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L Pusztai

Publications and source records attributed to L Pusztai.

At least 37 records · Page 2Linked to original sources
PubMed1998

High-dose chemotherapy: how resistant is breast cancer?

This report reviews clinical experience with high-dose chemotherapy with stem-cell support in breast cancer and attempts to integrate clinical and molecular biological observations into a model of drug resistance. Despite the remarkable initial chemosensitivity of breast cancer, the majority of patients with advanced breast cancer die of their disease. In trials to date, high-dose chemotherapy has not been able to overcome primary drug resistance and patients with disease progression during induction therapy benefit little from further high-dose therapy. On the other hand, high-dose chemotherapy produces improved objective response rates compared with standard-dose chemotherapy due to converting some partial responses achieved by standard-dose induction therapy to complete response. This suggests that high-dose chemotherapy may overcome partial clinical drug resistance and may result in a more complete elimination of chemosensitive cells. Whether increased complete response rates will translate into higher cure rates and increased overall survival remains to be unequivocally demonstrated. There are multiple clinical patterns of drug failure including continued growth during chemotherapy, partial response followed by a period of stable disease, initial complete response with subsequent recurrence within a few months or after several years. Different mechanisms of drug resistance may operate at different stages of the disease and predispose patients to different clinical patterns of failure. A model of clonal progression of cancer is proposed that could explain several intriguing features of clinical drug resistance. We hypothesize that drug-sensitivity is an acquired characteristic of neoplastic cells and that a 'physiological drug-resistant' state may precede drug sensitivity at early stages of neoplastic transformation. Some recurrences may, in this context, represent progression of physiologically drug-resistant clones to sensitivity and subsequently to 'pathologic resistance' to chemotherapy. Optimal therapy to delay or prevent recurrence may differ depending on the stage and biology of the tumor and may include combinations of cytotoxic drugs and chemopreventive agents to arrest progression of early physiologically drug-resistant neoplastic stem cells.

Journal Article↗
PubMed1998

Physiologic and pathologic drug resistance in ovarian carcinoma--a hypothesis based on a clonal progression model.

Conventional models for successful chemotherapy suggest that early-stage ovarian cancer should be more responsive to cytotoxic drugs than advanced disease, that multiple drugs will prove more efficacious than single agents and that more intensive chemotherapy will prove superior to conventional doses. The purpose of numerous clinical studies has been to test these predictions and the results often fall short of the expectations. In trials to date, adjuvant chemotherapy for high-risk, early-stage ovarian cancer has provided only a modest, equivocal increase in disease-free survival. Combination chemotherapy produces higher response rates but this has not consistently resulted in prolonged survival. Dose intensification with high-dose chemotherapy increases rate of response further, but most responses are of short duration. The objective of this review is to integrate clinical and molecular biological observations into a novel model of drug resistance. We hypothesize that drug sensitivity is an acquired characteristic of neoplastic cells, and that there are two broad cellular forms of resistance to cytotoxic drugs. 'Physiological drug resistance' is a cellular state when drug sensitivity of cancer cells is similar to that of the corresponding normal tissue. This form of drug resistance can precede the acquisition of drug sensitivity and may be predominant in the early stages of neoplastic progression. A distinct, 'pathological drug resistance' can reappear later during tumor progression or during chemotherapy as a result of increased detoxification, upregulation of repair pathways or defective apoptosis. Tumors are formed of heterogeneous cell populations and in terms of drug sensitivity three distinct cell types may be present: drug-sensitive, physiologically drug-resistant and pathologically drug-resistant. Clinical response to chemotherapy is determined by the relative contribution of these different cell populations to the total cellular mass. Depending on the predominant type of surviving population, distinct patterns of clinical failure may develop that require different treatment strategies for optimal management. For chemosensitive cells that survived insufficient chemotherapy, consolidation with further, perhaps, high-dose chemotherapy is a rational option. For pathologically drug-resistant cells, pharmacological manipulation of drug resistance, and signaling pathways in combination with chemotherapy could be exploited. For physiologically drug-resistant cells, non-chemotherapy-based, 'chemopreventive' strategies to arrest tumor progression may prove beneficial.

Apoptosis↗
PubMed1998

Coexpression of the HER-2 gene product, p185HER-2, and epidermal growth factor receptor, p170EGF-R, on epithelial ovarian cancers and normal tissues.

Monoclonal antibodies (MAbs) and immunoconjugates reactive with different antigens expressed by neoplastic cells can inhibit tumor growth. Use of these agents in combination with one another or with chemotherapy can exert additive or synergistic cytotoxicity against tumor cells. An augmented therapeutic activity with favorable therapeutic index might be attained when coexpression is observed on tumor cells, but not in normal tissues. In this study frozen sections of 19 ovarian cancers (2 stage I, 10 stage III, 2 stage IV, and 5 recurrent), as well as 29 normal tissues, were evaluated by immunohistochemistry using 11 distinct MAbs against HER-2/p185 and 2 antibodies against EGF-R/p170 to assess coexpression of these receptors. HER-2/p185 expression was detected in 5 to 100% of ovarian cancers and 0 to 50% of normal ovarian epithelia, depending on the antibody used. EGF-R/p170 expression was detected in approximately 70% of cancers and 40% of normal ovaries by both antibodies. Coexpression of p185 and p170 was observed in 47-68% of ovarian cancers and 9-18% of normal ovarian epithelial specimens depending upon the combination of antibodies used. Staining of 273 specimens from 29 normal tissues indicated that coexpression of HER-2 and EGF-R is rare. Normal tissues that coexpressed both receptors in > or =50% of the cases included cervix, endometrium, esophagus, skin, and prostate. These data confirm that HER-2 and EGF-R are more frequently expressed in advanced ovarian cancers than in normal ovarian epithelium and a significant fraction of these tumors coexpress both HER-2 and EGF-R.

Antibodies, Monoclonal↗
PubMed1998

Daily oral etoposide in patients with heavily pretreated metastatic breast cancer.

The objective of this phase II study was to evaluate the activity and toxicity of oral etoposide (50 mg/m2 daily for 21 days in 28-day cycles) in patients with heavily pretreated metastatic breast cancer. Thirty patients were entered into the study; all had clinical or radiologic evidence of disease progression, median age was 51 years, and the majority of patients (82%) had a Zubrod performance status equal to or lower than 1 and a median of 3 disease sites. All patients had received chemotherapy, and more than 80% had received 3 or more regimens. More than 70% of the patients had received taxanes as one of their previous therapies. Twenty-four and 28 patients were evaluable for tumor response and toxicity, respectively. One partial response was seen (<4%), and seven patients (25%) demonstrated stable disease with a median duration of four months. There was significant hematologic toxicity. In two patients therapy had to be stopped because of excessive toxicity, and five patients required hospitalization for neutropenic fever. Overall, 57% of patients experienced grade 2 or higher degree of neutropenia including two patients with grade 4 toxicity. Seventeen percent of patients developed grade 2 or greater thrombocytopenia, including one patient who experienced grade 4 toxicity, and 71% of the patients had grade 2 or more severe anemia including two patients with grade 4 toxicity. Oral etoposide has limited activity as third- or fourth-line agent and produces significant hematologic toxicity in patients with heavily pretreated metastatic breast cancer.

Administration, Oral↗
PubMed1998

Coincident renal cell carcinoma and nonHodgkin's lymphoma: the M. D. Anderson experience and review of the literature.

PURPOSE: We recently observed nonHodgkin's lymphoma and renal cell carcinoma occurring simultaneously in several patients. We determine whether the incidence of co-occurrence of the 2 malignancies is greater than expected based on the incidence of each disease in the general population. MATERIALS AND METHODS: Patients diagnosed with simultaneous renal cell carcinoma and nonHodgkin's lymphoma were identified through the medical informatics data base at our cancer center. Charts of all patients were reviewed to collect detailed demographic information and confirm both diagnoses. United States population based cancer statistics (Surveillance, Epidemiology and End Results Program data) were used to arrive at the expected age adjusted incidence of co-occurrence of these diagnoses, and statistical analysis was performed to ascertain any differences between expected and observed incidences. RESULTS: We identified 41 cases with both diagnoses between 1954 and 1995, including 21 diagnosed after 1987. The latter group was used for statistical analysis. The observed rates of renal cell carcinoma developing in the nonHodgkin's lymphoma population (1.86) and nonHodgkin's lymphoma developing in the renal cell carcinoma population (2.67) were greater than expected and both reached statistical significance. CONCLUSIONS: There is a higher than expected incidence of co-occurrence of renal cell carcinoma and nonHodgkin's lymphoma. The cause remains speculative.

Carcinoma, Renal Cell↗
PubMed1998

Cell surface density of p185(c-erbB-2) determines susceptibility to anti-p185(c-erbB-2)-ricin A chain (RTA) immunotoxin therapy alone and in combination with anti-p170(EGFR)-RTA in ovarian cancer cells.

Approximately 30% of ovarian and breast cancers overexpress p185(c-erbB-2) with as many as 10(6) receptors/cell. Normal cells have as few as 10(4) receptors/cell. We have examined the susceptibility of SKOv3 human ovarian cancer cells to anti-c-erbB2 antibodies and immunotoxins as a function of c-erbB-2 density on the cell surface. A panel of SKOv3 clones that expressed different densities of p185(c-erbB-2) receptor were generated through transfection with the c-erbB-2 gene. A significant correlation was found between p185(c-erbB-2) density and susceptibility to killing by anti-p185(c-erbB-2)-ricin A chain (anti-p185(c-erbB-2)-RTA) immunotoxins. With 10(5) copies/cell of p185(c-erbB-2), <10% of clonogenic ovarian cancer cells could be eliminated, whereas in clones that expressed 10(6) copies/cell of p185(c-erbB-2), 99.9% of clonogenic tumor cells were killed. In cell lines that overexpressed p185(c-erbB-2) and also expressed p170(EGFR), anti-p185(cerbB-2)-RTA and anti-p170(EGFR)-RTA immunotoxins exerted synergistic cytotoxicity. Treatment with the two immunotoxins could eliminate 99.99% of clonogenic cells. Importantly, tumor cells that had survived first treatment with anti-p185(c-erbB2)-RTA alone still retained sensitivity to repeat treatment with the same immunotoxin and also proved susceptible to the synergistic cytotoxicity of anti-p185(cerbB-2)-RTA in combination with anti-p170(EGFR)-RTA. Growth characteristics of the clones expressing various levels of p185(c-erbB-2) were also studied. No correlation was found between p185(c-erbB-2) expression levels and the rate of anchorage-dependent growth, anchorage-independent growth, or in vivo growth in nude mice.

Animals↗
PubMed1994

Expression of tumour necrosis factor alpha and its receptors in carcinoma of the breast.

The expression of tumour necrosis factor alpha (TNF-alpha) and its two distinct receptors, TNF-R p55 and TNF-R p75, was assessed by immunocytochemistry in 28 primary breast cancer and three reduction mammoplasty specimens ('normal' breast tissue). Expression of TNF-alpha or TNF-R p75 was not detectable in normal breast tissue or in non-malignant breast tissue adjacent to the tumours. By contrast, TNF-R p55 was expressed by occasional stromal cells in normal tissue. TNF-alpha was expressed focally in 50% of the tumours studied, being largely localised to macrophage-like cells in the stroma. TNF-R p55 was expressed by a population of stromal cells in all the tumours examined, and a varying proportion of neoplastic cells in 75% of these tissues. TNF-R p75 was detected in about 70% of the tumours, immunoreactivity being confined mainly to cells in the stroma. In this preliminary study there was no association between the above cytokine parameters and such measures of tumour biology as lymph node status, tumour grade, proliferative activity or degree of angiogenesis. However, there was a correlation between the expression of TNF-R p55 by blood vessels and the number of leucocytes present.

Biopsy↗
PubMed1993

Growth factors: regulation of normal and neoplastic growth.

This paper presents an overview of current trends in growth factor research. The first part of the review considers the current classification of growth factors and their receptors. A model of cell proliferation regulation by growth factors is then presented. The final section reviews the latest concepts of the involvement of growth factors in the development of neoplasia.

Cell Division↗
PubMed1993

Epidermal growth factor, insulin-like growth factor-1 and basic fibroblast growth factor modulate the cytostatic effect of tumour necrosis factor-alpha on the breast cancer cell line, T47D.

The effect of epidermal growth factor (EGF), basic fibroblast growth factor (bFGF) and insulin-like growth factor-1 (IGF-1) on the cytostatic activity of tumour necrosis factor-alpha (TNF-alpha) was studied on the breast cancer cell line, T47D. TNF-alpha completely blocked the potent growth-promoting activity of all three factors on T47D cells. EGF, bFGF and IGF-1 partially antagonized the inhibition of cell growth and thymidine incorporation induced by TNF-alpha. These data suggest that the growth of these breast cancer cells is regulated, in part, by the antagonistic interaction between the cytostatic effect of TNF-alpha and the growth-promoting activity of factors such as EGF, IGF-1 and bFGF.

Breast Neoplasms↗
PubMed1993

Growth arrest of the breast cancer cell line, T47D, by TNF alpha; cell cycle specificity and signal transduction.

The effects of tumour necrosis factor-alpha (TNF alpha) on the growth and DNA synthesis of the human breast cell line, T47D, were studied. A dose-dependent, reversible inhibition of thymidine incorporation and cell growth was observed in the range of 0.1 ng ml-1 to 100 ng ml-1 of TNF alpha. Cell viability was not impaired in any of the experiments. Flow-cytometric DNA analysis demonstrated that after 24 h exposure to TNF alpha, T47D cells accumulated in the G1 phase of the cell cycle, and were depleted in the G2/M and S phases, suggesting a block in the progression of the G1/S transition. The involvement of protein kinases (PK) and protein phosphatases in TNF alpha-induced signal transduction was also investigated. A transient and rapid 2-fold increase in total cellular protein kinase C (PKC) activity was detected after 10 min exposure to TNF alpha. To study the role of the observed PKC activation in the cytostatic effect of TNF alpha, T47D cells were exposed to the cytokine in the presence of the potent PKC inhibitor, H7. The inhibitory effect of TNF alpha on thymidine incorporation was not affected by exposure to H7 at concentrations sufficient to block the stimulation of thymidine up-take induced by the PKC agonist, phorbol-12-myristate-13-acetate (PMA). The involvement of other signalling pathways was addressed using the cyclic nucleotide-dependent PK inhibitor, H8; the calmodulin-dependent PK inhibitor, W7; and the inhibitor of protein phosphatases PP1 and PP2B, okadaic acid. Exposure of T47D cells to these enzyme inhibitors failed to antagonise the inhibition of thymidine incorporation by TNF alpha. Taken together, these results indicate that the cytostatic effect of TNF alpha on T47D cells occurs at the G1/S transition of the cell cycle, and is mediated by an intracellular pathway which does not involve the activity of protein kinases C and A, nor protein phosphatases PP1, PP2B.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗