Resistance to diverse apoptotic triggers in multidrug resistant HL60 cells and its possible relationship to the expression of P-glycoprotein, Fas and of the novel anti-apoptosis factors IAP (inhibitory of apoptosis proteins)

We studied the human HL60 leukemia cell line and its multidrug resistant (MDR) variant HL60R. In contrast to the HL60, HL60R showed an inability to undergo apoptosis from doxorubicin (Dox) or other different stimuli, including cisplatin, Fas ligation and serum withdrawal. HL60R cells lost surface Fas expression, but we found no evidence that Fas/FasL mediates the apoptotic effects of Dox in HL60. P-glycoprotein (P-gp) did not seem to play a major role as a specific inhibitor of apoptosis. In fact, the P-gp inhibitor verapamil reversed only partially the resistance to Dox-induced apoptosis of the MDR cells. In addition, it did not modify the rate of apoptosis induced from the other stimuli in the same cells. The expression of p53 or Bcl-2 was not different between HL60 and HL60R. However, in HL60R there was an increase in the mRNAs of inhibitory of apoptosis proteins (IAPs) like neuronal apoptosis inhibitory protein (NAIP), c-IAP-2 and survivin. Treatment with Dox or serum starvation strongly down-regulated X-linked IAP and survivin mRNAs in HL60. Cisplatin decreased NAIP and survivin mRNAs in the same cells. However, in HL60R the levels of these IAP mRNAs were much less affected by the treatments. These results support that IAPs may be involved in tumor resistance to chemotherapeutic drugs or other apoptotic agents.     

A multicenter trial of infusional etoposide, doxorubicin, and vincristine with cyclophosphamide and prednisone (EPOCH) in patients with relapsed non-Hodgkin's lymphoma

A phase II study was performed in a multicenter community setting of EPOCH (etoposide/doxorubicin/vincristine/cyclophosphamide/prednisone) chemotherapy in 93 patients with relapsed non-Hodgkin's lymphoma. Patients included 41 females and 52 males, ranging in age from 31-81 years (median, 63 years). Lymphoma histologies included diffuse large-cell (56), follicular (21), mantle cell (11), peripheral T-cell (3), and small lymphocytic (2) lymphomas. Patients had received a median of two previous chemotherapy combinations (range, 1-9). Most patients had received the drugs in EPOCH with their previous chemotherapy regimens (vincristine 97%, cyclophosphamide 97%, doxorubicin 87%, and etoposide 28%). A total of 350 cycles of EPOCH were administered. EPOCH chemotherapy gave a response rate of 51% in the entire cohort of 93 patients. Among the 83 evaluable patients, a response rate of 57% was observed (24% complete response, 33% partial response). Seven of the 47 responders remain in clinical remission at 3 years after EPOCH chemotherapy alone. Additionally, 11 patients are alive after further salvage chemotherapy (four patients) or bone marrow transplantation (seven patients). Myelosuppression was common, with 36% of all cycles resulting in an absolute neutrophil count nadir < 500/microL. This study confirms the activity of infusional chemotherapy with EPOCH in patients with relapsed non-Hodgkin's lymphoma.     

A Multicenter Trial of Infusional Etoposide,Doxorubicin, and Vincristine with Cyclophosphamide and Prednisone (EPOCH) in Patients with Relapsed Non-Hodgkin's Lymphoma

A phase II study was performed in a multicenter community setting of EPOCH (etoposide/doxorubicin/vincristine/cyclophosphamide/prednisone) chemotherapy in 93 patients with relapsed non-Hodgkin's lymphoma. Patients included 41 females and 52 males, ranging in age from 31-81 years (median, 63 years). Lymphoma histologies included diffuse large-cell (56), follicular (21), mantle cell (11), peripheral T-cell (3), and small lymphocytic (2) lymphomas. Patients had received a median of two previous chemotherapy combinations (range, 1-9). Most patients had received the drugs in EPOCH with their previous chemotherapy regimens (vincristine 97%, cyclophosphamide 97%, doxorubicin 87%, and etoposide 28%). A total of 350 cycles of EPOCH were administered. EPOCH chemotherapy gave a response rate of 51% in the entire cohort of 93 patients. Among the 83 evaluable patients, a response rate of 57% was observed (24% complete response, 33% partial response). Seven of the 47 responders remain in clinical remission at 3 years after EPOCH chemotherapy alone. Additionally, 11 patients are alive after further salvage chemotherapy (four patients) or bone marrow transplantation (seven patients). Myelosuppression was common, with 36% of all cycles resulting in an absolute neutrophil count nadir < 500/μL. This study confirms the activity of infusional chemotherapy with EPOCH in patients with relapsed non-Hodgkin's lymphoma.     

Successful Use of Full-Dose Dexamethasone,High-Dose Cytarabine,and Cisplatin as Part of Initial Therapy in Non-Hodgkin and Hodgkin Lymphoma with Severe Hepatic Dysfunction

Anthracycline-based chemotherapy is the cornerstone of modern curative regimens for aggressive lymphomas; however, these drugs cannot be safely administered in the setting of severe hepatic dysfunction. Alternative regimens for this setting are required. We describe 2 patients with newly diagnosed advanced aggressive lymphoma (diffuse large B-cell lymphoma [DLBCL] and classic Hodgkin lymphoma [HL]) presenting with severe hepatic dysfunction with hyperbilirubinemia (4.3-13.2 mg/dL). Because of the inability to safely administer unattenuated doses of anthracycline-based regimens, dexamethasone, high-dose cytarabine, and cisplatin (DHAP) was used at full doses (along with rituximab for the DLBCL patient) until hepatic function normalized (1-5 cycles). The treatment was then converted to R-CHOP (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone) and ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) for the DLBCL and HL patient, respectively, to complete therapy. The patients had a partial remission and complete remission, respectively. These data suggest that DHAP is a safe and effective regimen that can be used without dose modification as part of initial therapy in the setting of aggressive lymphoma and hepatic failure. The literature on the use of treatment regimens for aggressive lymphoma in the setting of hepatic dysfunction is reviewed.     

Involved-field radiotherapy for patients in partial remission after chemotherapy for advanced Hodgkin's lymphoma

PURPOSE: The use of radiotherapy in patients with advanced Hodgkin's lymphoma (HL) is controversial. The purpose of this study was to describe the role of radiotherapy in patients with advanced HL who were in partial remission (PR) after chemotherapy. METHODS: In a prospective randomized trial, patients <70 years old with previously untreated Stage III-IV HL were treated with six to eight cycles of mechlorethamine, vincristine, procarbazine, prednisone/doxorubicin, bleomycine, vinblastine hybrid chemotherapy. Patients in complete remission (CR) after chemotherapy were randomized between no further treatment and involved-field radiotherapy (IF-RT). Those in PR after six cycles received IF-RT (30 Gy to originally involved nodal areas and 18-24 Gy to extranodal sites with or without a boost). RESULTS: Of 739 enrolled patients, 57% were in CR and 33% in PR after chemotherapy. The median follow-up was 7.8 years. Patients in PR had bulky mediastinal involvement significantly more often than did those in CR after chemotherapy. The 8-year event-free survival and overall survival rate for the 227 patients in PR who received IF-RT was 76% and 84%, respectively. These rates were not significantly different from those for CR patients who received IF-RT (73% and 78%) or for those in CR who did not receive IF-RT (77% and 85%). The incidence of second malignancies in patients in PR who were treated with IF-RT was similar to that in nonirradiated patients. CONCLUSION: Patients in PR after six cycles of mechlorethamine, vincristine, procarbazine, prednisone/doxorubicine, bleomycine, vinblastine treated with IF-RT had 8-year event-free survival and overall survival rates similar to those of patients in CR, suggesting a definite role for RT in these patients.     

Synergistic chemsensitization and inhibition of tumor growth and metastasis by the antisense oligodeoxynucleotide targeting clusterin gene in a human bladder cancer model.

Clusterin expression is highly up-regulated in several normal and malignant tissues undergoing apoptosis. Although recent studies have demonstrated a protective role of clusterin expression against various kinds of apoptotic stimuli, the functional role of clusterin in the acquisition of a therapy-resistant phenotype in bladder cancer remains unknown. The objectives of this study were to determine whether antisense (AS) oligodeoxynucleotide (ODN) targeting the clusterin gene enhances apoptosis induced by cisplatin and to evaluate the usefulness of combined treatment with AS clusterin ODN and cisplatin in the inhibition of KoTCC-1 tumor growth and metastasis in a human bladder cancer KoTCC-1 model. We initially revealed the dose-dependent and sequence-specific inhibition of clusterin expression by AS clusterin ODN treatment in KoTCC-1 cells at both mRNA and protein levels. Clusterin mRNA was increased in a dose-dependent manner by cisplatin treatment at concentrations < or =10 mg/ml, and clusterin mRNA up-regulation induced by 10 mg/ml cisplatin peaked by 48-h post-treatment and began decreasing by 72-h post-treatment. Although there was no significant effect on growth of KoTCC-1 cells, AS clusterin ODN treatment significantly enhanced cisplatin chemosensitivity of KoTCC-1 cells in a dose-dependent manner, reducing the IC(50) by >50%. Characteristic apoptotic DNA ladder formation and cleavage of poly(ADP-ribose) polymerase protein were detected after combined treatment with AS clusterin ODN and cisplatin but not either agent alone. In vivo systemic administration of AS clusterin and cisplatin significantly decreased the s.c. KoTCC-1 tumor volume compared with mismatch control ODN plus cisplatin. Furthermore, after the orthotopic implantation of KoTCC-1 cells, combined treatment with AS clusterin and cisplatin significantly inhibited the growth of primary KoTCC-1 tumors, as well as the incidence of lymph node metastasis. Collectively, these findings demonstrated that clusterin helps confer a chemoresistant phenotype through inhibition of apoptosis and that combined AS clusterin ODN may be useful in enhancing the effects of cytotoxic chemotherapy in patients with bladder cancer.     

Effect of therapy with cytostatic drugs on the hemostasis system in patients with small cell and non-small cell bronchial cancers, malignant lymphomas and plasmacytomas

Hemostatic analyses were carried out on 43 patients with small and non-small cell lung cancer, malignant lymphomas and plasmacytomas prior to, 4 h and 24 h after application of chemotherapy. The fibrinopeptide A (FPA) level and the FPA in vitro generation rate (delta FPA) increased significantly only in the small cell lung cancer and malignant lymphomas after 4 h. This supports the thesis of the clotting activation after cytostatic-induced exposition of the tumour cell thromboplastins. An increase in the FPA was observed in those tumor patients, where a high therapy-induced cell destruction was expected. An increase in the activity of factor VIII, as was seen in acute phase reactions, also led to hypercoagulability. Fibrinogen and plasminogen decreased significantly after chemotherapy. Evidence of relevant contact activation was not found in the missing deviation of the C1 inhibitor. The increase in protein C may possibly be attributed to the high-dose corticoid therapy.     

Secondary amenorrhea after Hodgkin's lymphoma is influenced by age at treatment, stage of disease, chemotherapy regimen, and the use of oral contraceptives during therapy: a report from the German Hodgkin's Lymphoma Study Group.

PURPOSE: Long-term survivors of successfully treated Hodgkin's lymphoma (HL) are at risk for late complications. Among these, infertility for female patients is of major importance. The subject of this analysis is to evaluate the menstrual status after HL therapy. PATIENTS AND METHODS: From 1994 to 1998, the German Hodgkin's Lymphoma Study Group conducted clinical trials for early-, intermediate-, and advanced-stage HL (trials HD7 to HD9) involving a total of 3,186 patients. A survey was carried out to evaluate the menstrual status after therapy. The following factors were assessed concerning their influence on amenorrhea: age, treatment, stage, and the use of oral contraceptives during chemotherapy. RESULTS: A total of 405 women aged younger than 40 years answered the study questions. After a median follow-up of 3.2 years, 51.4% of the women receiving eight cycles of dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) had continuous amenorrhea. Amenorrhea was significantly more frequent after dose-escalated BEACOPP compared with doxorubicin, bleomycin, vinblastine, and dacarbazine; cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine; or standard BEACOPP (P = .0066). Amenorrhea after therapy was most pronounced in women with advanced-stage HL (P < .0001), in women older than 30 years at treatment (P = .0065), and in women who did not take oral contraceptives during chemotherapy (P = .0002). CONCLUSION: Most women who are treated for advanced-stage HL experience amenorrhea after therapy. Amenorrhea is significantly more frequent in women with advanced-stage HL receiving eight cycles of dose-escalated BEACOPP and in women older than 30 years at first treatment. Furthermore, the data show a statistical association between the use of oral contraceptives and return of menstrual cycle, which is subject to further investigation.     

18F-FDG PET/CT对霍奇金淋巴瘤患者化疗后无事件生存的预测价值

  目的  评估18氟-氟代脱氧葡萄糖-正电子发射计算机断层显像(fluorine-18 fluorodeoxyglucose positron emission tomography, 18F-FDG PET/CT)对接受4个周期阿霉素、博来霉素、长春新碱、达卡巴嗪(ABVD)方案化疗的霍奇金淋巴瘤(Hodgkin's lymphoma, HL)患者预后的预测价值。  方法  回顾分析2005年8月至2009年7月共62例初治的霍奇金淋巴瘤患者在接受4个周期ABVD方案化疗后18F-FDG PET/CT的检查结果, 并与3年无事件生存率(EFS)、3年总生存率(OS)进行比较, 评价其对接受4个周期ABVD方案化疗的霍奇金淋巴瘤患者无事件生存的预测价值。  结果  治疗结束后, PET/CT阳性患者18例, 其中11例患者(61.1%)治疗失败, PET/CT阴性患者46例, 其中5例患者(11.4%)治疗失败, PET/CT阳性组的治疗失败率显著高于阴性组(P < 0.01)。PET/CT阳性组和PET/CT阴性组患者的3年EFS分别是44.4%和81.8%(P < 0.01), 单因素分析显示PET/CT是霍奇金淋巴瘤患者3年EFS的独立预测因素(P < 0.01)。  结论  PET-CT是预测HL患者在接受4个周期ABVD方案化疗后EFS的可靠方法。      

Expression of CCR5 receptors on Reed-Sternberg cells and Hodgkin lymphoma cell lines: involvement of CCL5/Rantes in tumor cell growth and microenvironmental interactions

The expression of CCL5/Rantes by Hodgkin (H) and Reed-Sternberg (RS) cells has been recently documented. In the present study we demonstrated that the CCL5 receptor (CCR5) is constitutively expressed by Hodgkin Lymphoma (HL)-derived cell lines (i.e. L-428, KM-H2, L-1236 and L-540) as shown by immunohistochemistry, flow cytometry and western blotting and also detected by immunohistochemistry on primary H-RS cells from lymph node tissues. sCD40L never significantly affected CCR5 expression, whereas a short exposure to doxorubicin down regulated its expression. CCR5 receptors on HL cell lines were functionally active, since neutralizing anti-CCL5 monoclonal antibodies inhibited basal proliferation of HL-derived cell lines and recombinant CCR5 ligands (CCL3/Mip-1 alpha, CCL4/Mip1 beta and CCL5/Rantes) increased their clonogenic growth. CCL5 secretion by L-1236, L-428 and KM-H2 cells was stimulated by CD40 engagement and also by coculturing L-1236 cells on primary stromal fibroblasts from HL-involved lymph nodes (HLF). Coculture experiments indicated that a direct contact of H-RS cells induces HLF cells to produce CCL5. Supernatants from L-1236, L-428 and KM-H2 cells stimulated migration of purified CD4+ T-cells and eosinophils in vitro. The migratory response to HL-cell lines supernatants was only partially neutralized (CD4+ cells: 70%; esinophils: 36%) by anti-CCL5 antibodies, reinforcing the notion that multiple chemokines are involved in the recruitment of nonmalignant reactive cells in HL tissues. Taken together, our results indicate a possible involvement of the CCR5/CCR5-ligands signaling in the regulation of H-RS cells growth and in the formation/maintenance of the typical tissue microenvironment of HL.     

Fertility among female hodgkin lymphoma survivors attempting pregnancy following ABVD chemotherapy

Although ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy is infrequently associated with premature amenorrhea, little is known about the success rate of women attempting pregnancy following ABVD. In the present study females treated for HL with ABVD chemotherapy without pelvic radiation therapy (RT) and who were alive without relapse > or =3 years after treatment were identified from a clinical database and screened for inclusion. Using a standardized questionnaire, we determined the pregnancy rate (i.e. time-to-pregnancy, TTP) among survivors who had become pregnant, tried to become pregnant, or who had been sexually active for over 2 months without using contraception at any time following ABVD. The cumulative incidence of pregnancy was calculated using the Kaplan-Meier method. Cox proportional hazards models were constructed to compare the pregnancy rate among HL survivors to that reported by friend or sibling controls. Thirty-six female HL survivors, who had attempted pregnancy after ABVD treatment, and 29 controls, completed the survey. Eighteen patients (50%) received 2-4 cycles of ABVD, 16 (44%) received 4-6 cycles, and 2 (6%) received >6 cycles. The median TTP among both HL survivors and controls was 2.0 months. The 12-month pregnancy rates were 70% and 75%, respectively. The fertility ratio (FR) for HL survivors versus controls was 0.94 (95%CI = 0.53-1.66; p = 0.84) after adjusting for age and frequency of intercourse (where FR < 1 indicates subfertility). Age at treatment and the number of cycles of chemotherapy were not associated with pregnancy rate among HL survivors. Female HL patients who had survived without recurrence > or =3 years and who had attempted pregnancy after ABVD did not experience significant sub-fertility.     

Management of advanced-stage peripheral T-cell lymphomas

Peripheral T-cell lymphomas (PTCLs), several entities with great clinical, histologic, and biologic heterogeneity, represent 8% to 15% of all malignant lymphomas. With current treatment regimens, 5-year survival is only about 30% to 35%. Outcome is poorer with PTCL than with aggressive B-cell lymphoma because of more frequent adverse clinical features at diagnosis, a lower response rate to chemotherapy, and a higher incidence of relapses, but it is also known that the T-cell phenotype itself is associated with a poor prognosis independent of other prognostic factors. Initial treatment of patients with advanced-stage PTCL mostly consists of six to eight courses of anthracycline-based chemotherapy such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). In fit elderly patients, standard therapy is still six cycles of CHOP-14, but up-front consolidation with intensive chemotherapy and autologous stem cell transplantation are often used in younger patients. The humanized CD52 monoclonal antibody alemtuzumab has shown activity in some T-cell malignancies; with appropriate antibiotic and virostatic prophylaxis, its use seems feasible for PTCL, both as a single agent and in conjunction with chemotherapy. New drugs such as denileukin diftitox, histone deacetylase inhibitors, and pralatrexate have shown promising activity in PTCL.     

Up-regulation of clusterin during phthalocyanine 4 photodynamic therapy-mediated apoptosis of tumor cells and ablation of mouse skin tumors

Photodynamic therapy (PDT) using the silicon phthalocyanine photo-sensitizer Pc 4 is an oxidative stress associated with the induction of apoptosis in many cancer cells in vitro and in vivo. The mechanisms of PDT-induced tumor cell killing leading to apoptosis are incompletely understood. Clusterin, a widely expressed glycoprotein, is induced in tissues regressing as a consequence of oxidative stress-mediated cell death. Treatment of apoptosis-sensitive human epidermoid carcinoma cells (A431) with PDT resulted in significant up-regulation of clusterin with a maximum at 12 h after treatment, whereas clusterin levels in Pc 4-PDT-treated, apoptosis-resistant, radiation-induced fibrosarcoma (RIF-1) cells remained unchanged. The i.v. administration of Pc 4 to mice bearing chemically or UVB radiation-induced skin papillomas, followed by light application, led to increased clusterin protein expression, peaking 24 h after the treatment, when tumor regression was apparently visible. These data, for the first time, demonstrate the involvement of clusterin in PDT-mediated cell death and during tumor regression. This may have relevance in improving the efficacy of PDT using pharmacological inducers of clusterin.     

High expression of several tyrosine kinases and activation of the PI3K/AKT pathway in mediastinal large B cell lymphoma reveals further similarities to Hodgkin lymphoma.

Mediastinal large B-cell (MBL) and classical Hodgkin lymphoma (HL) have several pathogenic mechanisms in common. As we recently observed aberrant tyrosine kinase (TK) activities in HL, we now analysed also MBL for such activities. Indeed, MBL and HL were the only B-cell lymphomas where elevated cellular phospho-tyrosine contents were typical features. Three TKs, JAK2, RON and TIE1, not expressed in normal B cells, were each expressed in about 30% of MBL cases, and 75% of cases expressed at least one of the TKs. Among the intracellular pathways frequently triggered by TKs, the PI3K/AKT pathway was activated in about 40% of MBLs and essential for survival of MBL cell lines, whereas the RAF/mitogen-activated protein kinase pathway seemed to be inhibited. No activating mutations were detected in the three TKs in MBL cell lines and primary cases. RON and TIE1 were each also expressed in about 35% and JAK2 in about 53% of HL cases. JAK2 genomic gains are frequent in MBL and HL but we observed no strict correlation of JAK2 genomic status with JAK2 protein expression. In conclusion, aberrant TK activities are a further shared pathogenic mechanism of MBL and HL and may be interesting targets for therapeutic intervention.     

Induction of topoisomerase II activity after ErbB2 activation is associated with a differential response to breast cancer chemotherapy.

ErbB2 (HER-2) gene amplification and overexpression have been shown to predict a better outcome with doxorubicin-based chemotherapy as opposed to alkylator-based chemotherapy in early stage breast cancer. To understand the mechanism of differential response to these two regimens, we have evaluated the effect of signaling through the ErbB2 receptor on downstream enzymes that may affect drug response, using two different models. The first system employs breast cancer cells that have high levels of endogenous ErbB2 by gene amplification (BT-474 and SKBR3 cells). The second system allows us to isolate the effect of ErbB2 receptor-mediated intracellular signaling using an epidermal growth factor receptor-ErbB2 chimeric receptor activated by epidermal growth factor. Our experiments show that the cytotoxicity of doxorubicin is inhibited in ErbB2+ breast cancer cells by the anti-ErbB2 antibody, Herceptin. This is accompanied by a decrease in topoisomerase (topo) IIalpha protein and activity, suggesting that this is the mechanism of change in doxorubicin response. In addition, a 10-100-fold (1-2 log) decrease in the LD(50) of doxorubicin is seen after ErbB2 activation using the chimeric receptor model. Furthermore, we see a 100-fold decrease in the LD(50) of etoposide, another topo II inhibitor. This increase in doxorubicin sensitivity is associated with a 4.5-fold increase in the amount of topo IIalpha protein and an increase in topo II activity as measured by DNA decatenating and unknotting activities, as well as cleavable complex formation. In contradistinction to doxorubicin, we have observed an increased resistance to cyclophosphamide chemotherapy after chimeric receptor activation. We propose that the differential benefit seen with doxorubicin- versus alkylator-based chemotherapy in ErbB2+ breast cancer is due, in some cases, to ErbB2-mediated topo IIalpha activation. These data also suggest hypotheses for the optimal sequencing of Herceptin and chemotherapy agents in ErbB2+ breast cancer.     

GM-CSF incubation prior to treatment with cytarabine or doxorubicin enhances drug activity against AML cells in vitro: a model for leukemia chemotherapy

We studied the effect of preincubation with recombinant GM-CSF on the activity of cytarabine and doxorubicin against clonogenic acute myeloid leukemia cells (CFU-AML). Leukemia cells from seven persons with AML, three myeloid cell lines (HL60, KG1, K562) and two control cell lines (U937, MOLT3) were tested. Preincubation with GM-CSF (0.01-0.1 microgram/ml) increased DNA synthesis as measured by tritiated thymidine incorporation and intranuclear Ki67 expression in cells from six persons with AML and in HL60 cells. Leukemia cells preincubated with GM-CSF for 6-48 h were exposed to cytarabine (2-200 micrograms/ml) or doxorubicin (0.01-0.1 microgram/ml) for 3 h and CFU-AML assayed. This approach further reduced CFU-AML in samples from six persons with AML and in HL60 and KG1 cells compared to cells not preincubated with GM-CSF prior to drug treatment. In most instances, reduced CFU-AML correlated with GM-CSF induced DNA synthesis. These data suggest a possible strategy of GM-CSF pretreatment to increase anti-leukemia efficacy of chemotherapy in AML.     

A Chinese patient with relapsed and refractory Hodgkin lymphoma treated with brentuximab vedotin

At present,approximately 20%of Hodgkin lymphomas(HL)are relapsed and refractory,and therapeutic methods including chemotherapy,radiotherapy,and even stem cell transplantation are unsatisfactory.Brentuximab vedotin,composed of CD30 antibody and a chemotherapeutic agent,is a new targeted drug that eradicates tumor cells by binding to the CD30 antigen on their surface.In clinical trials,the response rate and complete remission rate of this drug were 73%and 40%,respectively,for relapsed and refractory HL.Here we report a case of CD30-positive relapsed and refractory HL that was treated with brentuximab.Before the treatment with brentuximab,the patient underwent chemotherapy,radiotherapy,and autologous stem cell transplantation.However,the disease continued to progress,affecting multiple organs and prompting symptoms such as persistent fever.After the treatment with brentuximab,the patient′s condition improved.Body temperature returned to normal after 4 days.Lung nodules were reduced in size and number after a single course of treatment,and PET/CT showed partial remission and complete remission after 3 and 6 courses of treatment,respectively.The entire treatment process progressed smoothly,though the patient experienced some symptoms due to chemotherapy,including peripheral neuritis of the limbs,irritating dry cough,and mild increase in aminotransferase.No serious adverse effects were observed.The current general condition of the patient is good;the continuous complete remission has amounted to 6 months.     

Clusterin-mediated apoptosis is regulated by adenomatous polyposis coli and is p21 dependent but p53 independent

Clusterin is a widely expressed glycoprotein that has been paradoxically observed to have both pro- and antiapoptotic functions. Recent reports suggest this apparent dichotomy of function may be related to two different isoforms, one secreted and cytoplasmic, the other nuclear. To clarify the functional role of clusterin in regulating apoptosis, we examined its expression in human colon cancer tissues and in human colon cancer cell lines. We additionally explored its expression and activity using models of adenomatous polyposis coli (APC)- and chemotherapy-induced apoptosis. Clusterin RNA and protein levels were decreased in colon cancer tissues largely devoid of wild-type APC when compared with matched normal tissue controls, suggesting a means for invasive cancers to avoid apoptosis. Conversely, induction of apoptosis by expression of wild-type APC or by treatment with chemotherapy led to increased clusterin RNA and protein levels localizing to apoptotic nuclei. We found that transient transfection of clusterin to colon cancer cell lines directly enhanced basal and chemotherapy-induced apoptosis. Clusterin-induced apoptosis was inhibited by antisense clusterin and was found to be highly dependent on p21 but not p53 expression, yet a deficit in p21 can be subverted by clusterin transfection. Collectively, these data support the hypothesis that nuclear clusterin function is proapoptotic when induced by APC or chemotherapy in the context of p21 expression. Absent of p21, clusterin in not induced, and apoptosis is significantly inhibited. These data support a potential therapeutic role for clusterin in enhancing chemotherapy-induced apoptosis and in promoting apoptosis in cells deficient in p21.     

Azidothymidine and interferon-alpha induce apoptosis in herpesvirus-associated lymphomas.

Lymphoproliferative diseases that occur in immunocompromised patients are frequently associated with herpesviruses. These patients often fare poorly after treatment with conventional chemotherapy. We reported previously that patients with AIDS-related Burkitt's lymphoma (BL) responded to parenteral azidothymidine (AZT) and IFN-alpha. We found that EBV-positive lymphoma cells derived from these patients cultured with AZT express CD95 and undergo apoptosis. AZT-mediated apoptosis was caspase dependent and occurred despite Fas receptor blockade. In contrast, EBV-negative lymphomas were resistant to AZT-induced apoptosis, as were EBV-positive lymphomas that expressed high levels of bcl-2. Primary effusion lymphoma (PEL) cell lines infected with human herpesvirus type 8 required IFN-alpha to potentiate AZT-induced apoptosis. IFN-alpha did not up-regulate CD95 in BL or PEL but did induce expression of the death receptor ligand, CD95 ligand. AZT-sensitive lymphomas also accumulated significantly higher intracellular AZT monophosphate than did resistant lymphomas. Our data demonstrated distinct apoptotic responses to AZT and IFN-alpha in herpesvirus-associated lymphomas. EBV-positive BL cells that expressed low BCL-2 levels were sensitive to AZT alone; PEL cells required the addition of IFN-alpha to enhance apoptosis, and EBV-negative lymphomas were insensitive to both agents. AZT-sensitive BL cells transfected with BCL-2 became resistant. Susceptibility to antivirus-mediated apoptosis may be exploited to improve the therapy of certain herpesvirus-associated lymphomas.