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M A Carducci

Publications and source records attributed to M A Carducci.

29 records · Page 2Linked to original sources
PubMed1998

Impaired expression and function of signal-transducing zeta chains in peripheral T cells and natural killer cells in patients with prostate cancer.

Detection of functional, circulating T cells and NK cells may serve as a clinical test for the selection of individuals who can benefit from immunotherapy. Incidence of the T-cell receptor zeta (TCRdelta) chain within these populations appears to correlate with adequate effector cell function. In patients with advanced malignancy, the absence or reduced expression of delta chain has been documented. Flow cytometric analysis in the present study revealed a significant reduction in delta chain expression in peripheral blood lymphocytes (PBL) of 14 of 22 prostate cancer patients (P < 0.000001) as compared to normal donors, apparent in both T cells (CD3+, CD4+, CD8+), and NK (CD16+) cells. Compared to normal donor PBL, patient PBL cultured in the presence of CD3 and CD28, also demonstrated reduced expression of CD69 and/or CD25, and in some cases, failed to activate at all. Furthermore, evidence of cell proliferation in activation-stimulated patient PBL was muted: average PCNA positivity equaled 14%, a marked difference from what was observed in normal donors (P < 0.0002). In 8 of 16 samples of PBL, where delta expression was originally low, delta levels returned to the normal range after 48 hour culture in serum-free medium, suggesting that the loss of delta is reversible and may be caused by a tumor-derived substance. These data support the premise that monitoring the expression of delta in a cancer patient may provide a unique insight into the immune status and functionality of the individual, with the potential to redirect or augment therapies and ultimately alter prognosis.

Adult↗
PubMed1998

Cytotoxic effects of sodium phenylbutyrate on human neuroblastoma cell lines.

Sodium phenylbutyrate (NaPB) is used in urea cycle disorders. We screened 6 neuroblastoma cell lines for in vitro potency of NaPB as an antiproliferative agent, evaluated multiple dosing schedules, and assessed its activity in combination with clinically active agents for neuroblastoma. We determined that NaPB achieves a 30-80% growth inhibition at 5 mM. Repeated dosing and prolonged drug exposure enhanced the cytotoxic effect. NaPB had additive cytotoxic effects when administered with vincristine; however, NaPB did not affect the activity of etoposide, adriamycin, 4-hydroxycyclophosphamide or cisplatinum. These results suggest that NaPB is an active agent against neuroblastoma and could be combined with vincristine in novel chemotherapy regimens.

Antineoplastic Agents↗
PubMed1997

Bioactivity of autologous irradiated renal cell carcinoma vaccines generated by ex vivo granulocyte-macrophage colony-stimulating factor gene transfer.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced, irradiated tumor vaccines induce potent, T-cell-mediated antitumor immune responses in preclinical models. We report the initial results of a Phase I trial evaluating this strategy for safety and the induction of immune responses in patients with metastatic renal cell carcinoma (RCC). Patients were treated in a randomized, double-blind dose-escalation study with equivalent doses of autologous, irradiated RCC vaccine cells with or without ex vivo human GM-CSF gene transfer. The replication-defective retroviral vector MFG was used for GM-CSF gene transfer. No dose-limiting toxicities were encountered in 16 fully evaluable patients. GM-CSF gene-transduced vaccines were equivalent in toxicity to nontransduced vaccines up to the feasible limits of autologous tumor vaccine yield. No evidence of autoimmune disease was observed. Biopsies of intradermal sites of injection with GM-CSF gene-transduced vaccines contained distinctive macrophage, dendritic cell, eosinophil, neutrophil, and T-cell infiltrates similar to those observed in preclinical models of efficacy. Histological analysis of delayed-type hypersensitivity responses in patients vaccinated with GM-CSF-transduced vaccines demonstrated an intense eosinophil infiltrate that was not observed in patients who received nontransduced vaccines. An objective partial response was observed in a patient treated with GM-CSF gene-transduced vaccine who displayed the largest delayed-type hypersensitivity conversion. No replication-competent retrovirus was detected in vaccinated patients. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous GM-CSF gene-transduced tumor vaccine for RCC patients.

Adult↗
PubMed1996

Early evaluation of abdominal/hepatic irradiation and 5-fluorouracil/leucovorin infusion after pancreaticoduodenectomy.

PURPOSE: To describe the toxicities of a combined modality adjuvant regimen for patients with resectable periampullary adenocarcinoma. METHODS AND MATERIALS: Fourteen patients with surgically resected periampullary adenocarcinoma were treated with adjuvant therapy consisting of prophylactic hepatic irradiation and pancreatic bed irradiation and concurrent infusional 5-fluorouracil and leucovorin (5-FU/LV). Starting within 60 days of surgery, patients received radiation treatments of 1.8 Gy per fraction to the liver and pancreatic bed (13 fractions), followed by 1.8 Gy per fraction to the pancreatic region (15 fractions). All radiation treatments were given with infusional 5-FU (200 mg/m2/day) and leucovorin (5 mg/m2/day) for 5 out of every 7 days during the 38-day treatment sequence. After a 1-month break, patients were scheduled to receive four cycles of infusional 5-FU/LV (2 weeks on/2 weeks off). RESULTS: All 14 patients completed the initial combination treatment. Toxicities were tolerable; three patients had Grade 3/4 toxicities that were primarily gastrointestinal in nature. Six patients required hospitalization during therapy for treatment-related toxicities. Two patients required radiation treatment breaks of less than 1 week, and two others had radiation held for 2-4 weeks. Three patients required chemotherapy dose reductions secondary to toxicities. Toxicities in the subsequent chemotherapy-alone cycles were few and primarily manifested by Grade 2 rises in liver injury tests. Higher toxicity grades were associated with tumor progression. Twelve patients have developed recurrent disease with an equal number of recurrences occurring in the pancreatic bed as in the liver over the 12-month median follow-up. Median survival for this cohort is 417 days, not significantly different from previously reported adjuvant trials in this patient population. CONCLUSION: These data indicate that adjuvant therapy with concomitant large-field radiation and infusional chemotherapy is feasible and associated with mangeable toxicities in patients undergoing pancreaticoduodenectomy for periampullary adenocarcinoma. Improvement in survival over other adjuvant regimens has not thus far been observed. Modification of this strategy may be required.

Adenocarcinoma↗
PubMed1996

Prostate cancer treatment strategies based on tumor-specific biological principles: future directions.

Prostate cancer represents a heterogeneous disease entity with varying degrees of behavior, aggressiveness, patterns of metastasis, and response to therapy. Progressive metastatic prostate cancer is associated with a formidable array of morbidity that ultimately contributes to death of the patient. Thus far, there has been no convincing evidence to support routine use of non-hormonal chemotherapeutic agents or combinations over symptomatic treatment only. Furthermore, no single compound or combination has shown a dramatic improvement in conventional quality of life parameters over symptomatic treatment only. Androgen ablation remains the primary systemic therapeutic modality for this disease, yet the intense delineation of mechanisms involved in tumor cell metastasis has lead to new therapeutic strategies, ranging from cytotoxic to cytostatic, including immunomodulators. Among those strategies currently being studied are granulocyte-macrophage colony-stimulating factor-transduced prostate cancer vaccines, differentiation therapy, gene therapy, inducers of apoptosis, antimetastatic agents, angiogenesis inhibitors, radiation therapy (local and systemic), and systemic approaches targeted at prostate cancer morbidity. The difficult issue is which agents should be developed and how should we best assess the response using standard and newly identified endpoints. Certainly, the future of advanced prostate cancer therapy will undergo dramatic changes as a result of the continued interaction between the laboratory and the clinic.

Antineoplastic Agents↗
PubMed1996

Phenylbutyrate induces apoptosis in human prostate cancer and is more potent than phenylacetate.

Phenylbutyrate (PB), a novel lead compound for prostate cancer therapy, has molecular activities distinct from its metabolite, phenylacetate (PA). Both PB and PA promote differentiation in human prostate cancer cell lines, yet little data exist comparing the cytotoxic effects of each drug. We found that PB is more potent than PA in vitro; PB is 1.5-2.5 times more active at inhibiting growth and inducing programmed cell death than PA at clinically achievable doses against each human prostate cancer line studied. PB is equipotent to sodium butyrate, which induces apoptosis and differentiation through multiple mechanisms. Exposure of prostate cancer cell lines to PB reduces their DNA synthesis, leads to fragmentation of genomic DNA, and causes 50-60% of cells to undergo apoptosis. These PB-induced effects are 2-10 times greater than those of the control or PA. The stereotypical changes of apoptosis can be seen with sodium butyrate at similar concentrations, but not with PA. Prostate cancer cell lines overexpressing P-glycoprotein or possessing heterogeneous molecular alterations, including p53 mutations, are also sensitive to the effects of PB. In vivo, Copenhagen rats treated with oral PB had delayed growth of the androgen refractory Dunning R-3327 MAT-LyLu prostate cancer subline by 30-45% in a dose-dependent manner. These results demonstrate that PB induces cytotoxicity via apoptosis in human prostate cancer, in addition to its differentiating properties.

Animals↗
PubMed1995

Interleukin-6: a candidate mediator of human prostate cancer morbidity.

OBJECTIVES: Interleukin-6 (IL-6) is evaluated as a candidate mediator of morbidity in patients with metastatic adenocarcinoma of the prostate. METHODS: IL-6 concentration is measured by enzyme-linked immunoadsorbent assay (ELISA) in the ejaculate plasma of healthy men, in primary culture of prostate epithelial cells, in human prostate cancer cell line cultures and SCID mouse xenografts, and in the plasma of 73 men with metastatic adenocarcinoma of the prostate. RESULTS: High levels of IL-6 secretion are found in the normal human ejaculate, in prostate epithelial primary culture, and in three of four anaplastic, androgen-independent human prostate cancer cell lines tested. In contrast, the hormone-responsive and PSA-secreting cell lines and the hormone-independent line PPC-1 do not secrete detectable levels of IL-6 by ELISA: The acquisition of a p53 mutation in LNCaP-GW and PPC-1 is not sufficient to confer the phenotype of high IL-6 secretion. Seventy-three men with well-characterized, advanced, hormone refractory prostate cancer prior to suramin therapy are tested for incidence of abnormal circulating levels of IL-6. Plasma IL-6 levels have a bimodal distribution, with the upper quartile of patients having abnormal levels from 9 to 61 pg/mL. A direct comparison of the high and low serum IL-6 groups show that elevated IL-6 levels are strongly correlated with objective measures of morbidity: decreased hematocrit, hemoglobin, and serum cholesterol, and increased white blood cell count and serum lactate dehydrogenase levels all in the absence of clinical infection. CONCLUSIONS: These data show that IL-6 is a prostate exocrine gene product, a candidate mediator of prostate cancer morbidity, and a candidate marker of disease activity for prospective clinical testing.

Adenocarcinoma↗
PubMedDate not supplied

Allopurinol-induced pyrimidinuria in cancer patients.

Allopurinol induced pyrimidinuria is a sensitive and specific test that identifies the increased de novo pyrimidine mononucleotide biosynthesis accompanying ornithine trans carbamylase deficiency. We hypothesize that the increased de novo DNA synthesis characteristic of malignant tumors can be detected using this method. Eleven cancer patients and a 30 subject control group were studied. The allopurinol test protocol consists of five urine collection periods--a baseline collection after which time a 300 mg dose of allopurinol is taken, followed by collection of four 6 hour fractional urine collections. Orotate, orotidine and creatinine were measured on the samples. Eight of 11 patients had significantly elevated urine levels of either orotate or orotidine either prior to challenge with allopurinol or during one of the time periods. The allopurinol test for this unstratified group has a sensitivity of 0.73 and a specificity of 1.0. This observational and preliminary report suggest that further study of the potential significance and usefulness of the allopurinol test in patients at risk for or with malignancy is warranted.

Acidosis↗