European Journal of Cancer and Clinical Oncology最新文献

A STUDY was undertaken to compare the effect of recombinant interferon alfa-2b (IFN alfa-2b) plus hydroxyurea (HU) with that of HU alone on haematological remission (HR) in patients with chronic phase chronic myelogenous leukaemia (CML). Twenty-one patients were randomized to receive either IFN alfa-2b plus HU (n = 12; seven male and five female; mean age 40 years, range 29–57 years) or HU alone (n = 9; three male and six female; mean age 35 years, range 24–50 years). All patients initially received cytoreductive therapy with HU alone, at a dose according to the white blood cell (WBC) count. When the WBC count decreased to 5−10 × 10³/μl, patients were randomized to receive either IFN alfa-2b 2 million units per day by subcutaneous (s.c.) injection plus the adjusted daily dose of HU (> 150 × 10³/μl, 4g; 50−150 × 10³/μl, 3g; 30−50 × 10³/μl, 2g; 10−30 × 10³/μl, 1g; and 5−10 × 10³/μl, 0g), or HU alone. Thus, patients received no HU until their WBC count rose above 5−10 × 10³/μl. Eleven of 12 patients on IFN plus HU achieved a haematological response, including nine with complete haematological remission (CHR) (A1: n = 0, A2: n = 4, A3: n = 3, A4: n = 2) and two with partial haematological remission (PHR) (B1: n = 0, B2: n = 2), while none of the nine patients on HU alone achieved a remission with the above-mentioned doses of HU according to our criteria (A[CHR]: WBC count maintained below 9 × 10³/μl without blast and no symptoms or signs associated with CML; subclassified according to the percentage of Ph¹ chromosome: A1, Ph¹ chromosome present in all analyzable metaphases; A2, Ph¹ chromosome present in 35–59%; A3, 5–34%; A4, Ph¹ chromosome absent from all analyzable metaphases. B[PHR]: B1, reduction of peripheral WBC count by at least 50% to < 20 × 10³/μl; B2, normalization of peripheral WBC count but persistence of immature form or clinically palpable splenomegaly. Failure: patients who failed to achieve a PHR or CHR as defined above). Using two sets of primer pair sequences encoding bcr-abl mRNA (A primer: 5′-GGAGCTGCAGATGCTGACCAAC-3′ encoding bcr exon II; B primer: 5′-TCAGACCCTGAGGCTCAAAGTC-3′ encoding abl exon II; A′ primer: 5′-CCTGATCTCCTCTGA CTATGAG-3′ encoding bcr exon I; B′ primer: 5′-TCCAGCGAGAAGGTTTTCCTTG-3′ encoding abl exon I), we performed the cDNA-PCR analysis, which revealed persistent bcr-abl mRNA expression in the peripheral mononuclear cells from two patients who achieved CHR induced by IFN. We suggest that IFN therapy should be continued at least until molecular remission is achieved.

A systematic survey of all centres of diagnosis and care of breast cancer patients in the Rhône “département” of France was carried out to evaluate, for the year 1985, the incidence rate of breast cancer in an urban, industrialised part of France not covered by a cancer registry. Two hundred and fifty seven institutions or individuals were involved, covering the public and private sectors in the Rhône département, but also in neighbouring cities and elsewhere in France, which also enabled a search to be carried out for cases diagnosed or treated outside the département. Altogether, over this 1-year period, 801 new cases were identified (791 women and 10 men). This study demonstrated a high incidence of female breast cancer (80.5 new cases per 100 000 woman-years, standardised to the world population) which was particularly marked among women aged 40–60. This incidence is higher than that described by the cancer registry of the neighbouring département of Isère, but is close to the incidence found in Geneva. Results also concur with the relatively high mortality rate from breast cancer observed in the Rhône département.

The antineoplastic agent, hexadecylphosphocholine, a phospholipid analogue, inhibited phosphatidylserine-activated protein kinase C in vitro at concentrations higher than 40 μmol/l. The half-inhibitory concentration (IC₅₀) was 62 μmol/l. Another alkylphosphocholine, dodecylphosphocholine, did not have an inhibitory effect on protein kinase C. At the same concentrations, hexadecylphosphocholine antagonised the phorbol ester-stimulated proliferation of Madin-Darby canine kidney cells whereas dodecylphosphocholine had no effect. In addition, phorbol ester-induced morphological changes of these epithelial cells were antagonised by hexadecylphosphocholine. Both effects of hexadecylphosphocholine, the inhibition of protein kinase C and the antagonisation of the altered cell morphology induced by phorbol ester, were comparable to those observed after treatment with sphingosine, a known protein kinase C inhibitor. We conclude that one possible mechanism of the antineoplatic action of hexadecylphosphocholine is mediated by inhibition of protein kinase C.

Fifty-four patients with Ph¹-positive chronic myelogenous leukaemia (CML) (48 with chronic-phase and six acute-phase disease) were treated with interferon alfa-2b subcutaneously (s.c.). The starting dose was 4 million units (MU)/m² body surface area daily. It was reduced in parallel with serially determined leucocyte counts, and minimal effective doses were given as maintenance after achieving remission. Haematological remissions were induced in 22 of the 48 patients (46%) with chronic-phase disease. Thirteen patients (27%) revealed partial haematological remission and another 13 no response to treatment. No complete remission could be induced, although minor or partial cytogenetic responses were seen in 16 patients (33%). Moreover, a bcr-abl reduction was detected on Southern blot analysis in two patients. In chronic-phase disease, results of treatment were influenced by elapsed time after diagnosis, extent of previous treatment and interferon dosage. No beneficial effects of interferon were detected in the six patients with acute-phase disease. Principal acute side effects were fever and flu-like symptoms at the beginning of the therapy, which usually subsided within 3–7 days. Chronic side effects, especially weakness and neuropathy, were less frequent but more severe and necessitated discontinuation of treatment in 10 patients. In summary, interferon alfa-2b seems to be an effective treatment in early chronic-phase CML. Long-term effects on the course of the disease, however, must be determined.

Alpha interferon has shown initial promise in the treatment of low-grade non-Hodgkin's lymphoma (NHL), especially with the nodular form of the disease. The present study enrolled 70 NHL patients who received either chlorambucil (CB; 10 mg/day) or CB plus interferon alfa-2b (5 million units (MU)/m² subcutaneously three times a week). Among 63 evaluable patients, similar response rates (62.1% and 64.7% respectively) were recorded for the treatment arms. In patients receiving no maintenance therapy, those who received interferon alfa-2b during the induction phase showed a favourable trend in terms of incidence of relapse compared to those who had received chlorambucil alone. During maintenance therapy with interferon alfa-2b, no significant differences in the occurrence of relapse have yet been seen compared to patients on no maintenance therapy. A longer observation period is needed to make a definitive conclusion about the usefulness of interferon maintenance therapy and to evaluate further the effects of the combined schedule of chlorambucil and interferon induction on the duration of remission.

Several basic experimental and clinical studies were carried out in an attempt to improve the efficacy of alpha interferon therapy for chronic myelogenous leukaemia (CML). First, the combined use of hydroxyurea (HU) and interferon (500–1000 mg daily) in interferon-resistant cases facilitated maintenance of reduced leucocyte production, or a reduction in the dose of interferon, although suppression of Philadelphia chromosome (Ph¹)-positive clones was not observed in most cases. In order to try and decrease the rate of lymphoblastic crisis during the course of interferon therapy, we recently added methotrexate (MTX) (10–15 mg, weekly) to the treatment protocol. Since then, no lymphoblastic crisis has been observed. Second, the in vitro expression of alpha interferon-stimulated gene (ISG) mRNA was shown to be markedly decreased in granulocytes of one representative interferon-resistant case, compared to that in granulocytes of the three interferon-sensitive cases. Interestingly, it was found that the transcriptional activity in this case became almost normal when the blood granulocytes were controlled by the addition of HU. These findings suggest that the in vitro transcriptional assay of ISG mRNA may be clinically useful for predicting alpha interferon efficacy. Third, when genetically manipulated, alpha interferon-producing NIH/3T3 cells were co-transplanted using diffusion chambers into nude mice bearing a CML cell line, KU812, the CML tumour growth was shown to be markedly suppressed. This experimental model for alpha interferon replacement gene therapy suggests some directions for future studies on interferon therapy.

In order to compare the effects of interferon versus hydroxyurea for the treatment of chronic myelogenous leukaemia (CML), 58 CML patients, having received no previous treatment, were randomized into two treatment groups (hydroxyurea or interferon) for an open multicentre study from 1 May 1987 until 1 July 1990. Fifty patients were evaluable: 24 in the interferon group and 26 in the hydroxyurea group. Haematological response was obtained in $\text{16}\text{24}$ interferon-treated patients and $\text{23}\text{26}$ hydroxyurea patients. Failure to obtain haematological remissions occurred in eight of 24 interferon-treated patients and in three of 26 hydroxyurea patients. Four interferon-treated patient failures and one hydroxyurea-treated failure were due to drug intolerance. Progression occurred in one interferon-treated patient and in three patients given hydroxyurea. Fourteen of 16 patients in the interferon group and $\text{17}\text{23}$ in the hydroxyurea group continue on study and show no progression.