). These downstream sequence elements, termed DSE, can bind both AP-1 and CREB/ATF transcription factors. Recently, we demonstrated that the DSE are also cAMP-responsive elements (CRE), since they mediated activation signals elicited by cholera toxin (Ctx), a potent activator of the cAMP-dependent protein kinase A (PKA) signal transduction pathway. In the present study, we demonstrate that the HIV-1 DSE can mediate the transcriptional synergy elicited by the combination of Ctx and TNFα. Ctx combined with TNFα or IL-1β to produce a synergistic increase in p24 antigen production in U1 promonocytic cells. Transfection studies of LTR reporter constructs indicated that mutation of the DSE sites abrogated the LTR-mediated synergy induced by Ctx and TNFα, whereas the synergy induced by Ctx and IL-1β was unaffected, suggesting TNFα and IL-1β cooperate differently with the cAMP/PKA activation pathway to induce HIV-1 expression in U1 cells. Because the DSE are also TRE sites, we assessed the effect of the agonist combinations on AP-1-dependent transcription. TNFα as well as IL-1β cooperated with Ctx to produce a synergistic activation of AP-1-mediated transcription. These data indicate that the TRE-like cAMP-responsive DSE sites within the 5′-untranslated leader can mediate the transcriptional cooperativity between TNFα and the cAMP/PKA pathway. Since the DSE and TRE sites cannot bind CREB/ATF homodimers, we propose a mechanism in which the HIV-1 DSE bind heterodimers composed of both AP-1 and CREB/ATF proteins.

The Unexpected G0/G1 Cell Cycle Status of Mobilized Hematopoietic Stem Cells From Peripheral Blood

AbstractTreatment with a combination of cytokines and chemotherapy can effectively stimulate the release of hematopoietic stem cells (HSC) into the peripheral blood (PB), which can then be harvested for transplantation. The cell cycle status of the harvested HSC from mobilized PB (MPB) is of interest because of the impact that cell cycling may have on optimizing the conditions for ex vivo expansion, retrovirus-mediated gene transfer, and the engraftment of transplanted tissues. Therefore, we characterized the cell cycling status of mobilized HSC from mice and humans. The murine HSC, which express the phenotype c-kit+ Thy-1.1lo Lin−/lo Sca-1+, were purified from PB, bone marrow (BM), and spleen after the mice were treated with the mobilizing regimen of granulocyte colony-stimulating factor (G-CSF ) or a combination of cyclophosphamide (CTX) and G-CSF. Human HSC (CD34+ Thy-1+ Lin−) and progenitor cells (CD34+ Thy-1− Lin−) were isolated from the BM of untreated healthy volunteers and from MPB of healthy volunteers and patients treated with G-CSF or a combination of CTX and GM-CSF. Cell cycle status was determined by quantitating the amount of DNA in the purified cells after staining with the dye Hoechst 33342. Fluorescence-activated cell sorting analysis of the progenitor cells from the murine and human samples showed an unexpected finding, ie, virtually none of the cells from the MPB was cycling. The G0/G1 status of HSC from MPB was surprising, because a significant proportion of HSC from BM are actively proliferating and, after mobilization, the HSC in the spleen and BM were also actively cycling.

Effect of radiation dose rate and cyclophosphamide on pulmonary toxicity after total body irradiation in a mouse model

Purpose : Interstitial pneumonitis (IP) is still a major complication after total body irradiation (TBI) and bone marrow transplantation (BMT). It is difficult to determine the exact role of radiation in this multifactorial complication, especially because mot of the experimental work on lung damage was done using localized lung irradiation and not TBI. We have thus tested the effect of radiation dose rate adn combining cyclophosphamide (CTX) with single fraction TBI. on lung lung damage in a mouse model for BMT. Methods and Materials : TBI was given as a single fraction at a high dose rate (HDR, 0.71 Gy/min) or a low dose rate (LDR, 0.08 Gy/min). CTX (250 mg/kg) was given 24 H before TBI. Bone marrow transplantation (BMT) was performed 4–6 h after the last treatment. Lung damage ws assessed sing ventilation rate (VR) and lethality between 28 and 180 days (LD 50/28–180). Results : The LD 50 for lung damage, ± standard error (SE), increased from 12.0 (± 0.2) Gy using single fraction HDR to 15.8 (± 0.6) Gy using LDR. Adding CTX shifted the dose-response curves towards lower doses. The LD 50 values for the combined treatment were 5.3 (± 0.2) and 3.5 (± 0.2) Gy for HDR and LDR, respectively. This indicates that the combined effect of CTX and LDR was more toxic than that of combined CTX and HDR. Lung damage evaluated by VR demonstrated two waves of VR increase. The first wave of VR increase occurred after 6 weeks using TBI only and after 3 weeks in the combined CTX-TBI treatment, irrespective of total dose or dose rate. The second wave of VR elevation resembled the IP that follows localized thoracic irradiation in its time of occurrence. Conclusions : Lung damage following TBI could be spared using LDR. However, CTX markedly enhances TBI-induced lung damage. The combination of CTX and LDR is more to the lungs than combining CTX and HDR.

835 Modification of the sparing effect of using low dose rate total body irradiation on murine pulmonary toxicity by cyclophosphamide

We have thus tested the effect of radiation dose rate and combining cyclophosphamide (CTX) with single fraction TBI on lung damage in a mouse model for BMT. Total body irradiation (TBI) was given as a single fraction at high dose rate (HDR, 0.71 GY/min) or at low dose rate (LDR, 0.08 Gy/min). CTX (250 mg/kg) was given 24 hours before TBI. Bone marrow transplantation (BMT) was performed 4–6 h after the last treatment. Lung damage was assessed using ventilation rate (VR) and lethality between 28 and 180 days (LD50/28–180). The LD50 for lung damage increased from 12.0 Gy (±0.2) using single fraction HDR to 15.8 Gy (±0.6) using LDR. The LD50 values for the combined treatment were 5.3 Gy (±0.2) and 3.5 Gy (±0.2) for HDR and LDR, respectively. This indicates that thed e LDR anf combinefect ofd CTX was more toxic than that of combined CTX and HDR. Lunfter treg damage evaluated by VR demonstrated two went. We conclude that aves of VR increase within the first 180 days aatmlung damage following TBI could be spared using LDR, however, CTX markedly enhanceTBI-induced lung damage. The combination of CTX and LDR is more toxic to the lungs than combining CTX and HDR. Supported by a grant from the Danish Cancer Society.

Recent advances in chemotherapy for advanced breast cancer.

Current status of chemotherapy for advanced breast cancer in Japan was reviewed with special reference to some recent studies of special interest. As for single drug chemotherapy, cyclophosphamide (CTX) and 5-fluorouracil (5-FU) were used most commonly. Ftorafur, (N1[2′-tetrahydrofuryl]-5-fluorouracil), a cytotoxic agent which was under clinical trial until recently, showed more favorable results than these conventional agents, averaging a 36% response rate and 5.7 months duration of response, an. Tamoxifen, a new antiestrogenic agent, also showed encouraging results with a 36% response rate and 9.7 months duration of response. As for combination chemotherapy, higher response rates were observed in regimens including CTX, 5-FU, and adriamycin (ADR): 50% in a combination of CTX and 5-FU, 70% in a combination of CTX, 5-FU, ADR and methotrexate (MTX). Intra-arterial infusion chemotherapy produced prominent effects in locoregional lesions with a response rate of 82%. It is useful as a preoperative procedure for locally advanced breast cancer.