[Cytomorphological and enzyme histological studies of bilaterally inoculated Dibromdulcit-sensitive and-resistent Yoshida tumors]. / Cytomorphologiai és enzimhisztokémiai vizsgálatok bilaterálisan oltott Dibromdulcit-érzékeny és rezisztens Yoshida-tumorokon

In the bilaterally growing DBD sensitive Yoshida tumours deformed nuclear divisions necrosis of the majority of the tumour and appearance of giant cells can be observed due to the single administration of the LD50 of the preparation. The histochemical activity of the LDH the activity alcalyc Adenosine triphosphatase and the nonspecific alcalyc phosphatase become negative while the acidic phosphatase's activity does increase after the administration of the LD25 of the preparation appearance of giant cells are very marked more than 60% of tumours cells are polynuction. The activity of the alcalyc ATP-ase and nonspecific phosphatase decrose's after a transitory increase and become negative while the acid phosphatase's activity increases. In the case of the DBD resistant tumours the morphological and histochemical alternations due to LD50 of the preparation are much slighter and their timecourse is shorter. No morphological and histochemical changes are observed after the administration of LD25 of the preparation.

Evaluation of an intermittent schedule of dibromodulcitol in breast cancer.

Dibromodulcitol was administered orally on Days 1-10 every 3-4 weeks to 29 patients with metastatic breast carcinoma refractory to previous combination chemotherapy. Initial doses between 70 and 280 mg/m2/day were utilized. The dose was escalated as tolerated in subsequent cycles in individual patients. Hematosuppression was dose-limiting. At doses of greater than 200 mg/m2/day leukopenia (greater than 1000 cells/mm3) and thrombocytopenia (greater than 25,000 platelets/mm3) occurred in one of 28 cycles and two of 27 cycles respectively. In contrast, at doses of less than or equal to 200 mg/m2/day leukopenia and thrombocytopenia occurred in four of 18 cycles and five of 18 cycles respectively. Recovery of leukocytes (less than 4000 cells/mm3) and platelets (less than 100,000 platelets/mm3) by Day 29 after the start of therapy was also delayed at higher doses. Responses were observed in three of 29 evaluable patients and subjective improvement of osseous disease in one additional patient. A dose of 180 mg/m2/day X 10 Every 28 days is recommended in previously treated patients to avoid severe hematologic side effects.

Positive phase II trial of dibromodulcitol in patients with metastatic melanoma refractory to DTIC and a nitrosourea.

Twenty-five patients with measurable metastatic melanoma refractory to DTIC and a nitrosourea were treated with dibromodulcitol (DBD). DBD was administered orally at bedtime at a dose of 100 mg/m2/day until hematologic toxicity (a greater than or equal to 50% decrease in the wbc or platelet count) was induced. Five patients experienced clinically useful objective remissions; responding lesions included both soft tissue metastases and visceral metastatic disease. It is concluded that DBD is useful in the treatment of patients with metastatic melanoma and thus joins DTIC and the nitrosoureas as single agents which are active against this malignancy.

Effect of phenobarbital on the toxicity and antitumor activity of dibromodulcitol and dianhydrogalactitol.

5-Ethyl-5-phenylhexahydropyrimidin-2,4,6-trione (phenobarbital) pretreatment significantly decreased the acute toxicity of 1,6-dibromo-1,6-dideoxygalactitol (dibromodulcitol) in H/Riop-Swiss mice and Wistar rats. Toxicity of dianhydrogalactitol, however, was not influenced to a considerable measure. Phenobarbital did not alter in itself the growth rate of the tumours examined. It significantly reduced, however, the antitumor activity of dibromodulcitol in NK/Ly-mouse lymphoma and Yoshida rat tumor. In contrast, the cytostatic effect of dianhydrogalactitol was not influenced at all by phenobarbital. The dissimilar effects of phenobarbital on the toxicity and anti-tumour activity of dibromodulcitol and dianhydrogalactitol are probably due to differences both in their metabolism and pharmacodynamics.

Pilot studies of various combinations of dibromodulcitol, VP-16, and AMSA.

Pilot studies to obtain drug dosages for the combinations of dibromodulcitol (DBD) and BP-16, DBD and AMSA, and DBD, VP-16 and AMSA were carried out to levels of acceptable clinical toxicity. Myelosuppression was the dose-limiting toxicity in all combinations. While regressions were few in this group of heavily pretreated patients, we feel the drug combinations need further study in central nervous system, breast, and lung cancers.

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.

Mutagenicity of dibromodulcitol (DBD), an alkylating anticancer drug) and its mono- and bifunctional conversion products studied by the Salmonella/microsome assay.

Dibromodulcitol (DBD) and one of its most important bifunctional transformation products, dianhydrogalactitol (DAG) with similar cytostatic effect, were tested by the Salmonella/microsome assay on strains TA 1535, TA 1538, TA 98 and TA 100 using the plate incorporation technique. Both drugs were direct mutagens in strains TA 1535 and TA 100 and non-mutagenic in other strains. Their mutagenic effect was not influenced by S-9 mix from rat liver. Mutagenicity of DAG was very limited because of its marked toxicity. The other monofunctional alkylating derivatives, i.e., 1-bromo-3,6-anhydrodulcitol and 1,2-epoxy-3,6-anhydrodulcitol were highly mutagenic in strains TA 1535 and TA 100 with and without S-9 mix despite having no anticancer effect. Anticancer activity was exerted only by the bifunctional alkylating hexitols (DBD, DAG) which showed moderate mutagenic activity compared to the monofunctional derivatives. No correlation could be established between the mutagenic and anticancer effect of the four structurally related hexitols. Mutagenicity of urine and bile from rats after a single administration of the maximum tolerated (450 mg/kg) dose of DBD was also examined, and the hexitol components of the same urine sample were identified by t.l.c. DBD and its mutagenic transformation products were excreted in urine and not through the bile. The mutagenic effect of DBD observed cannot be attributed exclusively to DBD observed cannot be atributed exclusively to DBD itself, because the parent molecule, like other alkylating agents, easily undergoes spontaneous decomposition under in vitro and in vivo conditions to release both bi- and monofunctional alkylating solvolysis products and there highly reactive derivatives may play a role in this effect. No significant difference in the relative mutagenicity was detected between DBD and cyclophosphamide, used as a reference substance.

Phase II study of mitolactol in chemotherapy-refractory metastatic breast cancer.

Thirty-eight evaluable patients with metastatic breast cancer refractory to hormonal therapy and multiple chemotherapy regimens were treated with mitolactol at a dose of 130 mg/m2/day orally for 10 days every 6 weeks. Only one patient, with nodal and chest wall metastases, had a sustained complete regression; two patients had stable disease; and 35 patients had disease progression. The toxicity, which was primarily hematologic, was acceptable.

Dibromodulcitol, mitomycin C and vinblastine (DMV) chemotherapy in advanced breast cancer.

A combination of dibromodulcitol 500 mg orally, mitomycin C 10 mg i.v. and vinblastine 10 mg i.v. all given on day 1 and repeated every 4 weeks was given to 40 patients with advanced breast cancer. All but one had received previous endocrine therapy. The response rate (CR + PR) in 24 previously untreated patients was 66% and was 37% in 16 previously treated patients. The survival of responders was significantly longer than non-responders. Thirty-two per cent of patients experienced nausea and vomiting. There was little myelosuppression or thrombocytopenia on the day of starting a new course of therapy but the haemoglobin dropped by 2 g/dl in 32% of patients during therapy. Thus DMV is a relatively non-toxic active regimen for patients with advanced breast cancer.

The biological activity of cisplatin and dibromodulcitol in combination therapy.

The efficacy and modes of action of dibromodulcitol (DBD) and cisplatin (CDDP) were studied in several model systems. Combination treatments produced a longer survival time in mice bearing P388 solid lymphomas than either of the drugs alone. In the human metastatic melanoma HT-168 xenograft model the combined application of DBD and CDDP was also very effective, inducing a reduction in the number and volume of metastatic nodules. For V79 spheroids, DBD was mainly cytotoxic against the internal, quiescent cells, whereas cisplatin primarily killed cells in the proliferating, external regions of the spheroids. When combined, the drugs appeared to act synergistically throughout the spheroids. Studies on plasmid DNA showed that CDDP primarily generates cross-links, whereas single-strand breaks were dominant after DBD treatment. Upon using an assay for cleavage by restriction nuclease, antagonistic action of DBD and CDDP in combination may occur, nevertheless more strand breaks were always observed in these samples. These results suggest that the efficacy of combined DBD and CDDP is in part a result of 'spatial cooperation' by the drugs (i.e. affecting different cells) and in part the result of DNA damage produced by the combination treatments.