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PubMed1991

Turcot's syndrome. Flow cytometric analysis.

Turcot's syndrome is a rare, genetically transmittable disease in which patients with colonic polyposis (possibly complicated by the progression to adenocarcinoma) have malignant central nervous system neoplasms. Dominant, recessive, and sporadic cases have been described. A 26-year-old man is reported with no relevant family history who had intermittent abdominal discomfort in 1986. Sigmoidoscopy revealed numerous polyps, several of which showed carcinomatous change. Dukes' Stage C colorectal carcinoma was diagnosed. Treatment consisted of total colectomy with construction of a Koch's pouch. He remained well for 3 years until onset of headache, nausea, and vomiting. Computed tomographic scan disclosed a large, circumscribed, enhancing, right frontoparietal mass. After craniotomy and partial resection, histologic review disclosed anaplastic astrocytoma. He received cranial radiation therapy, 6000 cGy, by parallel opposed ports to the tumor bed, and carmustine 200 mg/m2 intravenously every 8 weeks. Flow cytometric DNA analysis was done on the paraffin-embedded archival material from the patient's normal colon, colonic adenocarcinoma, and anaplastic astrocytoma. DNA histograms revealed diploid distributions in all three samples. The G2/M fraction of the astrocytoma was elevated at 16%, and the S-phase fraction of the colonic adenocarcinoma was 19.4%.

Adenocarcinoma↗
PubMed1993

Tamoxifen modulation of cisplatin resistance in patients with metastatic melanoma. A biologically important observation.

BACKGROUND: Treatment with the four-drug combination of dacarbazine (DTIC), carmustine (BCNU), cisplatin (DDP), and tamoxifen (TAM) has resulted in an overall response rate of more than 50% in patients with metastatic melanoma. Deletion of TAM from the regimen resulted in a decrease in the response rate to 10%, suggesting an important role for TAM. The authors have subsequently demonstrated that TAM is highly synergistic with DDP in a human melanoma cell line, T-289, which supports the clinical observation that TAM is important in this regimen. The authors conducted a clinical trial to determine whether the addition of TAM can overcome established DDP resistance in patients with malignant melanoma. METHODS: Patients with metastatic melanoma were initially treated with DDP 100 mg/m2 alone until they demonstrated DDP resistance. On the next cycle of treatment, patients received TAM 40 mg by mouth four times a day on the day before DDP treatment followed by 20 mg by mouth daily for the rest of the 3-week cycle plus the same dose of DDP. RESULTS: Among 24 patients treated with DDP alone there were one complete and two partial responses. Twenty patients, in whom single-agent DDP failed, were treated with the combination of TAM and DDP. Of these 20 patients, 19 were evaluable for response. Among these 19 patients, there were three partial responses (16%) and three mixed responses (16%), for an overall response rate of 32% (0% was expected) (P < 0.001). If the three mixed responses are eliminated, the statistical significance is of borderline significance (P = 0.058). CONCLUSIONS: The addition of TAM to DDP can overcome established DDP resistance in a subset of patients with metastatic melanoma.

Adult↗
PubMed1994

The impact of conventional plus high dose chemotherapy with autologous bone marrow transplantation on hematologic toxicity during subsequent local-regional radiotherapy for breast cancer.

BACKGROUND: Forty patients with Stage II-III breast cancer with 10 or more positive axillary nodes were treated with mastectomy followed by four cycles of standard dose CAF (cytoxan, Adriamycin, 5-FU), followed by high dose cytoxan, cisplatin, carmustine (HDCT) with autologous bone marrow transplant support (ABMT), and local-regional radiotherapy (LR XRT). During LR XRT, the hematologic toxicity experienced by these patients appeared more severe than that usually seen in patients not heavily pretreated with chemotherapy. Radiation therapy was interrupted in four patients (10%) because of thrombocytopenia and leukopenia. This observation prompted a comparison of the hematologic changes seen in this group with those seen in patients not treated previously with chemotherapy. METHODS: A detailed analysis of changes in hematologic parameters during LR XRT was performed in 33 evaluable patients who received CAF-HDCT/ABMT and compared with a "control" group of 17 women who did not receive prior chemotherapy. RESULTS: The mean pretreatment leukocyte, platelet, and hematocrit counts were lower in the CAF-HDCT/ABMT group than in the control group, with the differences indicating statistical significance for the latter two (P = 0.17, P < 0.001, and P = 0.001, respectively). None of the control patients required a treatment interruption because of hematologic toxicity, whereas four of the CAF-HDCT/ABMT patients did. Among the CAF-HDCT/ABMT patients, a leukocyte count nadir of less than 2.0, a platelet nadir of less than 50,000, and a hematocrit nadir of less than 25 occurred in 12%, 19%, and 9%, respectively. The corresponding rates of control patients were 6%, 0%, and 0%, respectively. Relative to their pretreatment levels, however, both groups experienced similar declines in platelet and leukocyte counts. CONCLUSION: The higher rate of hematologic toxicity observed in the patients who previously received conventional chemotherapy plus HDCT/ABMT appears to have been due primarily to lower preradiotherapy blood counts.

Adenocarcinoma↗
PubMed1995

Survival of infants with malignant astrocytomas. A Report from the Childrens Cancer Group.

BACKGROUND: Very young children with central nervous system malignant brain tumors have a poor prognosis. As compared with older children, survival is less likely, and those children who do survive frequently have severe impairment of growth and cognitive abilities, resulting partly from treatment with radiotherapy. Therefore, an intensive chemotherapeutic regimen was used to treat children younger than 2 years of age with a diagnosis of malignant astrocytomas. PATIENTS AND METHODS: Thirty-nine children younger than 24 months of age who were diagnosed with malignant astrocytoma were treated on a Childrens Cancer Group protocol with an eight-drug chemotherapeutic regimen (vincristine, carmustine, procarbazine, hydroxyurea, cisplatin, cytosine arabinoside, prednisone, and dimethyl-triazenoimidazole-carboxamide) after surgery and postoperative staging. Radiation therapy was to be deferred until the completion of chemotherapy. RESULTS: The objective response rate after two cycles of chemotherapy was 24%. Most patients did not receive radiotherapy. Progression-free survival (PFS) and survival at 3 years was 36% (standard error, 8%) and 51% (8%), respectively. The PFS of those children with anaplastic astrocytoma was 44% (11%), significantly better than that of glioblastoma multiforme (GBM) (0%). Extent of resection was not associated significantly with PFS, but tumors within the cerebral hemispheres were associated with a more favorable prognosis. Tumor progression occurred locally in almost all cases and early in treatment (median PFS, 8 months). CONCLUSION: Chemotherapy appears to be effective primary adjuvant treatment for some very young children with anaplastic astrocytomas. Overall, however, survival remains poor, especially for children with GBM. Strategies to improve outcome require early intervention, because tumor progression occurs soon after diagnosis in the majority of patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

A new preparatory regimen for autologous bone marrow transplantation for patients with lymphoma.

BACKGROUND: This trial studied the feasibility and efficacy of a new preparatory regimen for autologous bone marrow transplantation for patients with advanced lymphoid malignancies. METHODS: Twenty-one patients with Hodgkin's disease (n = 12) and non-Hodgkin's lymphoma (n = 9) were treated in this study. Lomustine was substituted for carmustine) in a dose-escalation study with an initial dose of 6 mg/kg and increasing by 3 mg/kg in groups of four patients. The preparatory regimen consisted of lomustine (6-15 mg/kg) orally on Day -6, etoposide (60 mg/kg) intravenously (i.v.) on Day -4, and cyclophosphamide (100 mg/kg) i.v. on Day -2. Peripheral blood progenitor cells and/or bone marrow were infused on Day 0. RESULTS: Lomustine was well tolerated in all patients with no significant toxicity specific to this drug. Engraftment was prompt: the time to achieving greater than or equal to 500 granulocytes/microliters was 12 days (range, 9-16 days) and the time to achieving greater than or equal to 25,000 platelets/microliters without transfusion support was 16 days (range, 9-22 days). Five patients experienced interstitial pneumonitis, three of whom had active or recent interstitial pneumonitis before bone marrow transplantation, and one who just completed mantle irradiation. Three patients died from this preparatory regimen, one of progressive interstitial pneumonitis, one of Legionella pneumonia, and one of multiorgan failure. Three patients with non-Hodgkin's lymphoma relapsed. Fourteen patients are currently alive and disease free to date. The actuarial are currently alive and disease free to date. The actuarial disease free survival was 57%, with a median follow-up of 23 months (range, 1-48 months). CONCLUSION: The preparatory regimen consisting of lomustine/etoposide/cyclophosphamide is active in treating patients with lymphomas. Further trials with high doses of lomustine are warranted.

Adolescent↗
PubMed1995

Improved long term survival after intracavitary interleukin-2 and lymphokine-activated killer cells for adults with recurrent malignant glioma.

BACKGROUND: The median survival for adults with glioblastoma multiforme (GBM) is 12 months, despite surgery, radiation, and chemotherapy. Regimens using interleukin-2 (IL-2) plus lymphokine-activated killer (LAK) cells have been beneficial against systemic cancers, albeit with significant toxicity. METHODS: Nineteen adults with recurrent malignant glioma (5 GBMs, and 4 anaplastic astrocytomas (AA)), Karnofsky performance status 60 or greater, were treated with intracavitary autologous LAK cells plus IL-2 after reoperation. Lymphokine-activated killer cells and IL-2 were given on day 1, and IL-2 alone was given 5 times during a 2-week cycle. This cycle was repeated at 2 weeks to constitute one 6-week course of therapy. Each two-cycle course of treatment was repeated at 3-month intervals for patients with stable disease or response to therapy. At the conclusion of immunotherapy, all patients were offered chemotherapy, generally carmustine or procarbazine, including responders. Corticosteroids were strictly limited during immunotherapy. Sequential reservoir aspirates were obtained for microbiologic and cytologic analyses. RESULTS: The maximal tolerated dose for a 12-dose course of therapy was 1.2 million international units (MIU) per dose. Dose-limiting, cumulative IL-2-related central nervous system (CNS) toxicity was observed at 2.4 MIU per dose. Three responses were confirmed by computed tomography scan during therapy: one complete response (CR) (1 AA), and two partial responses (PR) (2 GBM); as well as a significant increase in GBM survival. One additional CR (GBM) was observed at 17 months. The median survival for immunotherapy patients with GBM was 53 weeks after reoperation (N = 15) (mean, 87.9 +/- 21.4 weeks, standard error for the mean), with 8 of 15 surviving more than 1 year (53%). The median survival for 18 contemporary patients with GBM reoperated and treated with chemotherapy was 25.5 weeks (mean, 27.4 +/- 3.7 weeks), with 1/18 alive at 1 year (> 6%). Six of the 15 patients with GBM had additional surgery or biopsy, and chemotherapy after immunotherapy. The contribution of subsequent chemotherapy to survival cannot be discounted. CONCLUSIONS: Lymphokine-activated killer cells and IL-2 can be administered safely within the CNS resulting in improved long term survival in patients with recurrent glioblastoma. Increased survival was associated with significant biologic changes characterized by a regional eosinophilia, and extensive lymphocytic infiltration. A prospective randomized clinical trial is warranted.

Adult↗
PubMed2002

Phase I study of fotemustine in pediatric patients with refractory brain tumors.

BACKGROUND: Fotemustine is a nitrosourea with theoretic and preclinical advantages over the original analogs, carmustine and lomustine, in the treatment of brain tumors. This is the first pediatric Phase I study of fotemustine. METHODS: Patients younger than 21 with recurrent/resistant brain tumors were enrolled in a conventional Phase I study. Fotemustine was administered intravenously every 3 weeks at increasing dose levels starting at 100 mg/m(2). Toxicity and response data were monitored closely. RESULTS: Fifteen evaluable patients entered the study and received a total of 45 courses of fotemustine (dose range, 100-175 mg/m(2)). Myelosuppression was observed, with the dose-limiting toxicity being Grade 4 neutropenia and thrombocytopenia. Toxicity was delayed and cumulative. The maximum tolerated dose was 150 mg/m(2) every 3 weeks. There were three documented radiologic responses (20% of patients) comprising one partial response and two minor responses in patients with a sarcoma, medulloblastoma, and ependymoma, respectively. CONCLUSIONS: Fotemustine administered at a dose of 150 mg/m(2) every 3 weeks is well tolerated in children and has antitumor activity in several brain tumors. This is the first dedicated Phase I study of a single agent nitrosourea in a pediatric population. More comparative studies should be undertaken to define the optimum nitrosourea analog for use in children with brain tumors.

Adolescent↗
PubMed2002

Pulmonary complications in survivors of childhood and adolescent cancer. A report from the Childhood Cancer Survivor Study.

BACKGROUND: The Childhood Cancer Survivor Study is a resource that was designed to investigate long-term effects among 5-year survivors of childhood and adolescent malignancies. Previous studies have shown that exposure to chemotherapy and/or radiation can compromise pulmonary function in these survivors of childhood cancer. METHODS: Using information obtained from questionnaires from 12,390 childhood cancer survivors and 3546 randomly selected siblings, the authors evaluated the rate of first occurrence of 15 selected pulmonary conditions in three periods: during therapy, from the end of therapy to 5 years postdiagnosis, and >/= 5 years postdiagnosis. Multivariate analyses were used to determine the relative risks with 95% confidence intervals of reported pulmonary conditions by exposure to the following treatment variables: radiation therapy to the chest, bleomycin, cyclophosphamide, busulfan, lomustine (CCNU), and/or carmustine (BCNU). RESULTS: Compared with siblings, survivors had a statistically significant increased relative risk (RR) of lung fibrosis, recurrent pneumonia, chronic cough, pleurisy, use of supplemental oxygen, abnormal chest wall, exercise-induced shortness of breath, bronchitis, recurrent sinus infection, and tonsillitis for all three periods. During the period of >or= 5 years postdiagnosis, statistically significant associations were present for lung fibrosis and chest radiation (RR, 4.3; P = 0 001); for supplemental oxygen use and chest radiation (RR, 1.8; P < 0.001), BCNU (RR, 1.4; P = 0.05), bleomycin (RR, 1.7; P = 0.001), busulfan (RR, 3.2; P = 0.002), CCNU (RR, 2.1; P < 0.001), and cyclophosphamide (RR, 1.5; P = 0.01); for recurrent pneumonia and chest radiation (RR, 2.2; P = 0.001) and cyclophosphamide (RR, 1.6; P = 0.04); for chronic cough and chest radiation (RR, 2.0; P < 0.001), bleomycin (RR, 1.9; P < 0.001), and cyclophosphamide (RR, 1.3; P = 0.004); and for pleurisy and chest radiation (RR, 1.4; P = 0.02) and busulfan (RR, 5.1; P = 0.02). Chest radiation was associated with a 3.5% cumulative incidence of lung fibrosis at 20 years after diagnosis. CONCLUSIONS: For self-report of pulmonary conditions, treatment-related factors that continue to manifest > 5 years after diagnosis and treatment are important determinants of risk. Continued follow-up of childhood cancer survivors is needed to evaluate the impact of pulmonary conditions on quality of life.

Adolescent↗
PubMed2003

Irinotecan in the treatment of glioma patients: current and future studies of the North Central Cancer Treatment Group.

Other than nitrosoureas (carmustine and lomustine) and temozolomide, no agents have consistently demonstrated clinically meaningful benefits for patients with gliomas. The active metabolite of irinotecan, 7-ethyl-10-hydroxy camptothecin (SN-38), exhibited promising antitumor effects in preclinical glioma models. Clinical trials using weekly or every 3 weeks dosing of irinotecan have been completed. Toxicity consisted primarily of mild to moderate neutropenia and diarrhea with both schedules, with occasional severe toxicity including one death from neutropenia and infection. Preliminary analyses have suggested imaging responses in 10-15% of patients. Preclinical models and our understanding of the mechanism of action suggest that irinotecan may sensitize glioma cells to the cytotoxic actions of radiation therapy and alkylating agents; clinical trials designed to assess the therapeutic benefit of combination therapy currently are in progress. There is substantial clinical evidence that the concurrent administration of irinotecan with certain anticonvulsants produces reduced exposure to SN-38. In the absence of anticonvulsants, there is also substantial interpatient variability in drug exposure, perhaps reflecting inherited differences in drug metabolism. Finally several mechanisms of tumor cell resistance to irinotecan have been hypothesized, but the clinical significance of these observations has not been confirmed. Correlative studies to address these pharmacokinetic, pharmacogenetic, and drug resistance questions are ongoing.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Salvage chemotherapy with cyclophosphamide for recurrent, temozolomide-refractory glioblastoma multiforme.

BACKGROUND: The primary objective of the current prospective Phase II study of cyclophosphamide (CYC) in adult patients with recurrent, temozolomide-refractory glioblastoma multiforme was to evaluate 6-month progression-free survival (PFS). METHODS: Forty patients (28 men and 12 women) ages 28-67 years (median age, 51.5 years), with recurrent glioblastoma multiforme were treated. All patients had been treated previously with surgery and involved-field radiotherapy (median dose, 60 grays [Gy]; range, 59-61 Gy). In addition, all patients were treated adjuvantly with either nitrosourea-based chemotherapy (21 patients: procarbazine, lomustine, and vincristine in 13 patients; carmustine in 8 patients) or temozolomide (19 patients). Twenty-one patients who were treated previously with a nitrosourea were treated with temozolomide at the time of first recurrence. Twenty-one patients were treated with CYC at the time of second recurrence, and 19 patients were treated with CYC at the time of first recurrence. CYC was administered intravenously on 2 consecutive days (750 mg/m2 per day) every 4 weeks (operationally defined as a single cycle). Neurologic and neuroradiographic evaluations were performed every 8 weeks. RESULTS: All patients were evaluable. In total, 170 cycles of CYC (median, 2 cycles; range, 2-12 cycles) were administered. CYC-related toxicity included alopecia in all patients (100%), anemia in 6 patients (3.5%), thrombocytopenia in 7 patients (4.1%), and neutropenia in 9 patients (5.3%). Four patients required transfusions (two required red blood cell transfusion, and two required platelet transfusion). One patient developed neutropenic fever without bacteriologic confirmation. No treatment-related deaths occurred. Seven patients (17.5%; 95% confidence interval [95% CI], 8-33%) exhibited a neuroradiographic partial response, 11 patients (27.5%; 95% CI, 15-44%) had stable disease, and 22 patients (55%) had progressive disease after a single cycle of CYC. The time to tumor progression ranged from 2 months to 18 months (median, 2 months). Survival ranged from 3 months to 24 months (median, 4 months). In patients with either a neuroradiographic response or stable disease (n = 18 [45%]), the median time to tumor progression was 6 months (range, 4-18 months; 95% CI, 6-8 months), and the median survival was 10 months (range, 5-24 months; 95% CI, 8-10 months). The 6-month PFS rate was 20%. CONCLUSIONS: CYC exhibited modest efficacy with acceptable toxicity in the current cohort of adult patients with recurrent glioblastoma multiforme, all of whom had previously experienced treatment failure after temozolomide chemotherapy.

Adult↗
PubMed2026

Multi-Omics Integration Identifies a Five-Gene Metabolic Signature With Experimental Validation in Clear Cell Renal Cell Carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is hallmarked by profound metabolic reprogramming; however, its intricate crosstalk with the tumor immune microenvironment (TIME) and its clinical ramifications remain inadequately elucidated. This study aims to systematically decipher the metabolic-immune interplay in ccRCC through multi-omics integration, with the goal of identifying robust prognostic biomarkers and actionable therapeutic vulnerabilities. AIMS: This study aims to systematically decipher the metabolic-immune interplay in clear cell renal cell carcinoma (ccRCC) through multi&#x2011;omics integration, and to identify robust prognostic biomarkers and actionable therapeutic vulnerabilities that can inform precision risk stratification and individualized treatment strategies. METHODS: We integrated bulk transcriptomic, genomic, and clinical data from multiple ccRCC cohorts. Differential expression and functional enrichment analyses were performed to characterize metabolic pathway alterations. Mendelian randomization (MR) was employed to infer causal relationships between metabolic disorders and ccRCC risk. A machine learning-based prognostic framework, incorporating SHAP (SHapley Additive exPlanations) for feature interpretability, was constructed and rigorously validated. TIME heterogeneity was dissected using deconvolution algorithms, while drug sensitivity, tumor mutation burden (TMB), and TIDE scores were utilized to assess therapeutic responses and immune evasion. Candidate gene function was evaluated through in&#xa0;vitro gain- and loss-of-function assays, with expression validated via TCGA, HPA, western blot, and qRT-PCR. RESULTS: Enrichment analysis identified coordinated dysregulation in lipid metabolism, energy homeostasis, and hypoxia response pathways. MR analysis confirmed lipid metabolism disorders as a causal risk factor for ccRCC. Our machine-learning model, centered on five core SHAP-identified features (SUCLA2, ACAT1, PC, SUCLG1, and HMGCS2), demonstrated superior predictive accuracy over conventional clinical staging. Immune profiling unveiled dichotomous TIME states: the low-risk group retained active immune surveillance, whereas the high-risk group was enriched with immunosuppressive subsets. Drug sensitivity screening pinpointed LY2109761 and carmustine as high-risk-specific candidate agents. Furthermore, TMB and TIDE analyses stratified high-risk patients displaying genomic instability and immune evasion phenotypes. Functionally, SUCLA2 knockdown significantly enhanced ccRCC cell proliferation and invasion, while its overexpression suppressed these malignant phenotypes, corroborating its tumor-suppressive role. Expression patterns of the hub genes were consistently validated across multi-level datasets and experimental assays. CONCLUSION: This study establishes a precision oncology framework for ccRCC by functionally linking metabolic biomarkers, immunophenotypes, and stratified therapeutic strategies. Importantly, we identify SUCLA2 as a potential functional tumor suppressor and a promising target for further mechanistic and translational investigation.

Humans↗
PubMed2002

In vitro and in vivo characterization of graft-versus-tumor responses in melanoma patients after allogeneic peripheral blood stem cell transplantation.

It has been shown that after allogeneic peripheral blood stem cell transplantation (PBSCT), donor T cells can induce potent graft-versus-tumor (GVT) effects in hematologic malignancies and possibly solid tumors such as renal cell carcinoma. Two patients (27 and 30 years old) with metastatic melanoma received allogeneic PBSCT from an HLA-identical sibling donor after reduced conditioning with fludarabine, carmustine and melphalan. One patient showed a delayed mixed response with complete regression of lymph node metastases but persistent liver metastasis at day +60 and +120, consistent with a GVT response. In order to generate donor-derived tumor-reactive cytotoxic T lymphocytes (CTLs), peripheral blood mononuclear cells were stimulated with donor dendritic cells (DCs) loaded with host tumor lysate. Using these culture conditions, a marked increase in CD8(+) CTLs was observed in both donors exhibiting a strong MHC class I-restricted cytotoxic activity against the host tumor without cross-reactivity against nonmalignant host cells. CDR3 spectratyping was used to analyze the complexity of T-cell subpopulations in both CTL lines. Results demonstrate that oligoclonal T cells are expanded in vitro, exhibiting a marked overexpression of TCRVbeta3 (donor 1) and TCRVbeta4/Vbeta11 (donor 2) subfamilies. Functional (ELISPOT assay) and phenotypic (CDR3 spectratyping, sequencing Vbeta transcripts) analysis of patients' T cells at different time points after transplantation demonstrated an expansion of alloreactive T cells with a limited TCR Vbeta pattern. The Vbeta3 cDNA clone, being predominant in the CTL line from donor 1, could not be identified in patient 1 peripheral blood lymphocytes after transplant. Altogether, our results provide the first evidence that GVT effects against melanoma can induce tumor regression and that oligoclonal donor-derived CTLs specific against host tumor cells can be generated in vitro that may be used for adoptive T-cell transfer after allogeneic transplantation.

Adult↗
PubMed1992

Effective combination chemo/hormonal therapy for malignant melanoma: experience with three consecutive trials.

Our experience with the combination of dacarbazine, carmustine, cisplatin with and without tamoxifen is reported. In our initial study, with all 4 drugs, we had an overall response rate of 50% with a complete response rate of 15%. Due to a high incidence of deep venous thrombosis and the lack of effectiveness of tamoxifen as a single agent, we deleted tamoxifen from the regimen and treated another 20 patients. Surprisingly, the response rate decreased to 10%. We then re-incorporated tamoxifen into the regimen and treated 25 additional patients. In this third group of patients we experienced an objective response rate of 52% with a complete response rate of 8%. Overall, 65 patients have been treated: 45 with and 20 without tamoxifen. Twenty-three (51%) patients treated with tamoxifen have responded, with 5 (11%) patients achieving a complete response. Only 2 (10%) patients treated without tamoxifen have responded. Despite the improvement in the response rate, a corresponding increase in survival has not been seen. Patients treated with tamoxifen had a mean survival of 10.8 (SD 13.6) months compared with a mean survival of 9.8 (SD 7.3) months for those treated without tamoxifen. The absence of survival advantage for the tamoxifen-treated patients may be due to early failure in the central nervous system. In 48% of the responding tamoxifen-treated patients, the first site of failure was the central nervous system, while systemic disease was still responding.

Adult↗
PubMed1993

Tamoxifen modulation of cisplatin cytotoxicity in human malignancies.

Recent clinical trials have indicated that addition of tamoxifen (TAM) to a combination of cisplatin (DDP), carmustine and dacarbazine markedly increases the overall objective response rate of patients with metastatic malignant melanoma. Previous studies have determined that there is remarkable synergy between TAM and DDP in a human melanoma cell line T-289. Using the technique of median effect analysis, in clonogenic assay, we observed a highly synergistic interaction between TAM and DDP. To determine whether or not this synergistic interaction was unique to human melanomas, or is generally observed in other types of malignancy, we examined the nature of this interaction using a human ovarian carcinoma and small cell lung cancer cell line. Synergy was observed in both cell lines. In the case of all 3 types of malignancy, synergy was observed at concentrations of both TAM and DDP that can be achieved in patients. Our results demonstrate that cytotoxic synergy between the DDP and TAM is observed in cell lines established from multiple types of human malignancies. It is important to note that the synergy between TAM and DDP is not dependent on the presence of estrogen or progesterone receptors. Since TAM is well tolerated by patients, it is particularly attractive as a potential agent with which to sensitize human tumors to DDP.

Carcinoma, Small Cell↗
PubMed1989

Degradation and disposal of some antineoplastic drugs.

Bulk quantities and pharmaceutical preparations of the antineoplastic drugs carmustine (BCNU), lomustine (CCNU), chlorozotocin, N-[2-chloroethyl]-N'-[2,6-dioxo-3-piperidinyl]-N-nitrosourea (PCNU), methyl CCNU, mechlorethamine, melphalan, chlorambucil, cyclophosphamide, ifosfamide, uracil mustard, and spiromustine may be degraded using nickel-aluminum alloy in KOH solution. The drugs are completely destroyed and only nonmutagenic reaction mixtures are produced. Destruction of cyclophosphamide in tablets requires refluxing in HCl before the nickel-aluminum alloy reduction. Streptozotocin, chlorambucil, and mechlorethamine may be degraded using an excess of saturated sodium bicarbonate solution. The nitrosourea drugs BCNU, CCNU, chlorozotocin, PCNU, methyl CCNU, and streptozotocin were also degraded using hydrogen bromide in glacial acetic acid. The drugs were completely destroyed but some of the reaction mixtures were mutagenic and the products were found to be, in some instances, the corresponding mutagenic, denitrosated compounds.

Acetates↗
PubMed2006

Proteomic analysis reveals higher demand for antioxidant protection in embryonic stem cell-derived smooth muscle cells.

Embryonic stem (ES) cells can differentiate into vascular smooth muscle cells (SMCs), but differences in protein composition, function and behaviour between stem cell-derived and mature SMCs remain to be characterized. Using differential in gel electrophoresis (DIGE) and MS, we identified 146 proteins that differed between ES cell-derived SMCs (esSMCs) and aortic SMCs, including proteins involved in DNA maintenance (higher in esSMCs), cytoskeletal proteins and calcium-binding proteins (higher in aortic SMCs). Notably, esSMCs showed decreased expression of mitochondrial, but a compensatory increase of cytosolic antioxidants. Subsequent experiments revealed that mitochondrial-derived reactive oxygen species (ROS) were markedly increased in esSMCs. Despite a three-fold rise in glutathione (GSH) reductase activity, esSMCs had lower levels of reduced GSH, and depletion of GSH by diethyl maleate or inhibition of GSH reductase by carmustine (BCNU) resulted in more pronounced cell death compared to aortic SMCs, while addition of antioxidants improved the viability of esSMCs. We present the first proteomic analysis of esSMCs demonstrating that stem cell-derived SMCs are more sensitive to oxidative stress due to increased generation of mitochondrial-derived ROS and require additional antioxidant protection for survival.

Animals↗
PubMed1997

Chemotherapy for metastatic melanoma during pregnancy.

Melanoma during pregnancy represents a difficult problem. Although surgery is a definitive therapy for early-stage disease, rapidly progressive metastatic disease in pregnancy requires a series of more difficult decisions. We report the use of combination chemotherapy with tamoxifen, carmustine, dacarbazine, and cisplatin in a patient with metastatic melanoma during the second trimester of pregnancy. The patient received 2 cycles of chemotherapy prior to delivery of a healthy 1520-g baby girl at 30 weeks gestation. Placental pathology, however, revealed malignant melanoma in the intervillous space and melanin pigment granules in villous Hofbauer cells and synctial trophoblasts. This report also reviews the literature, assessing the importance of pregnancy as a prognostic factor, the effects of metastasis on the products of conception, and the use of chemotherapy in pregnancy. We conclude that combination chemotherapy can be administered in the second trimester of pregnancy for the treatment of rapidly progressive melanoma without interfering with the successful maturation and delivery of an infant of 30 weeks gestation.

Adult↗
PubMed1996

An in vitro study of m-dinitrobenzene toxicity on the cellular components of the blood-brain barrier, astrocytes and endothelial cells.

We have studied the effects of an industrial compound, m-dinitrobenzene (DNB), on cultured astrocytes and brain capillary endothelial cells in an in vitro blood-brain barrier (BBB) model. In single cultures, the threshold DNB concentration that induced cell death, as assessed by morphology and lactose dehydrogenase leakage into the culture medium, was 1 mM for both cell types after 1 day of incubation. In cocultures, astrocytes showed a dose-response curve similar to that obtained in single cultures, while endothelial cells showed an increased sensitivity to DNB cytotoxicity. DNB induced a dose-dependent increase in glucose consumption and lactate production in both cell types in single cultures, although astrocytes appeared to be more sensitive than endothelial cells. The role of oxidative stress was also studied using the reduction of nitroblue tetrazolium as an index of generation of active oxygen species. A dose-dependent increase was observed for both cell types in single cultures, although this could not be prevented by the addition of superoxide dismutase to the culture medium. Addition of 0.3 mM carmustine to the culture medium increased the cytotoxicity of 0.5 mM DNB in both astrocytes and endothelial cells, indicating a role of oxidative stress in DNB-induced damage. Desferrioxamine (20 mm) completely protected endothelial cells from damage by 1 mM DNB, suggesting that hydroxyl radicals mediated at least part of the DNB neurotoxicity. However, astrocytic damage by 2 mM DNB was only partially prevented by desferrioxamine. We conclude that our in vitro model is suitable for studying interactions between astrocytes and endothelial cells in toxicological situations.

Analysis of Variance↗