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1.
Cancer Chemother Pharmacol ; 76(1): 13-20, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25952795

ABSTRACT

PURPOSE: The purpose of the trial was to assess the efficacy and tolerability of Sym004, a novel 1:1 mixture of two chimeric monoclonal antibodies (992 and 1024) targeting non-overlapping epitopes of the anti-epidermal growth factor receptor (EGFR), in patients with squamous cell carcinoma of the head and neck (SCCHN). METHODS: Incurable, recurrent and/or metastatic SCCHN patients with acquired resistance to anti-EGFR monoclonal antibody-containing treatment received weekly infusions of 12 mg/kg Sym004 until disease progression or unacceptable toxicity. RESULTS: Among the 26 patients treated with Sym004, the proportion of patients alive without disease progression at 6 months was 12 % (95 % CI 1-39 %). The median duration of progression-free survival was 82 days (95 % CI 41-140 days). Of 19 patients evaluable for response, eight showed a decrease in the sum of the largest diameter in their target lesions (median 11 %; range 7-27 %). The best overall response was stable disease in 13 patients (50 %). Paired biopsies showed a significant down-regulation of EGFR in both skin and tumors following exposure to Sym004. All patients had EGFR-related adverse events, including grade 3 skin toxicities and grade ≥3 hypomagnesemia reported in 13 (50 %) and 10 (38 %) of 26 patients, respectively. One event fulfilling the protocol-defined criteria for infusion-related reactions (grade 2) was reported. No anti-drug antibodies were detected. CONCLUSIONS: The marked EGFR down-regulation shown in target tissues supports the proposed mechanism of action of Sym004. This trial revealed modest anti-tumor activity of Sym004 in extensively pretreated advanced SCCHN patients.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Carcinoma, Squamous Cell/drug therapy , ErbB Receptors/antagonists & inhibitors , Head and Neck Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/enzymology , Cell Line, Tumor , Disease Progression , Disease-Free Survival , ErbB Receptors/immunology , Female , Head and Neck Neoplasms/enzymology , Humans , Male , Middle Aged , Squamous Cell Carcinoma of Head and Neck
2.
Leukemia ; 26(2): 271-9, 2012 Feb.
Article in English | MEDLINE | ID: mdl-21844871

ABSTRACT

Although the cure rate of newly diagnosed acute lymphoblastic leukemia (ALL) has improved over the past four decades, the outcome for patients who relapse remains poor. New therapies are needed for these patients. Our previous global gene expression analysis in a series of paired diagnosis-relapse pediatric patient samples revealed that the antiapoptotic gene survivin was consistently upregulated upon disease relapse. In this study, we demonstrate a link between survivin expression and drug resistance and test the efficacy of a novel antisense agent in promoting apoptosis when combined with chemotherapy. Gene-silencing experiments targeting survivin mRNA using either short-hairpin RNA (shRNA) or a locked antisense oligonucleotide (LNA-ON) specifically reduced gene expression and induced apoptosis in leukemia cell lines. When used in combination with chemotherapy, the survivin shRNA and LNA-ON potentiated the chemotherapeutic antileukemia effect. Moreover, in a mouse primary xenograft model of relapse ALL, the survivin LNA-ON decreased survivin expression in a subset of animals, and produced a statistically significant decrease in tumor progression. Taken together, these findings suggest that targeting endogenous levels of survivin mRNA by LNA-ON methods may augment the response to standard chemotherapy by sensitizing otherwise resistant tumor cells to chemotherapy.


Subject(s)
Antineoplastic Agents/therapeutic use , Gene Knockdown Techniques , Inhibitor of Apoptosis Proteins/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Base Sequence , DNA Primers , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Reverse Transcriptase Polymerase Chain Reaction , Survivin , Treatment Outcome
3.
Gene Ther ; 18(4): 326-33, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21179173

ABSTRACT

Usually, small interfering RNAs and most antisense molecules need mechanical or chemical delivery methods to down-modulate the targeted mRNA. However, these delivery approaches complicate the interpretations of biological consequences. We show that locked nucleic acid (LNA)-based antisense oligonucleotides (LNA-ONs) readily down-modulate genes of interest in multiple cell lines without any delivery means. The down-modulation of genes was quick, robust, long-lasting and specific followed by potent down-modulation of protein. The efficiency of the effect varied among the 30 tumor cell lines investigated. The most robust effects were found in those cells where nuclear localization of the LNA-ON was clearly observed. Importantly, without using any delivery agent, we demonstrated that HER3 mRNA and protein could be efficiently down-modulated in cells and a tumor xenograft model. These data provide a simple and efficient approach to identify potential drug targets and animal models. Further elucidation of the mechanism of cellular uptake and trafficking of LNA-ONs may enhance not only the therapeutic values of this platform but also antisense molecules in general.


Subject(s)
Gene Expression Regulation , Neoplasms/genetics , Oligonucleotides, Antisense/pharmacology , Animals , Cell Line, Tumor , Gene Silencing , Gene Targeting , Humans , Receptor, ErbB-3/genetics , Transfection
4.
Leukemia ; 19(6): 1064-9, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15815716

ABSTRACT

A comparison of the therapeutic efficacy of a new bispecific monoclonal antibody (bsMAb)-pretargeting system vs the conventional direct targeting modality was undertaken. A bsMAb was made by coupling the Fab' of a humanized anti-CD20 antibody to the Fab' of a murine antibody directed against the peptide histamine-succinyl-glycine (HSG). The tumor targeting of the bsMAb was separated from the subsequent delivery of the radionuclide-bearing HSG peptide conjugated with (111)In or (90)Y. Nude mice bearing s.c. Ramos human B-cell lymphomas were injected with the bsMAb and then, 48 h later, (111)In/(90)Y-HSG peptide was given. At 3 h postinjection, tumor/blood ratios for pretargeted (111)In-HSG-peptide were similar to that observed with the directly conjugated (111)In-anti-CD20 IgG at its highest level on day 7, but by day 1, tumor/blood ratios were about 10-fold higher than the IgG. Tumors progressed rapidly in animals given 800 microCi of (90)Y-HSG peptide alone, whereas 5/10 animals in the group pretargeted by the anti-CD20 bsMAb were tumor-free 18 weeks later. The antitumor response in animals administered the pretargeted (90)Y-HSG peptide was also significantly superior to treatment with the directly radiolabeled (90)Y-anti-CD20 IgG, whether given as a single injection (P<0.007) or as a divided dose (P=0.016). This bsMAb-pretargeting procedure significantly improves the therapeutic response of targeted radionuclides in non-Hodgkin's lymphoma, warranting further development of this method of radioimmunotherapy.


Subject(s)
Antibodies, Bispecific/pharmacology , Antibodies, Monoclonal/pharmacology , Antigens, CD20/immunology , Lymphoma, Non-Hodgkin/radiotherapy , Radioimmunotherapy/methods , Animals , Antibodies, Monoclonal, Humanized , Disease Models, Animal , Female , Humans , Immunoglobulin G/pharmacology , Indium Radioisotopes/pharmacology , Lymphoma, Non-Hodgkin/mortality , Mice , Mice, Inbred BALB C , Mice, Nude , Xenograft Model Antitumor Assays
5.
J Clin Oncol ; 18(4): 927-41, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10673536

ABSTRACT

PURPOSE: To determine the maximum-tolerated dose, toxicities, and pharmacokinetic profile of the farnesyl protein transferase inhibitor R115777 when administered orally bid for 5 days every 2 weeks. PATIENTS AND METHODS: Twenty-seven patients with a median age of 58 years received 85 cycles of R115777 using an intrapatient and interpatient dose escalation schema. Drug was administered orally at escalating doses as a solution (25 to 850 mg bid) or as pellet capsules (500 to 1300 mg bid). Pharmacokinetics were assessed after the first dose and the last dose administered during cycle 1. RESULTS: Dose-limiting toxicity of grade 3 neuropathy was observed in one patient and grade 2 fatigue (decrease in two performance status levels) was seen in four of six patients treated with 1,300 mg bid. The most frequent clinical grade 2 or 3 adverse events in any cycle included nausea, vomiting, headache, fatigue, anemia, and hypotension. Myelosuppression was mild and infrequent. Peak plasma concentrations of R115777 were achieved within 0.5 to 4 hours after oral drug administration. The elimination of R115777 from plasma was biphasic, with sequential half-lives of about 5 hours and 16 hours. There was little drug accumulation after bid dosing, and steady-state concentrations were achieved within 2 to 3 days. The pharmacokinetics were dose proportional in the 25 to 325 mg/dose range for the oral solution. Urinary excretion of unchanged R115777 was less than 0.1% of the oral dose. One patient with metastatic colon cancer treated at the 500-mg bid dose had a 46% decrease in carcinoembryonic antigen levels, improvement in cough, and radiographically stable disease for 5 months. CONCLUSION: R115777 is bioavailable after oral administration and has an acceptable toxicity profile. Based upon pharmacokinetic data, the recommended dose for phase II trials is 500 mg orally bid (total daily dose, 1, 000 mg) for 5 consecutive days followed by 9 days of rest. Studies of continuous dosing and studies of R115777 in combination with chemotherapy are ongoing.


Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/therapeutic use , Neoplasms/drug therapy , Quinolones/therapeutic use , Administration, Oral , Adult , Aged , Anemia/chemically induced , Biological Availability , Bone Marrow/drug effects , Capsules , Drug Administration Schedule , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/pharmacokinetics , Farnesyltranstransferase , Fatigue/chemically induced , Female , Half-Life , Headache/chemically induced , Humans , Hypotension/chemically induced , Male , Metabolic Clearance Rate , Middle Aged , Nausea/chemically induced , Peripheral Nervous System Diseases/chemically induced , Quinolones/adverse effects , Quinolones/pharmacokinetics , Solutions , Vomiting/chemically induced
6.
Clin Cancer Res ; 6(2): 406-14, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10690517

ABSTRACT

A Phase II study of yttrium-90-tetra-azacyclododecanetetra-acetic acid-biotin (90Y-DOTA-biotin) pretargeted by NR-LU-10 antibody/streptavidin (SA) was performed. The primary objectives of the study were to evaluate the efficacy and safety of this therapy in patients with metastatic colon cancer. Twenty-five patients were treated with a single dose of 110 mCi/m2 (mean administered dose, 106.5 +/- 10.3 mCi/m2) of 90Y-DOTA-biotin. There were three components of the therapy. Patients first received NR-LU-10/SA on day 1. A clearing agent (biotin-galactose-human serum albumin) was administered approximately 48 h after the NR-LU-10/SA to remove residual circulating unbound NR-LU-10/SA. Lastly, 24 h after administration of clearing agent, patients received biotin-DOTA-labeled with 110 mCi/m2 90Y. All three components of the therapy were administered i.v. Both hematological and nonhematological toxicities were observed. Diarrhea was the most frequent grade 4 nonhematological toxicity (16%; with 16% grade 3 diarrhea). Hematological toxicity was less severe with 8% grade 3 and 8% grade 4 neutropenia and 8% grade 3 and 16% grade 4 thrombocytopenia. The overall response rate was 8%. Two partial responders had freedom from progression of 16 weeks. Four patients (16%) had stable disease with freedom from progression of 10-20 weeks. Despite the relatively disappointing results of this study in terms of therapeutic efficacy and toxicity, proof of principle was obtained for the pretargeting approach. In addition, valuable new information was obtained about normal tissue tolerance to low-dose-rate irradiation that will help to provide useful guidelines for future study designs.


Subject(s)
Antibodies, Monoclonal/toxicity , Colonic Neoplasms/radiotherapy , Radioimmunotherapy , Radiopharmaceuticals/therapeutic use , Adult , Aged , Anemia/etiology , Antibodies, Monoclonal/adverse effects , Biotin/administration & dosage , Biotin/analogs & derivatives , Colonic Neoplasms/pathology , Female , Humans , Leukopenia/etiology , Male , Middle Aged , Neoplasm Metastasis , Organometallic Compounds/administration & dosage , Radiopharmaceuticals/adverse effects , Thrombocytopenia/etiology , Yttrium Radioisotopes/adverse effects , Yttrium Radioisotopes/therapeutic use
7.
J Natl Cancer Inst ; 91(3): 244-51, 1999 Feb 03.
Article in English | MEDLINE | ID: mdl-10037102

ABSTRACT

BACKGROUND: With an hypothesis that post-chemotherapy changes in serum prostate-specific antigen (PSA) levels might serve as a surrogate marker for assessing prostate cancer outcome (i.e., survival), we studied the relationship between pretherapy and post-therapy prognostic factors and survival in patients with androgen-independent prostate cancer. METHODS: A prognostic model for survival based on pretherapy and post-therapy parameters was developed from the clinical data on 254 patients with androgen-independent prostate cancer treated with 11 different protocol therapies at Memorial Sloan-Kettering Cancer Center. The model was validated by use of an independent dataset of 541 patients enrolled in two randomized phase III trials. RESULTS: In multivariate analysis, a post-therapy decline in PSA levels of 50% achieved in 12 weeks was a statistically significant factor associated with survival (two-sided P = .0012). A similar outcome was obtained with the use of an 8-week time frame. Elevated pretherapy level of serum lactate dehydrogenase (two-sided P = .0001), lower pretherapy level of hemoglobin (P = .0001), and younger age (two-sided P = .0430) had a statistically significant negative impact on outcome. Median survival times were 23, 17, and 9 months for low-, intermediate-, and high-risk groups of patients defined by the prognostic model, respectively. CONCLUSION: This study confirms the prognostic value of a post-therapy decline in PSA of 50% or greater from baseline in relation to survival in patients with androgen-independent prostate cancer treated with a variety of therapies. Two consecutive determinations at 4-week intervals can be used as an end point for efficacy in phase II trials of therapies in this disease.


Subject(s)
Prostate-Specific Antigen/blood , Prostatic Neoplasms/immunology , Aged , Aged, 80 and over , Humans , Male , Middle Aged , Multivariate Analysis , Prognosis , Prostatic Neoplasms/therapy , Reproducibility of Results , Risk Factors , Survival Analysis
8.
Neoplasma ; 46(6): 342-8, 1999.
Article in English | MEDLINE | ID: mdl-10732862

ABSTRACT

G0 cells in a tumor are insensitive to the chemotherapeutical agents. The nature of this resistance is not completely understood. One of the factors modulating sensitivity of cells may be DNA repair of drug induced DNA damage. In this study we have compared gene-specific formation and repair of cisplatin-induced interstrand cross-links (ICL) in human G0 and proliferating CD4+ lymphocytes. Cisplatin killing of G0 CD4+ lymphocytes is inefficient, and these cells resemble those in a tumor. After exposure to cisplatin under similar conditions, the frequency of ICL introduced is twice as high in the proliferating compared to the resting lymphocytes. Repair of ICL was measured in the housekeeping gene, dihydrofolate reductase (DHFR), in the proliferation inducible c-myc gene, and in the inactive delta-globin gene. We observed similar relative rates and extent of ICL repair in all three genes studied, in G0 or proliferating CD4+ lymphocytes. The mechanisms responsible for the resistance of G0 CD4+ lymphocytes towards cisplatin are discussed.


Subject(s)
CD4-Positive T-Lymphocytes/drug effects , Cisplatin/pharmacology , DNA Repair , Resting Phase, Cell Cycle/drug effects , Antineoplastic Agents/pharmacology , CD4-Positive T-Lymphocytes/cytology , Cell Division/drug effects , Cross-Linking Reagents/pharmacology , Drug Resistance, Neoplasm/genetics , Humans , In Vitro Techniques
9.
Semin Oncol ; 25(2 Suppl 4): 33-9; discussion 45-8, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9578060

ABSTRACT

We report the updated results of an intensive treatment protocol for children (< 18 years) and adults (> or = 18 years) with advanced B-cell lymphomas. The protocol consists of two chemotherapy regimens: A, consisting of cyclophosphamide, doxorubicin, vincristine and high-dose methotrexate (CODOX-M), and B, consisting of ifosfamide, etoposide, and high-dose cytarabine (IVAC). Both cycles included intrathecal chemotherapy (cytarabine or methotrexate). Patients received a total of four cycles in the following sequence: A, B, A, B. Sixty-six previously untreated patients, enrolled before October 1996, were included in the present analysis. Of these, 55 had Burkitt's or Burkitt's-like lymphoma and 11 had diffuse large B-cell lymphoma. There were 53 males ad 13 females; 40 were children and 26 were adults (age range, 3 to 57 years). To date, 61 patients have achieved a complete response to therapy. Two patients subsequently relapsed, but one of these is a long-term survivor after further therapy and a bone marrow transplant. The event-free survival rate is 85% at I year and beyond. The median potential follow-up period is 48 months (range, 12 to 96 months) for patients remaining in complete remission. Neutropenia occurred in 98% of cycles and infection in 46% of A cycles and 50% of B cycles, but the duration was shortened in B cycles by the administration of granulocyte colony-stimulating factor. Positive blood cultures were observed in 21% of A cycles and 28% of B cycles, and there have been three toxic deaths. These results are better than those achieved with an earlier version of CODOX-M, suggesting that the addition of the IVAC regimen is responsible for the improved results. The similarity of the outcome in children and adults, however, confirms our previous observation that, at least in adults younger than 60 years with Burkitt's or Burkitt's-like lymphomas, treatment with regimens similar to those used in children is warranted.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, B-Cell/drug therapy , Adolescent , Adult , Child , Child, Preschool , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Cytarabine/administration & dosage , Doxorubicin/administration & dosage , Etoposide/administration & dosage , Female , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Humans , Ifosfamide/administration & dosage , Lymphoma, B-Cell/pathology , Lymphoma, B-Cell/radiotherapy , Male , Methotrexate/administration & dosage , Middle Aged , Neoplasm Staging , Survival Rate , Vincristine/administration & dosage
10.
Int J Cancer ; 70(2): 221-9, 1997 Jan 17.
Article in English | MEDLINE | ID: mdl-9009164

ABSTRACT

Geldanamycin belongs to the family of benzoquinoid ansamycin tyrosine-kinase inhibitors. We have examined its effects on Her-2/neu kinase activity, protein expression level, and proliferation of Her-2+ malignant cells. In SK-BR-3 breast-cancer cells, short-time treatment with geldanamycin completely abrogated gp30-ligand-induced activation of Her-2 without a change of receptor-expression level. Longer treatment of intact cells with geldanamycin induced decreased steady-state Her-2 autophosphorylation activity, which correlated with reduction of Her-2 protein expression and phosphotyrosine content of several proteins. The decrease was time- and dose-dependent, starting after 1 hr at 100 nM concentration and reaching completion by 24 hr. The reduction of the Her-2 protein level probably resulted from increased degradation, since the Her-2 mRNA level remained constant. Geldanamycin effects were not specific for Her-2, since the non-receptor tyrosine-kinase fyn was inhibited equally. In contrast to these results, protein-kinase-C activity was not affected. In 3 other malignant cell lines expressing different amounts of Her-2 (SK-BR-3 > SK-OV-3 > OVCAR3 > MCF7), geldanamycin also effectively reduced Her-2-kinase activity proportionally to the decrease of protein expression. In contrast, in a [3H]-thymidine-uptake assay, cell growth was meaningfully inhibited by geldanamycin at nanomolar concentrations only in SK-BR-3 (IC50 2 nM) and MCF7 (IC50 20 nM), while OVCAR3 was only moderately sensitive (IC50 2 microM) and SK-OV-3 was clearly resistant to geldanamycin. In direct comparison with herbimycin A, another benzoquinoid ansamycin that has been more thoroughly characterized, the biologic effects of geldanamycin were more pronounced.


Subject(s)
Enzyme Inhibitors/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Neoplasm Proteins/antagonists & inhibitors , Quinones/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Adenocarcinoma/pathology , Benzoquinones , Breast Neoplasms/pathology , Cell Division/drug effects , Enzyme Activation , Female , Humans , Lactams, Macrocyclic , Ligands , Ovarian Neoplasms/pathology , Protein-Tyrosine Kinases/antagonists & inhibitors , RNA, Messenger/biosynthesis , RNA, Neoplasm/biosynthesis , Rifabutin/analogs & derivatives , Tumor Cells, Cultured
11.
Baillieres Clin Haematol ; 9(4): 707-26, 1996 Dec.
Article in English | MEDLINE | ID: mdl-9138614

ABSTRACT

The NHLs are a group of neoplasms that share a common target tissue, and are characterized by a high degree of biological and clinical heterogeneity. Adult lymphomas with a high propensity for CNS involvement comprise SNCC, lymphoma (ATLL), LL, and PCL of immunocompromised patients. Despite recently reported encouraging results, there is no standard therapy available for ATLL or PCL. In contrast, recent data from several groups suggest that the therapeutic outcome of SNCC lymphoma in adults is similar to the excellent results in children, when the same regimens are used, and the toxicity, at least for adults less than 60 years, is also similar. Although more intensive chemotherapy combined with CNS prophylaxis has extended the long-term survival of patients with LL, the treatment results in adults fall short of those for children.


Subject(s)
Brain Neoplasms/therapy , Lymphoma, AIDS-Related/therapy , Lymphoma/therapy , Adult , Brain Neoplasms/pathology , Humans , Lymphoma/pathology , Lymphoma, AIDS-Related/pathology
12.
J Clin Invest ; 98(6): 1290-7, 1996 Sep 15.
Article in English | MEDLINE | ID: mdl-8823293

ABSTRACT

In attempt to elucidate the mechanism of the HIV infection induced T cell unresponsiveness, we studied signal-transducing molecules proximal to the T cell receptor (TCR) in T lymphocytes of HIV-infected individuals. Total amounts of protein tyrosine kinases (PTKs) Lck, Fyn, and ZAP-70 and the zeta chain of the TCR were found significantly decreased in T cells of symptomatic/AIDS patients as well as in T cells of individuals in acute and early asymptomatic stages of HIV infection. Unexpectedly, the detection of Lck, Fyn, and ZAP-70 was reversed after the treatment of cell lysates with dithiothreitol. This suggests that PTKs Lck, Fyn, and ZAP-70 were modified by a mechanism altering the status of sulfhydryl groups. Moreover, this mechanism seems to affect selectively T cells of HIV infected patients since B cell PTKs Syk and Lyn were detected structurally and functionally intact. Interestingly, similar alterations of signaling molecules were not detected in T cells of HIV-infected long-term asymptomatic individuals. Modification of T cell PTKs may thus underlie the HIV-induced impairment of lymphocyte function and may potentially predict disease progression.


Subject(s)
HIV Infections/immunology , HIV-1 , Protein Processing, Post-Translational/immunology , Signal Transduction/immunology , T-Lymphocytes/immunology , T-Lymphocytes/physiology , B-Lymphocytes/immunology , B-Lymphocytes/physiology , Disease Progression , Humans , Immunoblotting , Lymphocyte Specific Protein Tyrosine Kinase p56(lck) , Phosphorylation , Polymerase Chain Reaction , Protein-Tyrosine Kinases/analysis , Protein-Tyrosine Kinases/immunology , Proto-Oncogene Proteins/analysis , Proto-Oncogene Proteins/immunology , Proto-Oncogene Proteins c-fyn , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/physiology , Receptors, Antigen, T-Cell, gamma-delta/analysis , Receptors, Antigen, T-Cell, gamma-delta/immunology , Sulfhydryl Compounds/metabolism , ZAP-70 Protein-Tyrosine Kinase , src-Family Kinases/analysis , src-Family Kinases/immunology
13.
Mutat Res ; 363(3): 191-9, 1996 Aug 08.
Article in English | MEDLINE | ID: mdl-8765160

ABSTRACT

We have measured the gene-specific repair of ultraviolet irradiation (UV)-induced cyclobutane pyrimidine dimers (CPD) in freshly isolated human peripheral blood CD4+ T-lymphocytes. Two populations of CD4+ lymphocytes were assayed: resting and proliferating cells. DNA repair was assessed in the essential gene dihydrofolate reductase (DHFR) as well as in each of its strands, in the proliferation inducible c-myc gene and in the inactive delta-globin gene. Transcription rates in these genes were determined by nuclear run-on assay in the two cell populations. The rate of DHFR transcription increased 10-fold from resting to proliferating lymphocytes. Transcripts from c-myc were present only in proliferating cells, and we detected no delta-globin transcripts in either cell population. During the 24-h period after UV irradiation, there was little or no repair in any of the genes in the resting cells; there was some repair in the transcribed strand of the DHFR gene, but no repair in its nontranscribed strand. In the proliferating cells where the transcription of DHFR was much increased, the repair was efficient. The delta-globin gene was not expressed in either cell population, but it was more efficiently repaired in the proliferating than in the resting cells. We suggest that the gene-specific repair activity in CD4+ lymphocytes can reflect the proliferative state of the cells as well as the transcriptional state of the gene.


Subject(s)
CD4-Positive T-Lymphocytes/metabolism , DNA Repair , Transcription, Genetic , Autoradiography , CD4-Positive T-Lymphocytes/radiation effects , Cell Cycle , Cell Division , Cell Survival , Cells, Cultured , Chromosome Mapping , DNA Probes/analysis , Genes, myc/genetics , Globins/genetics , Humans , Pyrimidine Dimers/analysis , Restriction Mapping , Tetrahydrofolate Dehydrogenase/genetics , Transcription, Genetic/radiation effects , Ultraviolet Rays
14.
J Clin Oncol ; 14(3): 935-40, 1996 Mar.
Article in English | MEDLINE | ID: mdl-8622042

ABSTRACT

PURPOSE: We have observed a severe atypical neuropathy (SAN) in patients with small non-cleaved-cell (SNCL) and large-cell lymphoma (LCL) treated with intensive chemotherapy and hematopoietic colony-stimulating factors (CSFs). The present analysis was undertaken in an attempt to identify factors associated with the development of this syndrome. PATIENTS AND METHODS: Fifty-four adult and pediatric patients consecutively treated according to the same chemotherapy protocol were included in the analysis. Low-risk patients received three cycles of cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate (CODOX-M) while in high-risk patients this drug combination was alternated with high-dose cytarabine (ara-C), etoposide, and ifosfamide (IVAC) for a total of four cycles. Twenty-eight patients received a CSF (granulocyte [G]- or granulocyte-macrophage [GM]-CSF), and 26 patients received no CSF. A statistical analysis, which included a logistic regression model, was undertaken to examine the importance of potential contributing factors to the development of SAN. RESULTS: SAN, which consisted of excruciating foot pain, usually associated with marked motor weakness, was observed in 12 patients. There was a highly significant association between the occurrence of this syndrome and the administration of CSFs, and an independent association with the cumulative dose of vincristine given in the first cycle of chemotherapy. Furthermore, the analysis suggested a synergistic effect between administration of the CSFs and vincristine in the genesis of this neuropathy. CONCLUSION: Our results indicate that CSFs can precipitate SAN when given in conjunction with vincristine. The development of SAN was associated most strongly with the cumulative dose of vincristine -- the size of individual doses and the number of doses given in cycle 1 were important to the extent that they influenced the cumulative dose.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Foot Diseases/chemically induced , Granulocyte-Macrophage Colony-Stimulating Factor/adverse effects , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Pain/chemically induced , Peripheral Nervous System Diseases/chemically induced , Vincristine/adverse effects , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , Cyclophosphamide/administration & dosage , Cytarabine/administration & dosage , Doxorubicin/administration & dosage , Etoposide/administration & dosage , Female , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Humans , Ifosfamide/administration & dosage , Infant , Male , Methotrexate/administration & dosage , Middle Aged , Multivariate Analysis , Vincristine/administration & dosage
15.
J Clin Oncol ; 14(3): 925-34, 1996 Mar.
Article in English | MEDLINE | ID: mdl-8622041

ABSTRACT

PURPOSE: We have used identical treatment protocols for adults and children with small non-cleaved-cell lymphoma (SNCL) for many years and report here the results of two successive treatment regimens in these age groups. PATIENTS AND METHODS: Seventy-two patients (39 adults and 33 children) were treated with protocol 77-04 between 1977 and 1985. All patients, except those with resected abdominal disease, received 15 cycles of a combination of cyclophosphamide (CTX), doxorubicin (ADR), prednisone (PRED), vincristine (VCR), high-dose methotrexate (MTX), and intrathecal (IT) therapy. Forty-one patients (20 adults and 21 children) were treated with protocol 89-C-41, which has been used since 1989. High-risk patients received four alternating cycles (with a total duration of 12 to 15 weeks) of an intensified version of protocol 77-04 without PRED (CODOX-M), and a new drug combination consisting of ifosfamide, etoposide, high-dose cytarabine (ara-C), and IT MTX (IVAC). Low-risk patients received three cycles of the CODOX-M regimen. High-risk patients were randomized to either receive or not receive granulocyte-macrophage colony-stimulating factor (GM-CSF). RESULTS: Event-free survival (EFS) in protocol 77-04 was 56% at 2 years and beyond. EFS in protocol 89-C-41 was 92% at 2 years and beyond. GM-CSF was associated with increased thrombocytopenia. CONCLUSION: Adults and children with SNCL have a similar prognosis when treated with the same chemotherapy. EFS in high-risk patients has been markedly improved by including IVAC in protocol 89-C-41, and excellent results can be achieved with only four cycles of therapy. In protocol 89-C-41, GM-CSF was not beneficial.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Non-Hodgkin/drug therapy , Adolescent , Adult , Age Factors , Child , Child, Preschool , Cyclophosphamide/administration & dosage , Cytarabine/administration & dosage , Doxorubicin/administration & dosage , Etoposide/administration & dosage , Female , Granulocyte-Macrophage Colony-Stimulating Factor/administration & dosage , Granulocyte-Macrophage Colony-Stimulating Factor/adverse effects , Humans , Ifosfamide/administration & dosage , Lymphoma, Non-Hodgkin/blood , Lymphoma, Non-Hodgkin/mortality , Male , Methotrexate/administration & dosage , Middle Aged , Neutropenia/chemically induced , Prednisone/administration & dosage , Survival Analysis , Thrombocytopenia/chemically induced , Vincristine/administration & dosage
16.
Cancer Genet Cytogenet ; 86(2): 131-5, 1996 Feb.
Article in English | MEDLINE | ID: mdl-8603339

ABSTRACT

A chromosomal clone with unbalanced translocation resulting in partial trisomy of segment 1q22-qter and partial monosomy of segment 6p21-pter was revealed by fluorescence in situ hybridization (FISH) using a panel of different whole chromosome painting probes. The pathologic clone appeared after sequential chemotherapy treatment for AML-M5 when the patient was in complete remission before development of T-ALL. However, this clone was present during the whole period of treatment for T-ALL. The clone remained the only chromosomal aberration found. Breakpoints were detected more easily and more precisely with the use of the FISH technique than with G-banding only.


Subject(s)
Bone Marrow/pathology , Chromosomes, Human, Pair 1 , Chromosomes, Human, Pair 6 , Leukemia-Lymphoma, Adult T-Cell/genetics , Translocation, Genetic , Female , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Leukemia-Lymphoma, Adult T-Cell/diagnosis , Leukemia-Lymphoma, Adult T-Cell/pathology , Middle Aged
18.
J Med Chem ; 36(20): 3010-4, 1993 Oct 01.
Article in English | MEDLINE | ID: mdl-8105084

ABSTRACT

The fermentation product lavendustin A (1) is a protein-tyrosine kinase (PTK) inhibitor whose active pharmacophore has previously been shown to reside in the more simplified salicyl-containing benzylamine 2. Amine 2 bears some structural resemblance to two other natural product PTK inhibitors, erbstatin (3) and piceatannol (4). Non-amine containing analogues of 2 were therefore synthesized which incorporated additional aspects of either erbstatin or piceatannol. Examination of these inhibitors in immunoprecipitated p56lck, epidermal growth factor receptor (EGFR), and c-erb B-2/HER 2/neu PTK preparations showed that compound 12 (IC50 = 60 nM) was one of the most potent p56lck inhibitors reported to date. These results demonstrate that nitrogen is not an essential component of the lavendustin A pharmacophore 2 and that 1,2-diarylethanes and -ethenes bearing a salicyl moiety appear to be valuable structural motifs for the construction of extremely potent PTK inhibitors.


Subject(s)
Phenols/chemistry , Protein-Tyrosine Kinases/antagonists & inhibitors , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Immunosorbent Techniques , Lymphocyte Specific Protein Tyrosine Kinase p56(lck) , Molecular Structure , Phenols/pharmacology , Proto-Oncogene Proteins/metabolism , Receptor, ErbB-2 , Structure-Activity Relationship
19.
J Biol Chem ; 268(28): 20725-8, 1993 Oct 05.
Article in English | MEDLINE | ID: mdl-7691802

ABSTRACT

Bacterial lipopolysaccharide (LPS) induces a pleiotropic activation of the immune system which might subsequently result in septic shock. One of the cell surface receptors for LPS is the glycophosphatidylinositol-anchored protein CD14. Binding of LPS to CD14 induces production of lymphokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), IL-6, and IL-8, and CD14 is subsequently released from the cell surface. However, the mechanism of signaling via CD14 is still not known. We report here that protein tyrosine kinase (PTK) p56lyn is coupled to the LPS receptor CD14 in human monocytes. LPS rapidly activates CD14-associated p56lyn simultaneously with PTKs p58hck and p59c-fgr. Inhibition of PTKs by herbimycin A completely blocks LPS-induced down-modulation of CD14 and production of TNF-alpha and IL-1. These data suggest a critical role of PTKs in the LPS/CD14-mediated signal transduction pathway in human monocytes.


Subject(s)
Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , Lipopolysaccharides/pharmacology , Protein-Tyrosine Kinases/metabolism , src-Family Kinases , Humans , In Vitro Techniques , Lipopolysaccharide Receptors , Lymphokines/biosynthesis , Monocytes/metabolism , Phosphorylation , Precipitin Tests
20.
J Med Chem ; 36(20): 3015-20, 1993 Oct 01.
Article in English | MEDLINE | ID: mdl-8411019

ABSTRACT

The salicyl group figures prominently in several potent protein-tyrosine kinase (PTK) inhibitors, including the fermentation product lavendustin A (3), the salicylsulfonyl nitrostyryl 30, and our recently reported salicyl-containing stilbene 7. Taking compound 7 and the isomeric 8 as lead structures, bicyclic nuclei 9-12 were prepared as conformationally constrained mimetics in which the hydroxyphenyl rings of 7 and 8 are held coplanar with the stilbene ethylene bridge. A similar approach with styryl-based PTK inhibitors of structure 1 previously yielded analogues 2 with enhanced potency. In the present case, however, the resulting salicyl-containing bicyclics exhibited extremely poor inhibitory potency when examined against autophosphorylation of immunoprecipitated p56lck PTK preparations. The implications of these results are discussed as they relate to the potential ways in which salicyl-containing stilbenes may be oriented relative to styryl-based inhibitors of type 1 and to an emerging class of potent aryl-substituted bicyclic inhibitors exemplified by compound 31.


Subject(s)
Naphthalenes/chemical synthesis , Protein-Tyrosine Kinases/antagonists & inhibitors , Salicylates/chemical synthesis , Hydroxylation , Lymphocyte Specific Protein Tyrosine Kinase p56(lck) , Molecular Structure , Naphthalenes/pharmacology , Phosphorylation , Salicylates/pharmacology , Structure-Activity Relationship
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