Hematopoietic precursor cells in mice treated with 4-demethoxydaunorubicin and doxorubicin.

The hematologic toxicity of 4-demethoxydaunorubicin (4-dmDNR), a new anthracycline more potent and less cardiotoxic than doxorubicin (Dx), was studied. Dose-survival curves of bone marrow hematopoietic precursor cells (HPC) in situ were determined with the use of (C57BL X C3H)F1 mice and with assays of colony-forming units--spleen, culture, and erythroid--by in vivo and in vitro methods. Time response of HPC was followed in mice treated at days 0, 2, and 5 with 0.75 mg 4-dmDNR/kg of 4.5 mg Dx/kg and in mice receiving 2.23 mg 4-dmDNR/kg or 3.96 mg Dx/kg twice a week for 4 weeks. The dose-survival curves of HPC for 4-dmDNR were exponential. Slight differences in sensitivity among assayed populations were seen. Although the doses of 4-dmDNR required to reduce the survival of HPC to 37% were similar or lower than those of Dx, following intermittent treatment with doses of 4-dmDNR with the same optimal antitumor activity as with Dx, 4-dmDNR seemed to have a lesser effect on hematopoietic progenitors and a greater effect on peripheral blood cells than did Dx. However, during prolonged administration 4-dmDNR appeared to be toxic at every hematopoietic level.

Effects of high-dose methotrexate and leucovorin on murine hemopoietic stem cells.

This study compares the effects of a high dose of methotrexate (HDMTX) to that of a high dose of methotrexate plus leucovorin protection on the hemopoietic stem cells in a murine model. C57BL X C3H F1 mice were treated with a single large bolus (500 mg/kg body weight) of methotrexate or with the same dose of the drug plus leucovorin administered in fractionated doses during the following 24 hr. At 1 to 2 days after the administration of HDMTX, there was a large bone marrow and spleen depopulation of pluripotent stem cells and of committed and recognizable progenitors. At 2 to 3 days, a severe fall of white blood cells and reticulocytes ensued. The recovery process of hemopoietic precursors followed alternate phases of overshooting and secondary falls. Leucovorin administration appeared to protect all stages of hemopoiesis and prevented the severe drops of bone marrow cellularity and stem cell content which followed the HDMTX bolus. However, the effect of leucovorin on peripheral blood cell reduction was less significant. After treatment with HDMTX, the recovery of bone marrow cells and the burst of splenic hemopoietic activity followed a pattern similar in both leucovorin-protected and unprotected animals, but in the former, the increase in stem cells and hemopoietic progenitors appeared to reach higher values and to last longer. In particular, the overshooting of colony-forming units, culture and erythroid, reached a higher peak in leucovorin-treated mice and was more prolonged. Our results indicate that, in HDMTX-treated mice, leucovorin protection involves the earliest stages of hemopoiesis, assuring the maintenance of a satisfactory endowment of stem and progenitor cells.

[Endoscopic endoprosthesis insertion in the treatment of digestive diseases]. / L'utilizzo delle protesi endoscopiche nella patologia dell'apparato digerente.

Over the last few years the use of endoscopically placed endoprostheses for benign and malignant digestive diseases has considerably developed. The endoscopic placement of prostheses is usually well tolerated by patients; it does not require anaesthesia and it is a relatively low-risk procedure. New self-expandable metallic prostheses allow to treat even very tight stenoses; they do not usually require dilatation, therefore reducing the risks involved in dilatation procedure. This study presents a review of experience with prostheses placement in digestive diseases. Indications, limits and complications will be discussed according to data reported in the international literature.

Azidothymidine-induced depression of murine hemopoietic progenitor cells.

The toxicity of the antiviral drug 3'-azido-3'-deoxythymidine was studied in vivo on murine hemopoietic progenitor cells and peripheral blood cells. The drug induced a marked decrease of all tested populations, showing a severe toxicity on hemopoiesis.

Hemotoxic effects on mice of combined administration of azidothymidine and acyclovir.

This study reports the effects of a combination of azidothymidine (AZT) plus acyclovir (ACV) on both pluripotent (spleen colony-forming units, CFU-S) and committed (granulocyte-macrophage colony-forming units, CFU-GM; erythroid burst-forming units, BFU-E) murine hemopoietic progenitors. Administration of AZT alone was associated with severe hemotoxicity, as shown by the marked decrease of all the hemopoietic progenitor populations tested, that is, CFU-S, CFU-GM, and BFU-E. This, however, was followed by a prompt recovery of hemopoiesis. Administration of ACV alone did not modify the hematological parameters studied, whereas the combined administration of AZT and ACV led to changes in peripheral blood cells and bone marrow hemopoietic progenitors that were, on the whole, not significantly different from those observed with AZT alone. Only the decrease in CFU-S was significantly more severe, but their recovery was as rapid as that of the committed progenitors. Thus, in this experimental setting, the addition of ACV to AZT does not appear to increase the hemotoxicity of the latter.

Serum erythropoietin increase in patients receiving adjuvant therapy with 5-fluorouracil and leucovorin.

High-dose anticancer drugs have been shown to induce an increase in serum erythropoietin (sEpo) levels not mediated by hypoxia. In this study, sEpo was assessed in seven patients who had been administered a course of 5-day leucovorin-modulated 5-fluorouracil (5-FU-LV) as an adjuvant therapy after the removal of colon cancer. During this study, the mean hemoglobin (Hb) concentration stayed at a constant level, peripheral blood (PB) reticulocytes showed an early, sharp decline, and sEpo levels progressively increased for 15 days after the start of chemotherapy. These results appear to indicate that the increase in sEpo, which was not related to anemia, may have followed from the administration of a cytotoxic drug at doses used in routine, clinical practice.

In vitro synergistic inhibition of human bone marrow hemopoietic progenitor growth by a 3'-azido-3'-deoxy-thymidine, 2',3'-dideoxycytidine combination.

In vitro growth of human normal bone marrow granulocyte-macrophage colony forming units (CFU-GMs) and erythroid burst forming units (BFU-Es) was dose-dependently inhibited by 3'-azido-3'deoxythymidine (AZT) (from 0.1 microM to 4 microM) and 2',3'-dideoxycytidine (ddC) (from 0.01 microM to 1.0 microM). These ranges included minimum in vitro inhibitory concentrations to HIV-1 and concentrations corresponding to plasma level achievable in vivo. A synergistic inhibitory effect, statistically highly significant, was observed when combinations of the two drugs were added to cultures. This severe in vitro toxicity of ddC and the synergistic toxicity of AZT-ddC combinations on hemopoietic progenitor cells should be considered when the two drugs are administered in concurrent or alternating regimens.

Interferon-alpha inhibits CFU-GM mobilization following chemotherapy and G-CSF administration.

Changes in routine hematologic data and in circulating granulocyte-macrophage colony-forming units (CFU-GM) during granulocyte colony-stimulating factor (G-CSF) administration were evaluated in non-small cell lung carcinoma (NSCLC) patients treated with a combination of 5-fluorouracil (5-FU) and cisplatin (DDP) with and without the addition of interferon-alpha (IFN-alpha). The patterns of leukocyte changes following chemotherapy plus G-CSF were similar in both the IFN-alpha-inclusive and the IFN-alpha-devoid courses. However, the twofold increase in CFU-GM observed in patients receiving chemotherapy plus G-CSF was completely absent following the course including IFN-alpha. The activity of G-CSF on the hematologic pattern is seemingly affected by its combination with IFN-alpha treatment. Mechanisms of the possible in vivo interaction among IFNs and hematopoietic growth factors remain to be elucidated.

Regional pharmacokinetic selectivity of intrapleural cisplatin.

The pharmacokinetics and toxicity of cisplatin were investigated in 3 patients affected by malignant mesothelioma who received 90 mg/m2 of the drug intrapleurally. The mean area under the pleural Pt concentration versus time curve (AUC) [12.83 (S.D. 4.06) mg.min/ml] was about 50 times greater than that detected in plasma [0.27 (0.03) mg.min/ml], indicating a clear pharmacological advantage for this route of administration. The mean plasma total Pt concentration was 1.1 micrograms/ml and the apparent total body clearance was 268 (101) ml/min. Platinum plasma pharmacokinetic data measured following intrapleural cisplatin administration (4 patients) were compared with those observed in 7 patients treated intravenously with the same dose of cisplatin (90 mg/m2) under the same modalities of hydration. Intrapleural administration of cisplatin resulted in significantly lower plasma total partial AUC (P less than 0.05) and prolonged plasma levels of filterable Pt compared with intravenous administration. No difference between the two routes of cisplatin administration in the renal clearance (S.D.) of filterable Pt [132 (64) ml/min and 122 (39) ml/min for intravenous and intrapleural cisplatin, respectively] were observed. None of the mesothelioma patients developed clinical symptoms or signs of pleural inflammation. The intrapleural treatment did not produce haemotoxicity and the emetic toxicity was lower compared with that observed in patients receiving cisplatin intravenously.

Protective effect on cisplatin hematotoxicity by procaine hydrochloride.

The ability of procaine hydrochloride (P.HCl) to modulate the effects of cisplatin (DDP) on pluripotent (CFU-S) and committed (CFU-GM) murine hemopoietic stem cells was investigated. DBA/2NCrlBRF1 mice received DDP alone (10 and 16 mg/kg body wt. single i.p. injection) or in combination with P.HCl (40 mg/kg body wt. single i.p. injection). Hemopoietic progenitor cell (HPC) time survival curves were determined up to 14 days following treatment. The simultaneous administration of the lower DDP dose together with P.HCl greatly reduced the hemotoxicity of the antitumoral drug, while this protection was not significant with the higher DDP dose. These results support a role for P.HCl in protecting against DDP hematological toxicity.

In vitro activity on myeloid progenitors of a combination of 2-chloro-2'-deoxyadenosine and interferon alpha: the effects of IL-1 and GM-CSF.

The toxic effects of a combination of 2-chloro-2'-deoxyadenosine (CDA) and interferon alpha (IFN-alpha), with and without addition of interleukin 1 (IL-1) and/or granulocyte macrophage colony stimulating factor (GM-CSF), on the in vitro growth of peripheral blood granulocyte macrophage committed progenitors (CFU-GM) from 10 normal subjects were investigated. CDA concentration ranged from 15.6 nmol/l to 1 mumol/l, IFN-alpha sole concentration was 10 IU/ml. IL-1 and/or GM-CSF were added at concentrations of 2000 pg/ml and 10 ng/ml, respectively. CDA induced a dose dependent inhibitory effect on CFU-GM growth. Addition of IFN-alpha increased CFU-GM inhibition induced by CDA only at lower concentrations of the latter. IL-1 and GM-CSF, separately or in combination, did not counteract the inhibitory activity of the CDA-IFN-alpha combination.

Dexamethazone-induced acute tumor lysis syndrome in a T-cell malignant lymphoma.

We report a case of steroid-induced acute tumor lysis syndrome and review the literature. A 60-year-old woman was started on steroid therapy for dyspnea due to bilateral pleural effusion and a large mass involving the anterior mediastinum. The final diagnosis was precursor T-lymphoblastic lymphoma-leukemia. Following steroid therapy, the patient developed acute renal failure and laboratory evidence of metabolic changes induced by massive cytolysis. She received vigorous hydration, diuretic and allopurinol therapy, and haemodialysis. Her diuresis, renal function and laboratory data returned to normal within 2 weeks. A review of the medical literature on T-cell lymphoma revealed only one similar case of steroid-induced acute tumor lysis syndrome, a life-threatening metabolic emergency. This risk should be kept into account in the management of patients with lymphoproliferative disorders.

Surveillance after colorectal cancer surgery.

Early diagnosis of local and distant recurrences of colorectal cancer remains difficult and there is no agreement on the effectiveness of follow-up in these patients. The aim of this study is to assess the value of our method of follow-up. We consider 239 patients with colorectal cancer and at least 2 years follow-up following radical resection. A local recurrence appeared in 26 patients (10.9%), a distant metastasis in 41 (17.1%), while in seven (2.9%) local and distant recurrences appeared simultaneously. Local recurrence was detected because of an increase in carcinoembryonic antigen (CEA) level in 15 patients (57.7%), during a scheduled endoscopy in four (15.4%) and because of symptoms in seven (26.9%). In seven patients (26.9%) a radical resection was possible. Distant metastases were detected by CEA levels in 20 patients (48.8%), by ultrasonography (U.S.) in 12 (29.3%) and by chest X-ray in five (12.2%). In 13 of 26 patients with liver metastases a resection was performed. This study shows that few patients benefit from follow-up and only CEA levels and liver U.S. performed intensively between 15 and 36 months after surgery are useful in early detection of recurrences. A modification of the follow-up to the single patient, according to the stage, location and grading of cancer, could improve the results, so lowering the costs of this expensive practice.

Failure of N-acetylcysteine to protect against cis-dichlorodiammineplatinum(II)-induced hematopoietic toxicity in mice.

In view of the results showing a decrease in cis-dichlorodiammineplatinum(II) (cis-DDP) nephrotoxicity after administration of thiol donors, this study was carried out to test the possibility that N-acetylcysteine (NAC) was active against myelodepressive effects of the anticancer drug. Cis-DDP (15.5 mg/kg body weight, i.v.) was administered to control mice and to mice treated simultaneously or 1 h later with NAC (800 mg/kg body weight, i.v.). At various times after treatment, up to 11 days, assessments were made of peripheral blood cell levels and bone marrow progenitor cell (CFUs and CFUc) concentrations. Cis-DDP caused a decrease in hemopoietic precursor cells in the order of that caused by other hemopoietic precursor cells in the order of that caused by other myelodepressive drugs, whereas there was only a slight decrease in peripheral blood WBC. In this experimental setting, NAC administration did not afford significant protection against platinum toxicity on bone marrow precursors or peripheral blood cells.

The effect of N-acetylcysteine on toxicity of cyclophosphamide and doxorubicin on murine hemopoietic progenitors.

The effect of N-acetylcysteine on hemopoietic stem cells was studied. The drug was given to mice untreated and injected with a single dose of cyclophosphamide or doxorubicin. The results show that the antioxidant drug N-acetylcysteine does not induce any significant decrease in the cytotoxic effect of cyclophosphamide or doxorubicin.

Diltiazem does not increase the in vivo sensitivity of murine hemopoietic progenitor cells to doxorubicin.

The effect of doxorubicin and the calcium antagonist, diltiazem, on murine hemopoietic progenitor cells was studied in vivo. Dose-survival curves of murine bone marrow colony forming units (CFU)--spleen and granulocyte macrophage--were determined by in vivo and in vitro methods in DBA/2NCr/BR mice treated with doxorubicin alone or by simultaneous administration of doxorubicin (DX) and diltiazem (DTZ). Time response of bone marrow hematopoietic progenitor cells (HPC) was followed in mice similarly treated. Combination of DTZ with DX did not change the toxic effect of the latter on hemopoietic cells, either in the dose-survival model or in the time-related experiment.

Hematotoxicity of 5-fluorouracil and alpha-interferon on the human normal hemopoietic progenitors.

The toxic effects of a combination of 5 fluorouracil (5-FU) and interferon alpha on normal human hemopoietic progenitors were assessed in vitro. CFU-GM growth was evaluated following 1 h incubation of bone marrow cell suspension with 5-FU 100 micrograms/ml or IFN-alpha 2a 1000 U/ml, or with both drugs, either simultaneously or sequentially added. IFN-alpha did not show toxic effects on normal human hemopoietic progenitors and the severe toxicity of 5-FU on the latter was not modified by IFN-alpha. These results suggest that the changes observed in vivo of 5-FU toxicity induced by IFN-alpha should be attributed to indirect effects of the latter.

Leucovorin antagonizes the effects of trimetrexate on mouse hemopoietic progenitors.

Trimetrexate (2, 4, diamino -5- methyl - 6 [3, 4, 5, trimethoxyanilino) methyl] quinazoline) (TMQ) is a non-classic folate antagonist that is used as an antineoplastic and antipneumocystis agent with promising results. TMQ and methotrexate (MTX) toxicities are comparable. Leucovorin (N-5-formyltetrahydrofolate) (LV) is used to prevent the toxic effects of MTX. In this study the effects of LV on TMQ induced hemopoietic progenitor damage are studied in a murine model. Changes of pluripotent stem cells (colony forming units spleen, CFU-S), granulocyte-macrophage committed progenitors (GM-CFC), erythroid committed progenitor (BFU-E) levels in the bone marrow were followed after administration to mice of a single dose of TMQ or of simultaneous injection of TMQ and LV. Results show that the latter significantly reduces the effects of the former on peripheral blood cells and on hemopoietic progenitors.

Advanced colorectal cancer: quality of life and toxicity in patients after weekly 24-hour continuous infusions of biomodulated 5-fluorouracil.

It is generally agreed that chemotherapy prolongs survival and relieves symptoms more than the best supportive care in advanced colorectal cancer. Since its introduction over 35 years ago, 5-fluorouracil (5-FU) has been the only effective chemotherapeutic option available for the treatment of advanced colorectal cancer. Efforts have focused on the use of various 5-FU-based regimens. A commonly used regimen, frequently extolled as the "gold standard" for clinical trials in advanced colorectal cancer, is the Mayo Clinic regimen; this option has, however, been associated with considerable dose-limiting toxicity. Another approach has involved 5-FU administration by continuous intravenous infusion. In this paper we present our experience on 10 Dukes D colorectal cancer patients treated with 24-hour continuous infusion of biomodulated 5-FU delivered in an ambulatory setting with an intravenous infusional pump. The number of treated patients was admittedly not sufficient to evaluate the clinical response of this 5-FU chemotherapeutic regimen. This is not the goal of our work; however, other rationale for adopting this approach is justified: the regimen has a favourable toxicity profile and can provide considerable benefit in terms of improved quality of life while at the same time the health care costs are alleviated since hospitalization is generally not required.

Effects of docetaxel on the in vitro growth of human myeloid progenitors.

Haemotoxicity is usually the primary and dose-limiting side-effect of docetaxel (TXT) a semysyntetic analogue of paclitaxel which has acquired an important role in anticancer treatment. This research presents the results of an in vitro toxicity study of TXT on myeloid progenitors obtained from healthy volunteers and assayed as CFU-GM. Peripheral blood mononucleated non-adherent cells (MNAC) were incubated for 24 h at standard conditions with increasing concentrations of TXT and then cultured for CFU-GM assay. At every concentration severe CFU-GM growth inhibition was observed. In a second set of experiments MNAC were sequentially exposed to TXT and then to doxorubicin or cisplatin or vinorelbine or etoposide at appropriate concentrations. In a third set the sequence of exposure was reversed. No difference of CFU-GM growth inhibition was observed between the alternate sequences. These findings suggest that the toxicity on CFU-GM in vitro growth of TXT combinations with other anticancer drugs is sequence-independent.