Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Teniposide”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 361 records · Page 20Linked to original sources
PubMed1993

Degradation and inactivation of antitumor drugs.

Chemical methods for the degradation of 11 antineoplastic drugs [etoposide, teniposide, bleomycin, mitomycin C, cisplatin, cis-dichloro-trans-dihydroxy-bis(isopropylamine) platinum IV (CHIP), cyclophosphamide, ifosfamide, carmustine, lomustine, and methotrexate] were investigated. The success of the degradation procedures was assessed by HPLC and degree of biological inactivation by mutagenicity assays. The most widely applicable procedure was oxidation with potassium permanganate or 5.25% sodium hypochlorite solution (bleach). Oxidation completely degraded and inactivated etoposide, teniposide, bleomycin, mitomycin C, and methotrexate. In addition, oxidation followed by nucleophilic substitution resulted in the complete degradation and inactivation of cyclophosphamide and ifosfamide. Although carmustine and lomustine were chemically degraded by treatment with acidic potassium permanganate, the resulting reaction mixtures remained mutagenic. Therefore, this procedure cannot be recommended. The platinum-containing compounds, cisplatin and CHIP, were rendered nonmutagenic by reaction with sodium diethyldithiocarbamate. These easily performed, relatively safe procedures can be used to prevent exposure to mutagenic wastes and spills in the hospital setting.

Antineoplastic Agents↗
PubMed1993

A comparison of the effects of aphidicolin and other inhibitors on topoisomerase II-directed cytotoxic drugs.

We have compared the effects of a number of inhibitors including aphidicolin, 2,4-dinitrophenol (DNP) and novobiocin on the in vitro cytotoxicity of several topoisomerase II (topo II)-directed agents, using cultured murine Lewis lung carcinoma cells. These agents comprised amsacrine, CI-921 (9-[(2-methoxy-4-methylsulfonylamino)phenylamino]-N,5-dimethyl-4- acridinecarboxamide isethionate, isethionate, a derivative of amsacrine), DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride, a new DNA intercalator with high solid tumor activity), daunorubicin, doxorubicin, epirubicin, etoposide, mitoxantrone, and teniposide. Novobiocin, an antibiotic that affects topo II action, reduced the cytotoxic effect of DACA as well as that of amsacrine and doxorubicin, and reduced the extent of G2-phase arrest by DACA. DNP, an uncoupler of mitochondrial respiration, inhibited drug action in a manner similar to that of novobiocin but to a smaller extent. Aphidicolin, a specific inhibitor of DNA polymerase-alpha, reduced the cytotoxic effect of amsacrine, CI-921, etoposide, and teniposide but not that of DACA, daunorubicin, doxorubicin, epirubicin, or mitoxantrone. The immediate effect of each topo II-directed agent on the incorporation of thymidine into DNA was also measured at a drug concentration (D10) that killed 90% of cells. Susceptibility to aphidicolin reversal was strongly correlated with inhibition of thymidine incorporation (r = 0.91; p < or = 0.001). The results suggest that the involvement of DNA replication in the cytotoxic action of topo II-directed agents differs according to the agent used.

Acridines↗
PubMed1993

The cell cycle related differences in susceptibility of HL-60 cells to apoptosis induced by various antitumor agents.

The studies were aimed to detect the cell cycle-associated differences in the susceptibility of HL-60 cells to apoptosis induced by diverse agents. Exponentially growing HL-60 cells were treated with the DNA topoisomerase I inhibitor camptothecin; the DNA topoisomerase II inhibitors teniposide, m-AMSA, Mitoxantrone, or Fostriecin; the presumed tyrosine kinase inhibitor genistein; a serine/threonine kinase inhibitor H7; the protein synthesis inhibitor cycloheximide; the DNA replication inhibitor hydroxyurea; the nucleoside antimetabolites 1-beta-D-arabinofuranosylcytosine and 5-azacytidine; and the alkylating agent nitrogen mustard, cisplatin, hyperthermia, and gamma irradiation. Endonucleolysis, which accompanied apoptosis induced by these agents, was assessed by two different flow cytometric methods, one based on DNA content measurements following extraction of low molecular weight DNA, and another using exogenous terminal deoxynucleotidyl transferase to label in situ DNA strand breaks. Each method allowed for both identification of apoptotic cells and analysis of the cell cycle distribution of the unaffected cell population; the method using terminal transferase also allowed for identification of the cell cycle position of apoptotic cells. Confirmed by analysis of DNA degradation by gel electrophoresis and changes in cell morphology, apoptosis was observed as early as 3 h after administration of most drugs and for some drugs was cell cycle phase specific. Cells progressing through S phase were selectively susceptible when treated with camptothecin, teniposide, m-AMSA, Mitoxantrone, H7, hydroxyurea, and 1-beta-D-arabinofuranosylcytosine. Cells in G2-M preferentially underwent apoptosis in cultures treated with H7 or with gamma-irradiation. Cells in G1 phase were preferentially affected by 5-azacytidine, nitrogen mustard, and hyperthermia. No significant cell cycle specificity was observed in the case of Fostriecin, genistein, cycloheximide, or cisplatin. The cell cycle related difference in susceptibility to apoptosis may be a reflection of both the severity of the lesion induced by a given drug and the ability of the cells to repair that lesion; both can vary depending on the cell cycle phase.

Antineoplastic Agents↗
PubMed1996

Characterization of novel human leukemic cell lines selected for resistance to merbarone, a catalytic inhibitor of DNA topoisomerase II.

Merbarone is a catalytic inhibitor of DNA topoisomerase (topo) II that does not stabilize DNA-topo II cleavable complexes. Although the cytotoxicity of and resistance to complex-stabilizing topo II inhibitors, such as etoposide, is thought to be mediated through stabilization of these complexes, the mechanisms of cytotoxicity and resistance to catalytic inhibitors are not well known. To investigate this issue, we established 12 merbarone-resistant cell lines from human leukemia CEM cells, designated CEM/M70-B1 through -B12. Assessed by either growth inhibition or clonogenic assay, these cell lines are 3.5- to 6.6-fold resistant to merbarone, compared to the CEM parent cells. Karyotype analysis of three of the cell lines revealed that while CEM and drug-resistant cell lines had chromosome abnormalities in common, indicating a common origin, two of the merbarone-resistant lines (B1 and B8) each had unique structural markers. These novel cell lines are cross-resistant to complex-stabilizing topo II inhibitors, etoposide, teniposide, amsacrine, and doxorubicin, but not to other catalytic inhibitors, aclarubicin or SN-22995. Of considerable interest, these cell lines are cross-resistant to SN-38, a putative topo I inhibitor, but cross-resistance to other topo I inhibitors (camptothecin and topotecan) was lower and not seen in every cell line. In all 12 cell lines, there was a high correlation among drug resistance ratios between etoposide and teniposide and between merbarone and SN-38. By contrast, there was a low correlation between merbarone and etoposide and between SN-38 and other topo I inhibitors. These results suggest that resistance to merbarone and cross-resistance to etoposide might be through different mechanisms, whereas cross-resistance to SN-38 might be through a merbarone-related mechanism. Etoposide and SN-38 stabilized fewer DNA-topoisomerase complexes in CEM/M70-B cells than in CEM cells, but camptothecin stabilized more. Merbarone inhibited complex formation induced by etoposide in drug-sensitive and -resistant cells, but the degree of inhibition was lower in CEM/M70-B cells than in the parental cells. Moreover, merbarone did not affect complex formation stabilized by SN-38 or camptothecin. Immunoblot analysis of the CEM/M70-B cells showed decreased topo IIalpha, increased topo IIbeta, and no change of topo I protein, compared to CEM cells. We propose the hypothesis that decreased topo IIalpha may play a role in the resistance to merbarone that is different from that to complex-stabilizing drugs. Cross-resistance to catalytic inhibitors may be due to reduced complex formation as a consequence of decreased topo IIalpha. We also found that DNA-protein complexes stabilized by SN-38 might be different from those stabilized by topo II inhibitors and blocked by merbarone. Judging from both the high correlation of drug sensitivities and complex-formation assays, we postulate that mechanisms of cytotoxicity and cross-resistance of SN-38 in CEM/M70-B cells might be similar to those of merbarone. We believe that the CEM/M70-B cells are the first to be selected and characterized for resistance to a catalytic inhibitor of topo II. This study provides novel cell lines with characteristics of resistances to topo II and topo I inhibitors.

Aneuploidy↗
PubMed1996

A study of thiotepa, etoposide and fractionated total body irradiation as a preparative regimen prior to bone marrow transplantation for poor prognosis patients with neuroblastoma.

We report the toxicity and efficacy of a new conditioning regimen for bone marrow transplantation (BMT) in children with poor prognosis neuroblastoma (NBL). Twenty-seven patients with poor prognosis NBL were treated with teniposide (360 mg/m2) or etoposide (500 mg/m2), thiotepa (600-900 mg/m2), and 1200 cGy fractionated total body irradiation (fTBI) followed by autologous marrow rescue (n = 19) or allogeneic BMT from HLA-identical siblings (n = 8). The two patients who received teniposide, 600 mg/m2 thiotepa and fTBI had minimal toxicity but relapsed 4 and 12 months post-auto BMT. The next two patients received 750 mg/m2 thiotepa, 500 mg/m2 etoposide and TBI. They tolerated the conditioning regimen well and are alive and in remission 77 and 75 months post-BMT. At the next thiotepa dose level (900 mg/m2), the first two allograft recipients both experienced fatal regimen-related toxicity. All subsequent allograft recipients received 750 mg/m2 thiotepa and autograft recipients received 900 mg/m2 thiotepa. As of 1 April 1995, eight of the 19 patients who received autologous marrow are surviving disease-free 21 to 77 months post-BMT. Nine autograft recipients relapsed at 2 to 37 months following transplantation. One patient died of hepatic veno-occlusive disease 2 months after auto BMT, and one of pneumonia 6 months post-transplantation. Three allograft recipients have relapsed at 6, 10 and 39 months post-transplant and three are alive and in remission 75, 53 and 27 months post-BMT. Overall, 11/27 patients (41%) are alive and in remission 21-77 months (median 47 months) following BMT. A conditioning regimen consisting of 500 mg/m2 etoposide, thiotepa (750 mg/m2 for allograft recipients and 900 mg/m2 for autograft recipients) and 1200 cGy fTBI has acceptable toxicity and is at least as effective as melphalan-containing regimens in the treatment of high-risk NBL.

Adolescent↗
PubMedDate not supplied

In vitro chemosensitivity testing of human non-small cell lung cancer cell lines.

Three human non-small cell lung cancer (non-SCLC) cell lines, one each derived from squamous cell carcinoma, adenocarcinoma, and large cell carcinoma were tested for chemosensitivity to 23 cytostatic agents using the soft agarose clonogenic assay. Results were compared with in vitro responses of SCLC cell lines derived from patients with and without prior chemotherapy and with in vivo phase II clinical trials in non-SCLC. Carboplatin, daunorubicin, paclitaxel, and teniposide were active in two non-SCLC cell lines and actinomycin D, bleomycin, etoposide, irinotecan, and mithramycin were active in one cell line. The cell line from the treated SCLC patient was less sensitive to cytostatic agents than the cell line from the untreated SCLC patient and had a sensitivity pattern comparable to non-SCLC cell lines. These data are consistent with clinical experience in non-SCLC and suggest that non-SCLC cell lines in conjunction with the soft agarose clonogenic assay can be useful for in vitro drug screening. They confirm that carboplatin and paclitaxel are among the most active drugs in non-SCLC and suggest that daunorubicin and teniposide may be more active then their more frequently used analogues.

Adenocarcinoma↗
PubMed1996

Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy.

BACKGROUND: External beam radiotherapy is standard treatment for medium and large, or visually threatening, intraocular retinoblastoma but markedly increases the risk of cosmetic deformities and second malignant neoplasms in children with germline RB1 mutations. Large tumors and those with vitreous seeds do poorly despite radiotherapy. Chemotherapy traditionally is ineffective for intraocular retinoblastoma, perhaps because many retinoblastomas overexpress the multidrug resistance protein, P-glycoprotein. OBJECTIVE: To avoid radiotherapy in the management of intraocular retinoblastoma by using chemotherapy and focal therapy. INTERVENTIONS: We shrank retinoblastomas in 40 eyes of 31 patients that conventionally should be enucleated or receive radiotherapy by using chemotherapy (ie, vincristine-teniposide, 8 eyes; additional carboplatin, 32 eyes) combined with the administration of cyclosporine, a known multidrug-resistance-reversal agent. We then consolidated these responses to chemotherapy by subsequent 532- and 1064-nm laser therapy and cryotherapy. RESULTS: At the median follow-up of 2 2/3 [corrected] years (range, 1/10-4 3/4 years), the results of treatment were excellent. The actuarial relapse-free rate was 89% in patients not previously treated (91% for 28 eyes) and 67% in patients treated after relapse from previous therapy (70% for 12 eyes). For the eyes with the worst prognosis (ie, vitreous seeds), the relapse-free rate was 88%, better than previously reported. Cyclosporine is nontoxic and did not enhance the expected toxic effects of chemotherapy. Most eyes required laser therapy, cryotherapy, or both for consolidation of tumor control. CONCLUSIONS: This pilot study suggests that most retinoblastomas are curable by combining chemotherapy with cyclosporine therapy, laser therapy, and cryotherapy, without requiring external beam radiotherapy. We propose a randomized trial to clarify the role of cyclosporine.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Effect of extracellular magnesium on topoisomerase II activity and expression in human leukemia HL-60 cells.

Topoisomerase II (TopoII) is a Mg-dependent enzyme involved in topological modifications of DNA that are crucial to the regulation of cell proliferation and possibly differentiation. To investigate the role of Mg availability in the modulation of TopoII in whole cells, we studied enzyme activity and expression in HL-60 cells grown in the presence of decreasing amounts of extracellular Mg (0.5, 0.03, and 0.01 mM MgSO(4)). In comparison to cells grown in 0.5 mM Mg, cells grown in 0.03 mM Mg exhibited a decrease in TopoII activity, as evidenced by reduced induction of DNA/TopoII cleavable complexes and apoptosis by etoposide and teniposide. Enzyme activity was restored by the readdition of Mg (0.5 and 1.5 mM) in the incubation medium, confirming that this effect was indeed modulated by extracellular Mg. Restriction of Mg to 0.01 mM was associated with a dramatic decrease in TopoII activity resembling that observed in HL-60 cells differentiated by dimethyl sulfoxide treatment. The restriction of Mg, while decreasing enzyme activity, was found to upregulate TopoII protein expression, determined by Western blot analysis. The increase of TopoII protein levels was correlative with the degree of Mg deprivation. Collectively, these results indicate that extracellular levels of Mg may control availability of intracellular Mg, thus affecting the regulation of TopoII activity/expression and downstream processes of cell proliferation and/or differentiation.

Apoptosis↗
PubMed1997

Analysis of expression and function of topoisomerase I and II during meiosis in male mice.

Topoisomerases are nuclear enzymes that remove torsional stress in DNA. Their function is important for replication, transcription, chromosome condensation, and chromosome segregation during mitosis and meiosis. The goal of this work is to analyze both expression and function of topoisomerases during the meiotic stages of mammalian spermatogenesis. The patterns of expression of topoisomerase I and topoisomerase II alpha genes were followed on Northern blots of RNA from testes of mice of different ages and from specific germ cell populations. The transcript of the topoisomerase I gene was highest in somatic cells of the testis and in the mitotically proliferating spermatogonia and meiotic prophase spermatocytes, with the level of transcript decreasing dramatically in postmeiotic spermatids. In contrast, the levels of topoisomerase II alpha transcript were negligible in germ-cell free testes and highest in late meiotic prophase cells and round spermatids. Enzyme activity for both topoisomerase I and topoisomerase II was detected in both pachytene spermatocytes and in round spermatids; topoisomerase II exhibited a higher level of activity in meiotic spermatocytes than in round spermatids. In cultured cells, camptothecin, an inhibitor of topoisomerase I, caused some abnormalities of paired meiotic homologs, but did not inhibit the transition to metaphase. In contrast, teniposide and ICRF-193, inhibitors of topoisomerase II, dramatically inhibited the formation of metaphase chromosomes in cells induced to progress from prophase to metaphase. However, the disassembly of the synaptonemal complex was not inhibited, indicating that this process could be uncoupled from condensation of chromatin to form chromosomes. These studies constitute evidence for a functional requirement for topoisomerase II activity in the transition from meiotic prophase to meiotic metaphase I in mammalian spermatocytes.

Animals↗
PubMed1990

Multiagent chemotherapy in relapsed acute lymphoblastic leukemia in children.

Twenty-seven evaluable children with early first bone marrow relapse of acute lymphoblastic leukemia were treated with an intensive induction/consolidation and ongoing maintenance therapy. Induction therapy consisted of a 35-day course of daunomycin, vincristine, and prednisone, immediately followed by teniposide, cytosine arabinoside (Ara-C), and L-asparaginase. Intrathecal methotrexate, hydrocortisone, and Ara-C were given through the induction/consolidation phase. Twenty-three of 27 patients achieved remission by the end of induction/consolidation. Maintenance with the same drugs in a modified dosage schedule continued for approximately 2 years. A small subgroup of patients who were M3 at day 35 but M1 at day 56 (end of induction/consolidation) and had a cumulative event-free survival (EFS) of only 0.40 at 6 months, all had relapsed by 15 months. However, the EFS for M1 patients by day 35 and maintained on chemotherapy was 0.64 at 12 months and 0.32 at 30, 36, and 48 months, respectively. Although good reinduction and remission duration rates at 12 to 24 months were achieved and an apparent plateau in survival occurs at 30 months, fall-off in survival would not be unexpected with probably less than 20% alive after 5 years.

Adolescent↗
PubMed1991

Hypersensitivity reactions to epipodophyllotoxins in children with acute lymphoblastic leukemia.

The incidence, clinical characteristics, and outcome of hypersensitivity reactions to teniposide (VM-26), etoposide (VP-16), or both were determined in 108 children with acute lymphoblastic leukemia (ALL) treated with a contemporary regimen of intensive multiagent chemotherapy. Fifty (46%) of the 108 patients had one or more hypersensitivity reactions. The risk of any child having an initial reaction over the cumulative dose range studied was 52% (95% confidence limits, 41% and 63%) for VM-26, compared with 34% (95% confidence limits, 24% and 44%) for VP-16. The risk of having an initial reaction to VM-26 or VP-16 was clearly related to the cumulative dose. This risk peaked at 1500 to 2000 mg/m2 for VM-26 and at 2000-3000 mg/m2 for VP-16. All reactions were Type 1 reactions according to the Gell and Coombs classification, characterized by urticaria, angioedema, flushing, rashes, or hypotension, and 86% of reactions were of Grade 1 or 2 severity according to standard criteria. There was no evidence of increasing clinical severity on repeated rechallenge with premedication, and no deaths occurred. The findings suggested that hypersensitivity reactions to epipodophyllotoxins in children with ALL are more common than previously reported, but only rarely constitute dose-limiting toxicity.

Adolescent↗
PubMed1991

Improved treatment results in boys with overt testicular relapse during or shortly after initial therapy for acute lymphoblastic leukemia. A Pediatric Oncology group study.

Boys with acute lymphoblastic leukemia (ALL) who have overt testicular relapse (OTR) during initial continuation chemotherapy or within 6 months thereafter have poor outcomes, with long-term survival similar to patients with marrow relapse during treatment. In April 1983, the Pediatric Oncology Group (POG) adopted for these patients an intensive treatment protocol (POG 8303) consisting of a four-drug systemic reinduction (prednisone, vincristine, daunorubicin, and asparaginase), a brief intensive consolidation phase with teniposide and cytarabine, and a 2-year program of continuation chemotherapy with weekly rotating drug pairs (vincristine/cyclophosphamide and teniposide/cytarabine) with or without (by randomization) four-drug reinforcement pulses every 16 weeks. Bilateral testicular radiation (2600 cGy) was administered during reinduction, and intrathecal chemoprophylaxis was given every 4 to 6 weeks. Among 38 eligible study patients with OTR, 5 had prior or concominant extramedullary relapse in other sites. The median duration of complete remission before OTR was 27 months (range, 10 to 42 months). All 38 patients achieved clinical remission after reinduction. Three patients withdrew while in remission, 22 had another relapse (12 marrow, 5 central nervous system (CNS), 2 testicular, 1 retroperitoneal, 1 prostate, and 1 eye), and 13 (34%) remain in complete remission from 32+ to 74+ months after OTR (median, 53+ months). Eighteen patients had their therapy electively discontinued, and five relapses occurred thereafter. These results are superior to those observed in patients with first marrow relapse treated with the same protocol. Approximately one third of patients with OTR treated with POG protocol 8303 exhibit prolonged second remissions with the potential for cure.

Adolescent↗
PubMed1993

A VM 26-based regimen for patients with previously untreated non-Hodgkin lymphoma. Prolonged disease-free survival in patients younger than 60 years of age: a phase II trial of the eastern Cooperative Oncology Group.

BACKGROUND: The epidophyllotoxin VM 26 has been shown to have single-agent activity in patients with diffuse aggressive lymphoma. In an attempt to determine its activity in combination with other agents known to be effective in lymphoma, a Phase II trial of a novel chemotherapy regimen was conducted. METHODS: Forty-two patients with Stages II, III, and IV diffuse aggressive lymphoma were treated with teniposide, doxorubicin, prednisone, cyclophosphamide, vincristine, and bleomycin (PA Ten-CPOB) as part of a Phase II trial of the Eastern Cooperative Oncology Group. Fifty-five percent of patients had Stage IV disease, 21% Stage III, and 24% Stage II. RESULTS: The overall complete response rate was 64%. Of the 27 patients who had complete response, 19 (70% [45% of the entire group]) are still alive without disease (median follow-up, 5.7 years). No patient had a follow-up time of less than 5 years. On examination of factors that were predictive of survival and relapse, it was found that age younger than 60 years was predictive of long-term survival, as 76% of patients younger than 60 years of age were alive without disease. Forty patients were evaluable for toxicity. There were four (10%) early deaths, and six patients (15%) had Grade 4 hematologic toxicity. CONCLUSIONS: This alternating combination chemotherapy regimen (PA Ten-CPOB) results in a complete response rate comparable to what has been reported previously in the literature, but 45% of patients in this series demonstrated long-term disease-free survival. When patients younger than 60 years of age with follow-up times of at least 5 years were considered, disease-free survival was 76%.

Adult↗
PubMed1993

Intensive alternating drug pairs for treatment of high-risk childhood acute lymphoblastic leukemia. A Pediatric Oncology Group pilot study.

BACKGROUND: To prevent drug resistance, the authors designed a protocol that featured early intensive rotating drug pairs as part of the therapy for acute lymphoblastic leukemia (ALL). METHODS: After prednisone, vincristine, asparaginase, and daunorubicin induction, 12 intensive treatments (ABACABACABAC) were given in 30 weeks: A--intermediate-dose methotrexate (IDMTX) plus intermediate-dose mercaptopurine (MP); B--cytosine arabinoside (AC) plus daunorubicin (DNR); C--AC plus teniposide (VM-26). Triple intrathecal chemotherapy (AC, MTX, and hydrocortisone) was given for central nervous system (CNS) prophylaxis. Continuation therapy consisted of weekly MTX and daily MP until 2.5 years of continuous complete remission had been achieved. RESULTS: Seventy-four children (age range, 1-19 years) at high risk of relapse were treated. Of 55 with B-lineage (early pre-B, pre-B) ALL, 24 have failed (2 induction failures, 2 deaths from infection, and 20 relapses). The event-free survival (EFS) rate at 4 years was 55.5% (standard error [SE] +/- 7.7%). Of 19 patients with T-cell ALL, 12 have failed (2 induction failures and 10 relapses). The EFS rate at 4 years was 32.6% (SE +/- 26.8%). Toxicities were significantly more common after AC and DNR or AC and VM-26 than IDMTX and MP. There were no toxicity-related deaths during intensive treatments. CONCLUSION: Early intensive rotating therapy is tolerable and warrants consideration for additional trials of patients with high-risk, B-lineage ALL.

Administration, Oral↗
PubMed2001

Concomitant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy plus highly active antiretroviral therapy in patients with human immunodeficiency virus-related, non-Hodgkin lymphoma.

BACKGROUND: The feasibility and efficacy of concomitant chemotherapy and highly active antiretroviral therapy (HAART) is still unknown in patients with human immunodeficiency virus (HIV)-related malignancies. To evaluate the impact of chemotherapy plus HAART on the clinical course of patients with HIV-related, systemic, non-Hodgkin lymphoma (HIV-NHL), the authors compared retrospectively a group of 24 patients with HIV-NHL who were treated with the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy regimen plus HAART with a group of 80 patients who were treated with CHOP chemotherapy or a CHOP-like regimen (i.e., cyclophosphamide, doxorubicin, teniposide, and prednisone with vincristine plus bleomycin) without receiving antiretroviral therapy. METHODS: All patients were enrolled in two sequential trials performed at the Aviano Cancer Center, Italy, from April 1988 to December 1998. HAART was included with combination therapy from January 1997. Antiretroviral regimens consisted of two reverse transcriptase inhibitors and one protease inhibitor. RESULTS: The two treatment groups were well matched with regard to patient demographics, NHL characteristics, HIV status, and treatment, i.e., the number of cycles and chemotherapy dose. The response rates were similar between the two groups. Severe anemia (Grade 3-4 according to the World Health Organization criteria) was significantly greater in the patients who received CHOP-HAART compared with the patients who received CHOP alone (33% vs. 7%, respectively; P = 0.001). Leukopenia was similar between the two groups, but colony stimulating factor support was significantly greater in the CHOP-HAART group than in the control group (92% vs. 66%, respectively; P = 0.03). Seventeen percent of CHOP-HAART patients developed severe autonomic neurotoxicity, whereas none of the CHOP patients developed neurotoxicity (P = 0.002). At similar median follow-up, opportunistic infection (OI) rates and mortality were significantly lower in the CHOP-HAART patients than in the CHOP patients (18% vs. 52%, respectively; P = 0.05; and 38% vs. 85%, respectively; P = 0.001). The median survival for CHOP-HAART patients was not reached, whereas the medial survival of CHOP patients was 7 months (P = 0.03). CONCLUSIONS: The combination of CHOP plus HAART is feasible and may reduce the morbidity from OIs in HIV-NHL patients. However, careful attention must be directed to cross toxicity and possible pharmacokinetic interactions between antiretroviral and antineoplastic drugs. The impact of the combined chemotherapy plus HAART treatment on patient survival needs urgently to be evaluated in prospective studies.

AIDS-Related Opportunistic Infections↗
PubMed1984

Establishment of an etoposide-resistant human epithelial tumour cell line in vitro: characterization of patterns of cross-resistance and drug sensitivities.

A human tumour cell line resistant to etoposide ( VP16 -213) has been produced by fractionated X-irradiation exposure in vitro. Characterization of this line, derived from an epithelioid carcinoma of the tongue, revealed no significant differences in terms of several cytological and kinetic parameters compared with the parent line. Patterns of cross-resistance and drug sensitivities were determined by colony formation in soft agar after 24 h drug exposures. Three patterns of response were observed with the VP16 -213-resistant cells showing: marked cross-resistance to vincristine and teniposide , collateral sensitivity to 5- fluorouracil , hydroxyurea and cis-platinum, and comparable responses to the parent line for adriamycin, bleomycin, dibromodulcitol and methotrexate. This is the first demonstration that specific drug resistance can be induced by prior exposure to X-irradiation in vitro. This cell line appears to show a unique lack of cross-resistance between adriamycin and vincristine or etoposide. Preliminary investigations into possible mechanisms of etoposide resistance demonstrated similar DNA sedimentation profiles after etoposide exposure in both tumour cell lines, implying no differential effects of this drug on DNA of resistant cells. These data raise the possibility that the expression and mechanism of resistance may differ, depending on the manner in which drug resistance is induced.

Carcinoma, Squamous Cell↗
PubMed1994

DNA topoisomerases I & II cleavage sites in the type 1 human immunodeficiency virus (HIV-1) DNA promoter region.

Topoisomerase sites were mapped in the 5'-long terminal repeat of HIV-1 DNA by agarose and sequencing gel electrophoresis. Topoisomerase II sites were observed in the absence and presence of teniposide and amsacrine in the transcription initiation region and the TATA box, consistent with a possible role of topoisomerase II in transcription. The NF-kB and Sp1 regions were poorly cleaved. Topoisomerase I sites were relatively unfrequent even in the presence of camptothecin. They were absent in the core promoter and were concentrated in the TAR and the upstream region near the junction with the host DNA.

Amsacrine↗
PubMed1993

The mechanism of epipodophyllotoxin-induced thymocyte apoptosis: possible role of a novel Ca(2+)-independent protein kinase.

The epipodophyllotoxins, etoposide (VP-16) and teniposide (VM-26), inhibit topoisomerase II activity by stabilization of the cleavable complex between the enzyme and DNA and formation of protein-bound double-stranded DNA breaks. While it is thought that these agents are cytotoxic by preventing cells from completing the S phase or undergoing mitosis, recent evidence suggests that these agents are also potent inducers of programmed cell death or apoptosis in both normal and malignant cells. We have examined the intracellular pathway leading to epipodophyllotoxin-induced apoptosis in normal mouse thymocytes. Epipodophyllotoxin-induced apoptosis may proceed via a mechanism that is independent of inhibition of topoisomerase activity per se because novobiocin and coumermycin, which inhibit the ATPase subunit of topoisomerase II, were relatively inefficient inducers of apoptosis in these cells, under conditions where strong apoptosis by the epipodophyllotoxins and dexamethasone could be observed. In addition, camptothecin, which inhibits topoisomerase I by stabilization of the cleavable complex between that enzyme and DNA, was also a poor inducer of apoptosis in these cells. Our data suggest that epipodophyllotoxin-induced mouse thymocyte apoptosis, like that induced by dexamethasone, proceeds via a mechanism that involves protein kinase C (PKC) or a similar enzyme. Apoptosis induced by VM-26 or by dexamethasone was inhibited by 1-(5-isoquinolinylsulfonyl)-2- methylpiperazine dihydrochloride (H7), an inhibitor of both PKC and cAMP-dependent protein kinases, but was relatively unaffected by N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA1004), a more specific inhibitor of cAMP-dependent protein kinases. A more specific inhibitor of PKC, sangivamycin, also inhibited both VM-26-induced and dexamethasone-induced apoptosis. Both VM-26- and dexamethasone-induced apoptosis were unaffected by EGTA, a calcium (Ca2+) chelator, under conditions that inhibited apoptosis induced by the Ca2+ ionophore A23187. Moreover, while strong increases in intracellular Ca2+ were observed in thymocytes treated with A23187, we failed to detect increases in intracellular Ca2+ in cells induced to apoptose with either VM-26 or dexamethasone within the first 2 hr of culture. These results suggest that in mouse thymocytes there are at least two intracellular pathways leading to apoptosis: one, utilized by glucocorticoid and the epipodophyllotoxins, that proceeds in the absence of detectable increases in intracellular Ca2+ and possibly requires a novel Ca(2+)-independent PKC-like enzyme and another, utilized by Ca2+ ionophores, that is at least partially dependent on increased intracellular Ca2+.

Animals↗