[Anticancer drug research in Hungary, 1950-2000]. / Daganat-kemoterápiás kutatások Magyarországon az 1950−2000 közötti években.

The present review about the history of anticancer drug research in Hungary intends to call attention to the importance of studies on their mode of action. Several lines of evidence suggest that clinically usable oncopharmacological properties could be revealed by this way. Among the numerous compounds certain alkylating sugar alcohols and 2'-deoxyuridine derivatives were submitted to detailed investigations concerning their mode of action. Myelobromol with selective action on the myeloid elements of bone marrow has been justified for its application in chronic myeloid leukemia therapy and also in bone marrow ablation before transplantation. Mitolactol is able to cross bloodbrain barrier, consequently could control certain brain tumors. 5-etil-2'-deoxyuridine by reducing dihydropyrimidine dehydrogenase activity is able to increase 5-fluorouracil concentration in the blood, resulting in improved antitumor effect. In contrast, 5-hexil-2'-deoxyuridine, as an inhibitor of glycoconjugate pathway by reducing heparan sulfate production, has the ability to prevent metastasis. Noteworthy, the remarkable effects of vinca alkaloids, antiestrogens, and GNRH analogues were also presented in this review.

[A new radiation-free conditioning in bone marrow transplantation and dibromo-mannitol therapy in chronic myeloid leukemia]. / Uj, sugárzásmentes csontvelö-transzplantációs kondicionáló kezelés dibróm-mannitollal krónikus myeloid leukaemiában.

A new, radiation-free, conditioning protocol, containing the original Hungarian mitobronitol (DBM) (DBM/ cytosine arabinoside/cyclosphosphamide) has been applied to 36 chronic myeloid leukemia (CML) patients followed by bone marrow transplantation (BMT) from HLA identical sibling donors between 1990-1997. In spite of some prognostically disadvantageous factors (half of them were above 40 years, 10 out of 36 patients were in accelerated phase, the disease history was longer than 2 years in average) the overall survival (30/36) and the leukemia free survival rate (26/36) were in accordance with the best international results. Transplantation-related toxicity was remarkably reduced in comparison to bone marrow transplantation performed by total body irradiation/cyclophosphamide (TBI/Cy) or busulphan/cyclophosphamide (Bu/Cy) conditioning protocols. Acute graft versus host disease was present in lower percentage (9/36) and the number of serious cases was only 2/36. Chronic GVH disease, generally known to be associated with antileukemic effect (GVL), occurred in 25 of cases. Early haematological relapse among the 34 patients with functioning graft occurred in 6 patients which rate is slightly higher than reported after TBI/Cy or Bu/Cy conditioning treatment. There was no relapse among patients transplanted within one year post-diagnosis and patients having CML with accelerated phase. The leukemia free post-transplant period was in association with the chronic GVH disease and full chimeric state.

Reduction in the frequency of transplant-related complications in patients with chronic myeloid leukemia undergoing BMT preconditioned with a new, non-myeloablative drug combination.

A radiation-free, non-myeloablative, myelosuppressive protocol, containing dibromomannitol and cytosine arabinoside, that remarkably reduced the frequency of transplant-related complications, such as veno-occlusive liver disease (VOLD), severe mucositis, bacterial sepsis, hemorrhagic cystitis, interstitial pneumonitis, has been applied in 19 CML patients, allotransplanted from identical siblings. Five patients were in accelerated phase. Acute GVHD developed in two patients and chronic GVHD occurred in 66% of patients. Follow-up was 3 to 7 1/2 years. Although only eight patients were under 30 years of age, and only two patients had a history of less than 1 year, the leukemia-free survival was 82%. There were four hematological relapses. The reduction in post-BMT complications has greatly enhanced quality of life. The nurses reported significant reduction of work-load. Savings in eliminating the need for irradiation, parenteral nutrition, and several antibiotics are also remarkable. The remarkable reduction of certain transplant-related complications shows some advantage against busulphan-preconditioning.

Erythemas associated with essential thrombocythemia.

Two cases of erythemas associated with essential thrombocythemia (ET) are reported. Case 1: A 64-year-old woman, whose ET had been treated with myebronitol for about 10 years, developed erythematous plaques on her trunk after she stopped taking the medicine. Case 2: A 58-year-old man, who had had gallstones and ET, developed annular erythemas on his thighs, arms, and trunk. Operation for the gallstones had no effect on the eruption. In both cases, remission of thrombocythemia induced by myebronitol was associated with the disappearance of these erythemas.

Course and transformation of polycythaemia vera in relation to therapy.

The fate of the polycythaemic patient depends on the treatment employed which may determine the nature of the transformation commonly occurring late in the course of the disease. Treatment is, on the other hand, aimed at prevention of the most frequent complications, that is of thromboembolic processes. In the last 30 years the authors treated a total of 118 PV patients, of whom 60 have died. Initially 32P treatment was applied, which was modified later, because of acute leukaemia that had occurred in 9% of the treated cases, to a single 5 mC 32P+Myelobromol (DBM) treatment. Still later only DBM was administered in the form of stosstherapy (2500 mg per day over a period of 4 days). In the latter two groups, acute leukaemia occurred as few as two cases. The course of untreated polycythaemia vera is characterized by transformation into another myeloproliferative disease. This phenomenon occurs in 50% of the cases on drastic treatment and in patients treated with 32P. Of the patients who were alive when the report was finished 35% had been free of complications, while 5.2% were suffering from chronic granulocytic leukaemia (CGL), 34.5% from sclerotic osteo-myelofibrosis (OMF-SC) and 3.4% from chronic megakaryocytic granulocytiv leukaemia (CMGL). Of the 60 patients having died, 15% had suffered from other complications being predominantly of vascular nature. 11.8% of them died of AML, 10% of CGL, 26.7% of OMF-SC and 26.7% of CMGL. The terminal stage was characterized, in the majority of cases, by blastic crisis. Based on their own results and literary data authors recommend DBM treatment besides the indispensable phlebotomy.

A comparative study of dibromomannitol and busulfan in the treatment of chronic myeloid leukemia. A study of cancer and leukemia group B.

In a prospective, randomized trial the effectiveness of dibromomannitol (DBM), a brominated sugar alcohol derivative, was compared to busulfan in previously untreated patients. One hundred thirty-one patients were evaluated for response and survival. The effective dose of DBM was 4 mg/kg. The persistence of sensitivity to either DBM or busulfan was shown in a quantified fashion. Despite initial reports of the alleged unique effectiveness of DBM in treating chronic myeloid leukemia (CML), this study did not disclose any advantage of DBM over busulfan. Multivariate analysis investigating the importance of prognostic factors in CML indicated that age, sex, splenomegaly, and initial platelet count were important for predicting survival. Determination of such factors in CML are valuable in deciding those patients who could benefit from alternative forms of therapy. It also insures that study results are related to treatment rather than selection of patients with favorable or unfavorable prognostic factors.

Prognostic discrimination among younger patients with chronic granulocytic leukemia: relevance to bone marrow transplantation.

To obtain information relevant to the question of bone marrow transplantation, we examined the prognostic significance of disease features recorded at the time of diagnosis among 625 patients, aged 5 to 45, with Philadelphia chromosome-positive, nonblastic chronic granulocytic leukemia. The actuarial death rate for this population was 5% during the first year after diagnosis, 12% during the second year, and averaged 22.5% per year during the next eight years. Multivariable regression analysis of features recorded in nearly all cases indicated that sex, spleen size, hematocrit, platelet count, and percentage of circulating blasts were significant prognostic indicators. Analyses of additional data available in 113 to 421 cases suggested that serum lactic dehydrogenase activity, percentage of blasts in marrow, nucleated RBCs in blood, and percentage of basophils plus eosinophils might also provide useful prognostic information. A Cox model, generated with five variables representing features recorded regularly (the first five listed), permitted segregation of these patients into three groups with significantly different survival patterns. The high-risk group exhibited an actuarial mortality of 30% during the first two years after diagnosis and an annual risk of 30% thereafter. In contrast, the most favorable group had a two-year actuarial mortality of 9% and an average risk thereafter of 17% per year, with a median survival of 5 1/2 years. We conclude that it should be possible to classify potential candidates for bone marrow transplantation according to risk with conventional therapy. Such information may be useful in making decisions regarding early v deferred marrow transplantation.

Bone marrow transplantation in accelerated chronic granulocytic leukaemia using dibromomannitol-preconditioning instead of total-body irradiation.

In a preliminary study on five patients with accelerated CGL, transplantation of allogeneic matched bone marrow was shown to be feasible without whole-body irradiation. Animal experiments and studies with cells cultured in vitro suggest that the cytocastic drug used to kill leukaemic clones (Myelobromol-Chinoin) does not injure haemopoietic stroma. The administration of this protocol is cheap and easy. Our preconditioning does not, in itself, eradicate the malignant CGL clone immediately: 15-20% of marrow mitoses were Ph1+ one month after transplantation. For this reason, additional cytostatic therapy was given in the course of the 3rd to 6th post-transplant months. No Ph1+ cells were observed from the fourth post-transplant month onwards. Very few severe acute complications were seen and two out of three matched transplanted patients are disease-free 27 + and 13 + months later. On the basis of the developing normal spleen architecture and the changing pattern of circulating NAP score values, particularly the months-long persistence of distinctly low scores, and then the delayed emergence of normal levels, we put forward a hypothesis, emphasizing the role of environmental factors, including the formation of a normal haemopoietic stroma in the successfully transplanted CGL patient.

[Results and perspectives of therapy of chronic myelosis]. / Ergebnisse und Perspektiven der Therapie der chronischen Myelose.

A survey is given on the present state of the standard therapy of chronic myeloleucosis as well as on some newer tendencies of treatment. Since in the therapy of the chronic phase of the disease and also of the blast crisis despite application of combinations of cytostatics no decisive success is to be recorded, some newer techniques--the splenectomy as well as the various kinds of the transplantation of bone marrow (autologous, syngenic, allogenic)--and their chances for success are briefly discussed.

Toxicity, antitumour and haematological effects of 1,2-anhydro-6-bromogalactitol and d-mannitol: a comparison with the related dibromo- and dianhydro-derivatives.

1,2-Anhydro-6-bromo-6-deoxygalactitol (BrEpG) and its D-mannitol analogue (BrEpM) intermediary metabolites in the conversion of dibromodulcitol (DBD) and dibromomannitol (DBM) into dianhydrogalactitol (DAG) and dianhydromannitol (DAM) have been prepared. The three types of derivative of each hexitol have been compared in their toxicities towards mice, tumour inhibitory activities against the Walker carcinosarcoma and haematological effects in rats. The bromoepoxides showed intermediate potency in all tests. The galactitol derivatives were always more potent than their mannitol counterparts. The mannitol derivatives were selectively myelosuppressive, being twice as toxic towards granulocytes as towards lymphocytes. The lymphotoxic activity of DBM, in particular, relative to its other toxic effects was particularly mild. These differences have been ascribed principally to the more rapid reactivity of DAG compared with DAM towards target nucleophiles, modulated by the influence of the bromine substituent on the transport properties of the dibromo- and bromoepoxy-derivatives.

Clinical trials with the hexitol derivatives in the U.S.

Three hexitol derivatives, dibromomannitol (DBM), dibromodulcitol (DBD), and dianhydrogalactitol (DAG), originally investigated in Hungary, have been evaluated as anticancer agents in the United States. Their principal mechanism of action is attributed to alkylation via actual or derived epoxide groups. Their preclinical spectrum includes activity against murine leukemias and against the murine ependymoblastoma, which is particularly noteworthy for DAG. Dibromomannitol trials were targeted to chronic myelogenous leukemia but no advantage over busulfan therapy was demonstrable. Dibromodulcitol and DAG were sequentially evaluated for their usefulness against a wide variety of tumors. The activity of DBD against breast cancer has stimulated several continuing trials in this disease. On the other hand, DAG was disappointing in breast cancer and in several other malignancies, but some activity has been noted against lung cancer. Both DBD and DAG are being investigated for possible usefulness in the management of patients with intracranial neoplasms. The present clinical experience does not allow firm judgment on the advantage of one analogue over another. Such comparative analysis does point out the desirable direction of future studies as well as the limitations of current preclinical systems for the selection of analogues.