DNA-topoisomerase I and II: biologic features and their role in drug resistance.
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Animals↗
Biomedical subjects
D Russo
Publications and source records attributed to D Russo.
Computed tomography, magnetic resonance and gallium 67 scintigraphy for the imaging of residual lymphoma.
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Adolescent↗
Overcoming PGP-related multidrug resistance. The cyclosporine derivative SDZ PSC 833 can abolish the resistance to methoxy-morpholynil-doxorubicin.
BACKGROUND: The results obtained so far in studies designed to neutralize P glycoprotein (PGP)-related multidrug resistance (MDR) by using MDR reversal agents, have not yet fulfilled the promise of the experiments which were performed in vitro. In order to improve PGP-related MDR neutralization, we tested in vitro the activity of the cyclosporine derivative SDZ PSC 833 (PSC) together with doxorubicin (DOX) and with two new DOX derivatives named 4' iodo 4' deoxy-doxorubicin (IODODOX) and methoxy-morpholynil-doxorubicin (MMDOX, FCE 23762) using four different human cell lines and their multi-drug resistant variants. METHODS: Anthracycline toxicity was evaluated by using the MTT method after a 7-day culture with continuous exposure to the antitumor drugs with or without the addition of PSC. RESULTS: PSC significantly downmodulated the toxicity of all three anthracyclines in all the four cell systems. However, despite the great increase caused by PSC in the toxicity of DOX and a more modest effect on the toxicity of the two DOX derivatives, this MDR reversal agent could only completely block the PGP mediated MMDOX resistance whereas DOX refractoriness was only decreased. CONCLUSIONS: The combination of MMDOX or IODODOX with PSC 1.6 microM is more efficient than the combination of DOX plus PSC for the full reversion of PGP-mediated drug resistance. Careful clinical studies are required to evaluate if these associations can also effectively and safely neutralize MDR in vivo.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
All-trans retinoic acid in hematological malignancies, an update. GER (Gruppo Ematologico Retinoidi).
BACKGROUND AND OBJECTIVE: During the past ten years, the study of retinoids has undergone a total transformation. The Italian Society of Experimental Hematology decided to discuss these advances at a meeting in Florence on April 18, 1996. INFORMATION SOURCES: The material examined in the present review includes articles and abstracts published in journals covered by the Science Citation Index and Medline. In addition, all the authors of the present article have been actively working in the field of retinoids and have contributed several papers. Summaries of their oral presentations at the Florence meeting are reported in the Appendix to this review article. STATE OF ART AND PERSPECTIVES: One of the most important advances has been the elucidation of new molecular mechanisms of control of gene expression by retinoids. A number of new retinoids have been synthesized by chemists, some of which are being screened for potential clinical use, and a few have already had a tremendous impact on clinical practice. The most important achievements have been obtained in acute promyelocytic leukemia. In 1988 a Chinese group working in Shanghai showed that using all-trans retinoic acid (ATRA) alone 94% of acute promyelocytic leukemic patients obtained complete remission through differentiation of the leukemic clone. This result transformed a dream into reality and allowed researchers to move from laboratory experience to clinical applications of this differentiating therapy. Expanding the spectrum of hematological malignancies that may respond to ATRA remains a challenge; however, several results show some activity of retinoids alone or in combination with other drugs in juvenile chronic myeloid leukemia (CML), myelodysplastic syndrome, cutaneous T-cell lymphoma and CML. Particularly interesting are the studies that explored the potential clinical synergism of ATRA-based combination therapies with growth factors, other differentiating agents such as vitamin D3, immunomodulators like interferons, or chemotherapeutic agents, in particular Ara-C, all of which show promising in vitro effects when used in combination with retinoids.
Adult↗
Effect of fludarabine and arabinosylcytosine on multidrug resistant cells.
BACKGROUND AND OBJECTIVE: Anthracyclines are first-line drugs in the treatment of acute leukemia, but the sensitivity of leukemic cells to anthracyclines can be downmodulated by multidrug resistance (MDR) transport proteins like Pgp. Pgp overexpression is negatively related to treatment response. Alternative drugs may be required to overcome the MDR problem. METHODS: Arabinosylcytosine (ara-C) and 9-beta-D-arabinofuranosyl-2-fluoro-adenine monophosphate (fludarabine, F-ara) were tested alone and in combination in four pairs of leukemia and tumor non-MDR and MDR cell lines. Toxicity was assayed by growth inhibition with the microcultured MTT assay. RESULTS: MDR cells were more sensitive than or as sensitive as non-MDR cells to ara-C and to F-ara alone. The resistance index to ara-C was decreased upon pre-exposure of the MDR cells to low-dose F-ara (10 ng/mL), showing that the combination of ara-C and F-ara was more active on MDR cells than on non-MDR parental ones. INTERPRETATION AND CONCLUSIONS: Neither sensitivity to ara-C nor sensitivity to F-ara was influenced by Pgp overexpression. These data provide a rationale for more extensive and more intensive testing of combinations of ara-C and F-ara in Pgp-mediated MDR acute leukemia. In relapsed/resistant and in secondary acute leukemias, increasing the dose of ara-C and combining ara-C with F-ara might be more rewarding than administering anthracyclines or other Pgp-processable compounds.
Antineoplastic Agents↗
Retrospective analysis of 23 cases with peripheral T-cell lymphoma, unspecified: clinical characteristics and outcome.
BACKGROUND AND OBJECTIVE: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of post-thymic malignancies relatively uncommon in the Western world and their prognosis and therapeutic approach are still not well defined. The aim of this study was to retrospectively analyze the clinical, hematological and histological features at diagnosis, the relevance of the International Prognostic Index and the outcome of a group of 23 patients affected by peripheral T-cell lymphoma, unspecified (PTCL-U), according to the Revised European-American Classification of Lymphoid Neoplasms (REAL), observed between September 1985 and April 1995 at our Institution. METHODS: Patients were separated into different prognostic groups according to Ann Arbor stage, cell size and International Prognostic Index. All patients had been treated with multiagent combination chemotherapy, mainly CHOP (9 cases) and F-MACHOP (9 cases), and were evaluable for response. The treatment was intensified with allogeneic bone marrow transplantation (BMT) in 1 patient and with autologous BMT in 4 patients. RESULTS: Median age was 55 (range 18-77) years and 70% of the patients were males. Four patients were in stage II (17%), 5 in stage III (22%) and 14 in stage IV (61%). Patient risk was classified according to the International Prognostic Index as follows: 8 cases (35%) low risk, 2 cases (9%) low-intermediate, 8 cases (35%) high-intermediate, 5 cases (21%) high. Median follow-up time was 20 months (range 2-132). Median progression-free survival (PFS) and overall survival (OS) for all the patients studied were 10 and 34 months, respectively. Stage IV was associated with a poorer response rate and a shorter PFS (median 6 months) and OS (median 32 months). No statistical correlation was found between cell size and overall response (complete + partial remission), PFS (p = 0.38) or OS (p = 0.59), although a better trend was observed for the large cell group. A less favorable outcome was observed in patients in the high-intermediate + high risk groups, where median PFS and OS were 7 and 24 months, respectively, than in patients in the low + low-intermediate risk groups. No difference in response or outcome was detected between patients treated with the CHOP and the F-MACHOP regimens, while all 5 patients given high-dose chemotherapy and BMT are alive and in CR. INTERPRETATION AND CONCLUSIONS: Our experience shows that PTCL-U are rare lymphomas frequently having an aggressive presentation. The response to conventional polychemotherapeutic regimens like CHOP or F-MACHOP is generally poor, especially in those cases with advanced stage and a high-intermediate or high International Prognostic Index. The observation that all five patients who were treated with bone marrow transplantation are alive and in complete remission suggests using this strategy, particularly in young patients with a poor International Prognostic Index.
Adolescent↗
Response to sequential treatment with lymphoblastoid interferon-alpha in patients with Ph+ chronic myeloid leukemia unresponsive to recombinant interferon-alpha (rIFN alpha 2a) and neutralizing-rIFN alpha 2a antibodies negative.
Nine Ph+ CML patients in chronic phase who were hematologically and/or karyotypically unresponsive to recombinant-IFN alpha 2a (rIFN alpha 2a) and neutralizing-rIFN alpha 2a Abs negative were shifted from rIFN alpha 2a to lymphoblastoid-IFN alpha (IFN alpha-Ly) therapy. After 3 months of IFNa-Ly treatment, the hematologic response was reinduced in 3 out of the 6 pts who were resistant to previous rIFN alpha 2a therapy, and was maintained in 2 out of 3 patients who were hematologically but not karyotypically responsive to rIFN alpha 2a. After 6 and 12 months, the hematologic response was progressively lost, being present only in 3 out of 7 and in 2 out of 3 evaluable patients respectively. None of the hematologically responsive patients achieved a karyotypic response (Ph neg. metaphases-0%). One patient, who was hematologically responsive, continued being treated with IFN alpha-ly for 36 months but he did not achieve any karyotypic response. The results of this study suggest that in the unresponsive and neutralizing-rIFN alpha 2a Abs negative CML patients a change in therapy, by using a non cross-reactive type of IFN alpha, would not be advantageous.
Adult↗
Retrospective analysis of 34 cases of hairy cell leukemia treated with interferon-alpha and/or 2-chlorodeoxyadenosine.
The aim of the present study was to compare the outcome of patients affected by typical hairy cell leukemia (HCL) treated with interferon-alpha (IFN-alpha) and/or 2-chlorodeoxyadenosine (2CdA). Thirty-four consecutive patients were enrolled in the study. IFN was administered in 26 cases as first line therapy at a dose of 3 MU every other day for 12 months. 2CdA was given in 8 cases as first-line and in 14 cases as second-line therapy in patients resistant to (2 cases) or relapsed after (12 cases) IFN. The treatment schedule for 2CdA was 0.1 mg/kg/daily for 7 days for 1 cycle (17 patients) or 2 cycles (5 patients). Complete (CR) and partial remission (PR) were 19% and 58%, respectively, for IFN, 75% and 25% for 2CdA in first-line therapy, 86% and 14% for 2CdA in second-line therapy. Median progression-free survival for IFN patients was 19 months and no statistical advantage was detected for those who achieved a CR vs those in PR. In the group treated with 2CdA, only 1 patient (4%) relapsed after a median follow-up of 14 months. At a median follow-up of 59 months (range 4-134), overall survival of all 34 patients was 97%, with only 1 patient having died of an acute leukemia. Our results confirm the favorable outcome currently expected for HCL and emphasize the therapeutic activity of 2CdA in the treatment of this disease.
Adult↗
[Prevention of bacterial and fungal infections in neutropenic patients with malignant hematologic diseases].
Infections are a major cause of morbidity and mortality among immunocompromised patients. This report discusses bacterial and mycotic infections prophylaxis in the granulocytopenic patients with hematologic malignancies. Various strategies have been derived to prevent the infections: a combination of oral antibacterial and antifungal prophylaxis with quinolones and newer azoles (fluconazole, itraconazole), high efficiency particulate air filtration, protective isolation and management of central venous catheter. However, the emergence of antibiotic resistant organism continues to pose a major challenge to the successful eradication and prevention of infections in neutropenic host, and demands the development of innovative approaches to antibiotic use and infection control procedures.
Agranulocytosis↗