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PubMed2000

Clinical relevance of the lung resistance protein in diffuse large B-cell lymphomas.

Drug resistance of non-Hodgkin's lymphomas may involve mechanisms of the multidrug resistance phenotype including the lung resistance protein (LRP) and the multidrug resistance protein (MRP1). To determine the clinical relevance of these multidrug resistance factors in previously untreated diffuse large B-cell lymphomas (n = 48), we studied LRP and MRP1 expression in lymphoma cells and their impact on clinical outcome. LRP and MRP1 expression were immunohistochemically assessed by means of the monoclonal antibodies LRP-56 and MRPr1, respectively. LRP was positive in 23% and MRP1 in 44% of the samples. LRP expression was associated with higher tumor stage (P = 0.03), elevated serum lactate dehydrogenase levels (P = 0.01), and the International Prognostic Index (P = 0.0001). LRP-positive patients had a lower complete response rate to polychemotherapy than LRP-negative patients (18 versus 65%; P = 0.006). Patients with LRP expression had a shorter overall survival than those without LRP expression (median of 0.9 years versus median not reached; P = 0.001). MRP1 expression was independent of clinical and laboratory parameters and had no impact on the outcome of chemotherapy or survival of the patients. These data suggest that LRP expression but not MRP1 expression is an important mechanism of drug resistance associated with worse clinical outcome in previously untreated diffuse large B-cell lymphomas. Thus, the reversal of LRP-mediated drug resistance may improve clinical outcome in diffuse large B-cell lymphoma in the future.

ATP-Binding Cassette Transporters↗
PubMed2002

[Pharmacological aspects in the development of liposomal medicinal preparations for the internal injection of hydrophobic cytostatics].

To improve the action and selectivity of new drugs on tumor cells and the use of currently available pharmaceutical technologies to develop the systems of controlled transport of well-known antitumor compounds is one of the ways of enhancing the efficiency of drug therapy for tumors. The tropicity of steroid hormones to definite organs and tissues makes it possible to use them as specific messengers of alkylating groups to target tissues and tumors. Hormone cytostatics synthesized by this principle have a double mechanism of hormonal and cytotoxic actions. The original Russian water-insoluble hormone cytostatistics testifenon, kortifen, and cytestrol acetate demonstrated local tissue irritation together with high antitumor activity. No rational dosage forms make it possible to conduct clinical trials by parenteral administration. The aim of this paper is to summarize the authors' results of designing hydrophobic antitumor hormone cytostatics. The advantages and disadvantages of different approaches to designing traditional dosage forms and to applying colloid liposomal systems for intravenous administration of water-insoluble agents are shown.

Antineoplastic Agents, Alkylating↗
PubMed1991

Metallothionein expression and transient resistance to electrophilic antineoplastic drugs.

Intrinsic and acquired resistance to antineoplastic agents remains an important impediment to cancer therapy. Intracellular metallothioneins appear to be one factor in determining the responsiveness of malignant and normal cells to electrophilic anticancer agents. Metallothioneins are not only constitutively expressed but their expression can be transcriptionally activated by a host of endogenous and exogenous substances; this is a reversible phenomenon. This inducibility affords the possibility that cells can respond quickly to toxic substances and that under certain conditions transient drug resistance may occur. We review the evidence implicating metallothioneins in anticancer drug resistance and discuss this in the context of the possibility of transient resistance.

Animals↗
PubMed1984

Chemotherapy of hormonally unresponsive prostatic carcinoma.

The national Prostatic Cancer Project has evaluated single and combination chemotherapeutic agents for the treatment of patients with advanced prostatic cancer that has been unresponsive to hormonal therapy. Although regression rates have been modest, a number of drugs have shown some efficacy and are now undergoing testing in combination. Current trials of the LH-RH agonists and the antiandrogen flutamide are in progress. These trials have demonstrated a role for chemotherapy in the treatment of the patient who has failed hormonal therapy.

Antineoplastic Agents↗
PubMedDate not supplied

Bulky mediastinal Hodgkin's disease: results of a combined modality approach (ABVD/MOPP alternating chemotherapy plus radiation therapy).

BACKGROUND: Bulky mediastinal involvement is a challenging presentation of Hodgkin's disease (HD). Radiotherapy alone has provided a good response rate but also a high percentage of recurrences, and therefore many studies have been initiated to evaluate combined modality treatment. METHOD: In a prospective study 23 stage IIA/IIIB HD patients treated with ABVD/MOPP alternating chemotherapy and radiotherapy were evaluated with regard to overall (OS) and disease-free survival (DFS), acute and long-term toxicity. RESULTS: A 95% CR rate was obtained. Ten-year actuarial OS and DFS were 83 and 91%, respectively. Two patients (8.8%) relapsed 8 and 9 months after achieving CR. One patient (4.4%) died following severe bone marrow failure 25 months after diagnosis. No clinically evident acute or chronic cardiac or pulmonary toxicity was evident, and no second malignancies were observed. At the end of therapy 7/14 evaluable women became amenorrheal and remained so at their last follow-up. Two male patients were considered azoospermic on the basis of laboratory evaluation at the end of therapy, and after 68 and 122 months, respectively; 4 of 5 male patients had sexual intercourse freely but did not fertilize their partners. CONCLUSIONS: In our opinion and in agreement with available literature, chemotherapy has a fundamental place alongside radiotherapy in the treatment of bulky mediastinal HD. Combined modality treatment improves the disease-free survival obtained with radiotherapy or chemotherapy alone. In our experience a high percentage of patients (83%) can be considered cured without the need for second-line therapy. However, long-term and especially gonadal toxicity greatly influence the quality of life of these patients. Therefore treatment must be personalized according to age, sex, cardiopulmonary status and desire to preserve reproductive function.

Actuarial Analysis↗
PubMedDate not supplied

Ifosfamide, epirubicin and etoposide (IEV) therapy in relapsed and refractory high-grade non-Hodgkin's lymphoma and Hodgkin's disease.

BACKGROUND: A fundamental principle in the therapeutic strategy for recurrent lymphomas is the employment of agents that are not part of the usual front line combination regimens. Ideally, the cytotoxic agents should lack complete cross resistance with those utilized up front. PATIENTS AND METHODS: A three-drug combination of ifosfamide, epirubicin and etoposide (IEV) was used to treat 20 patients with relapsing or refractory high-grade non-Hodgkin's lymphoma (HG-NHL) or Hodgkin's disease (HD). RESULTS: Of 14 patients with HG-NHL, 5 (36%) achieved a complete response (CR) and 4 partial remission (PR), giving an overall response rate of 64%. To date, all the complete responders are still in CR at +5, +5, +6, +7, and +9 months, respectively. Of 6 patients with HD, 4 (66%) obtained CR and 2 PR, giving an overall response rate of 100%. The 4 CRs are still in remission after +4, +5, +9, and +13 months, respectively. Clinical and hematologic toxic effects were moderate: neutropenia was responsible for delaying treatment for a week in 6 patients. CONCLUSIONS: These results confirm the efficacy of the IEV regimen in inducing a good remission rate with moderate side effects in relapsing/refractory HG-NHL and HD patients and they show that further investigations with this combination are warranted.

Adult↗
PubMed1995

[Study on peripheral blood stem cells mobilized by different chemotherapies with granulocyte-colony stimulating factor in ovarian cancer].

A new therapeutic strategy for advanced ovarian cancer is to administer ultra-high doses of anticancerous drugs, followed by peripheral blood stem cell transplantation (PBSCT) to recover normal marrow functions. There are, however, no clear regimens to induce mobilization of peripheral blood stem cells (PBSCs). We therefore used three different chemotherapies and granulocyte colony-stimulating factor (G-CSF) to produce a rebound increase in PBSCs during myelosuppression by apheresis. Eleven patients with advanced ovarian cancer (FIGO Stage; IIc-1, IIIc-5, IV-4, Recurrence-1) received chemotherapy with CEP (cyclophosphamide: 500-750mg/m2, epirubicin: 50-70mg/m2, cisplatin: 70mg/m2), CEE (cyclophosphamide: 2,000mg/m2, epirubicin: 50mg/m2, etoposide: 300mg/m2, and PEC salvage (cisplatin: 75mg/m2, etoposide: 300mg/m2, cyclophosphamide: 1,000mg/m2) followed by lenograstim (G-CSF; 2 micrograms/kg subcutaneous injection daily for 14-18 days) to mobilize PBSCs. A range of 0-38.2 x 10(4) (mean +/- S.D.; 11.1 +/- 5.0 x 10(4) colony forming unit granulocyte-macrophage (CFU-GM)/kg in the CEP regimen (n = 15), 1.6-40.8 x 10(4) (mean +/- S.D.; 12.3 +/- 3.6 x 10(4) CFU-GM/kg in the CEE regimen (n = 11), and 8.6-11.4 x 10(4) (mean +/- S.D.; 10.0 +/- 2.0 x 10(4) CFU-GM/kg in the PEC salvage regimen (n = 2) were recruited by a single apheresis. Although the CEE regimen to mobilize PBSCs was much more efficient than the CEP regimen, a large number of PBSCs showing 38.2 x 10(4) CFU-GM/kg were mobilized by the CEP regimen with a dose-escalation of cyclophosphamide 750mg/m2 and epirubicin 70mg/m2. The number of CFU-GM/kg correlated well with that of CD34+ (r = 0.693).(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Autologous progenitor cell transplantation: prior exposure to stem cell-toxic drugs determines yield and engraftment of peripheral blood progenitor cell but not of bone marrow grafts.

Agents with stem cell-toxic potential are frequently used for salvage therapy of Hodgkin's disease (HD) and high-grade non-Hodgkin's lymphoma (NHL). Because many patients with relapsed or refractory lymphoma are candidates for autologous progenitor cell transplantation, possible toxic effects of salvage chemotherapy on progenitor cells must be taken into account. In a retrospective study, we have analyzed the influence of a salvage regimen containing the stem cell-toxic drugs BCNU and melphalan (Dexa-BEAM) on subsequently harvested bone marrow (BM)- and peripheral blood-derived progenitor cell grafts (PBPC) and compared it with other factors. Progenitor cells were collected from 96 patients with HD or high-grade NHL. Seventy-nine grafts were reinfused (35 PBPC and 44 BM) after high-dose chemotherapy. Compared with patients autografted with BM, hematopoietic recovery was significantly accelerated in recipients of PBPC. For PBPC, the number of Dexa-BEAM cycles ( > or = v > 1) was the predominate prognostic factor affecting colony-forming unit-granulocyte-macrophage (CFU-GM) yield (66 v 6.8 x 10(4)/kg, P = .0001), CD34+ cell yield (6.6 v 1.6 x 10(6)/kg, P = .0001), neutrophil recovery to > 0.5 x 10(9)/L (9 v. 11 days, P = .0086), platelet recovery to > 20 x 10(9)/L (10 v 15.5 days, P = .0002), and platelet count on day +100 after transplantation (190 v 107 x 10(9)/L, P = .031) using univariate analysis. Previous radiotherapy was associated with significantly lower CFU-GM and CD34+ cell yields but had no influence on engraftment. Patient age, patient sex, disease activity, or chemotherapy other than Dexa-BEAM did not have any prognostic impact. Multivariate analysis confirmed that Dexa-BEAM chemotherapy was the overriding factor adversely influencing CFU-GM yield (P < .0001), CD34+ cell yield (P < .0001), and platelet engraftment (P < .0001). BM grafts were not significantly affected by previous Dexa-BEAM chemotherapy or any other variable tested. However, prognostic factors favoring the use of BM instead of PBPC were not identified using joint regression models involving interaction terms between the graft type (PBPC or BM) and the explanatory variables investigated. We conclude that, in contrast to previous radiotherapy or other chemotherapy, exposure to salvage regimens containing stem cell-toxic drugs, such as BCNU and melphalan, is a critical factor adversely affecting yields and performance of PBPC grafts. Marrow progenitor cells appear to be less sensitive to stem cell-toxic chemotherapy. PBPC should be harvested before repeated courses of salvage chemotherapy involving stem cell-toxic drugs to preserve the favorable repopulation kinetics of PBPC in comparison with BM.

Adolescent↗
PubMedDate not supplied

Analysis of the risk of solid tumor following Hodgkin's disease.

BACKGROUND AND OBJECTIVE: This study examines the occurrence of solid tumor (ST) in relation to the different types of therapy (radiotherapy, chemotherapy and radiochemotherapy; splenectomy or splenic irradiation vs no splenectomy-no splenic irradiation) received by patients treated for Hodgkin's disease (HD). METHODS: The study included 1,045 HD patients treated at the Department of Radiation Oncology, the Institute of Radiology and the Department of Human Biopathology, Hematology Section, University of Rome, "La Sapienza", from 1972 to 1992. For 23% of the patients the follow-up period was longer than 10 years. The average follow-up period was 72 months. For a more accurate calculation of the risk of ST occurrence, the patients were first divided into 3 subgroups according to initial treatment and then according to the total treatment they had received. Moreover, to establish a probable connection between solid tumor and splenic treatment the patients were also divided into 3 subgroups (splenectomy, splenic irradiation and no splenectomy/no splenic irradiation). RESULTS: We recorded twenty-four cases of ST after initial treatment. Secondary solid tumor showed a cumulative risk of 0.2% and 13.4% at 5 and 20 years, respectively. After initial treatment with radiotherapy (RT) alone, the cumulative risk was 1.7% and 5.2% at 10 and 20 years, respectively; in the chemotherapy (CT) group, it was 2.4% and 18.1%; in the CT(+)RT group, it was 1.7% and 9%. No statistically significant differences were observed among the different types of treatment (splenectomy, splenic irradiation or no splenectomy/no splenic irradiation) as regards the occurrence of ST. According to multivariate analysis, the most important factor in the risk of ST was age (> 40). Relative risk was 5.2, p = 0.0001. INTERPRETATION AND CONCLUSIONS: We conclude that an age of over 40 at diagnosis and treatment with CT alone greatly increase the risk of solid tumor occurrence.

Adolescent↗