ABSTRACT
PURPOSE: To assess the toxicity and tumor response induced by DCVac/IR(R) dendritic cell (DC) immunotherapy combined with irradiation for refractory colorectal cancer patients with multiple liver metastases. MATERIALS AND METHODS: Between May 2004 and November 2006, applicants from a pool of refractory colorectal cancer patients with multiple liver metastases were enrolled. The patients were registered after having signed the informed consent form, which had been approved by the Institutional Review Board from the Dong-A University and Busan National University Hospital. DCs were obtained from peripheral blood of each patient, and then cultured in vitro. A total of 6x10(6) DCs were packed into a vial (DCVac/IR(R), 0.5 ml) at the convenience of each patient's schedule. On the day before and on the day of each vaccination, each patient received a 4 Gy radiation dose to the target tumor. On the day of vaccination, the indicated dose of autologous DCs was injected into the irradiated tumor using ultrasound-guided needle injection procedures. A total of four vaccinations were scheduled at three 2-week intervals and one 4 week interval at the Dong-A University and Busan National University Hospital. If the tumor status was deemed to be stable or responding to therapy, an additional vaccination dose or two was approved at 4 week intervals beyond the fourth immunization. A tolerance test for DCs was conducted by injecting a range of doses (3x10(6) to 12x10(6) DCs) after the 3rd injection. Moreover, the maximal tolerable dose was applied to additional patients. Treatment safety was evaluated in all patients who had at least one injection. Treatment feasibility was evaluated by the 10th week by assessing the response of patients having at least 4 injections. For systemic toxicities, the evaluation was performed using the National Cancer Institute Common Toxicity Criteria, whereas adverse effects were recorded using common WHO toxicity criteria. RESULTS: Of the 24 registered patients, 22 received the DCs injections. Moreover, of the 14 patients that applied for the tolerance test, only 11 patients completed it because 3 patients withdrew their testing agreement. A grade 3 or more side effect, which was possibly related to the DC injection, did not occur in additional patients. The 12x10(6) DC injection was identified as the maximum tolerable dose, and was then injected in an additional 8 patients. Patients tolerated the injection fairly well, with no fatal side effects. In order to assess the feasibility of DC immunotherapy, the response was evaluated in other hepatic lesions outside of the targeted hepatic lesion. The response evaluation was performed in 15 of the 17 patients who received at least 4 injections. Stable and progressive disease was found in 4 and 11 patients, respectively. CONCLUSION: The DC-based immunotherapy and radiotherapy is theoretically synergistic for the local control and systemic control. The DCVac/IR(R) immunotherapy combined with irradiation was tolerable and safe in the evaluated cases of refractory colorectal cancer with multiple liver metastases. Future work should include well designed a phase II clinical trials.
Subject(s)
Humans , Appointments and Schedules , Colorectal Neoplasms , Consent Forms , Dendritic Cells , Ethics Committees, Research , Immunization , Immunotherapy , Liver , Needles , Neoplasm Metastasis , Radiation Dosage , VaccinationABSTRACT
BACKGROUND: The multidrug resistance (mdr1), multidrug resistance associated protein (mrp1), and glutathione-s-transferase (gst) pi genes have been associated with treatment failure in acute myeloid leukemia (AML). c-jun N-terminal kinase (JNK) activity is increased in response to chemotherapeutic agent. METHODS: To investigate the significance of multidrug resistance (mdr) parameters and JNK activity, bone marrow or peripheral blood cells from 52 patients with AML were analyzed. RT-PCR was performed for mdr1, mrp1, and gst pi gene expression. JNK expression and activity were measured using an immunoe- nzymatic kinase assay and a western blot method. RESULTS: High level expression of mdr1, mrp1, and gst pi mRNA was observed in 38.5%, 48.1% and 54.3% of AML cases, respectively. The remission rate was significantly low in cases with an older age (>55 yr), a high WBC count, poor chromosomal abnormalities, a high level expression of mdr1 and mrp1. The WBC count and mdr1 mRNA expression were independent predictors for the outcome to induction chemotherapy. There was a shorter duration of overall survival in the patients with an older age, a high WBC count, chromosome aberrations, high level expressions of mdr1 and mrp1 mRNA, and JNK activation. The patient's age, WBC count and chromosomal abnormalities were independent predictors for overall survivals. The majority (28/30) of AML cases did not show any levels of JNK activation except for two cases, which were associated with an extremely high WBC count, chromosomal aberration, high level expressions of mdr1, mrp1 and gst pi mRNA, and treatment resistance. CONCLUSIONS: These data indicate the influences of mdr1 and mrp1 mRNA expression on the clinical outcome of AML to induction chemotherapy. But it will be necessary to investigate further whether blast cells of AML resistant to chemotherapy retain the capacity to activate JNK, and relate to MDR parameters.
Subject(s)
Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Drug Resistance, Multiple/genetics , Drug Resistance, Neoplasm/genetics , Glutathione S-Transferase pi/genetics , JNK Mitogen-Activated Protein Kinases/metabolism , Leukemia, Myeloid, Acute/drug therapy , Multidrug Resistance-Associated Proteins/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Survival Analysis , Treatment OutcomeABSTRACT
This study aimed to evaluate whether the elevated level of hypoxia-inducible factor-1 alpha (HIF-1 alpha) correlated with histologic types, angiogenesis, tumor cell proliferation, and clinical parameters in common non-small cell lung carcinomas (NSCLCs). We performed immunohistochemical stains using paraffin-embedded tissue blocks from 84 cases of operable NSCLC [No. of squamous cell carcinoma (SCC), 45; No. of adenocarcinoma (AC), 39]. HIF-1 alpha expression was related with histologic types (66.7% in SCCs vs 20.5% in ACs, p0.05, respectively). As for the histologic types, MVD and PCNA index were significantly higher in SCCs than in ACs (p=0.009 and p=0.016, respectively). Among HIF-1 alpha positive carcinomas, MVD was significantly higher in HIF-1 alpha positive SCCs than in HIF-1 alpha positive ACs (p=0.023). The overall survival curves were not associated with HIF-1 alpha expression or any other histologic parameters (p>0.05). These findings suggest that HIF-1 alpha expression in NSCLCs may play a differential role according to histologic types, but its prognostic significance is indeterminate.
