• Biomolecules & Therapeutics
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• v.1 no.2
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• pp.236-243
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• 1993

Immunologic potential of DA-125, a new anthracycline antitumor antibiotic, was investigated using guinea pigs and mice. In antigenicity experiments, guinea pigs were sensitized subcutaneously with DA-125 or DA-125 incorporated in complete Freund's adjuvant (CFA) once a week for three weeks. No systemic anaphylaxis was induced by intravenous injection of DA-125 or DA-125 incubated with guinea pig serum after 3 weeks from the last sensitization. None of sera of these animals showed any passive cutaneous anaphylactic reaction (PCA) when DA-125 or DA-125 incubated with guinea pig serum was used as a challenging antigen in homologous PCA experiment. On the other hand the treatment of guinea pigs with ovalbumin Incorporated in CFA induced systemic anaphylactic reaction when challenged by intravenous injection of 5 mg/body of ovalbumin. Immunodiffusion test revealed no precipitating antibodies as detected in guinea pigs sensitized with DA-125. In 24-hour heterologous PCA reaction with sera of C57BL/6 mice immunized with DA-125 or DA-125 mixed with aluminum hydroxide gel (Alum), None of sera showed positive reaction when DA-125 or DA-125 incubated with rat serum was used as a challenging antigen. Sera of animals immunized with a mixture of ovalbumin and alum showed positive PCA reaction when 5 mg/body of ovalbumin was injected as a challenging antigen. In lymphocyte proliferation tests, spleen lymphocyte proliferation to PHA and LPS was similarly impaired by 12 mg/kg of DXR or 36 mg/kg of DA-125, and the immunodepressive activity of DA-125 showed a dose-dependent manner. From these results, it could be concluded that immunosupression of DA-125 would be comparable to that of DXR and that DA-125 would not induce systemic allergic reaction in its clinical use.

• Biomolecules & Therapeutics
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• v.1 no.1
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• pp.20-25
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• 1993

DA-125, a new anthracycline derivative, shows significant anticancer activities. We conducted a study to examine the local irritating effect of DA-125 using mice and rabbits. In the skin test in mice, intradermal injection of 0.4 mg of DA-125, compared to a dosage of 0.2 mg of adriamycin, had weak irritating potentials to induce skin ulceration and erythematous induration. A dosage of 0.6 mg of DA-125 produced similar degree of lesions in perivascular irritation model to that of 0.2 mg of adriamycin, but the healing time was shorter in the case of mice treated with DA-125. In ocular irritation study in rabbit, the highest M.O.I.(mean ocular irritation index) of 0.5% DA-125 solution was 0.67, therefore DA-125 could be considered as a practically non-irritating anticancer agent. These results suggest that substitution of DA-125 for Adriamycin would reduces the possibility of outbreaks of local irritation and the severity of the lesions.

• Biomolecules & Therapeutics
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• v.1 no.2
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• pp.244-250
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• 1993

Hematotoxicity and vascular irritation of DA-125, a new anthracycline antitumor antibiotic, were investigated in mice and rabbits. In hematotoxicity study, healthy male ICR mice were treated with DA-125 by a single intravenous injection at doses of 18 and 24 mg/kg. After 4, 8, 12 and 16 days WBC count, RBC count, hemoglobin concentration, hematocrit value, and platelet counts were measured respectively. As a positive control, 12 mg/kg of doxorubicin (DXR) was used in the same manner. Remakable reductions of WBC counts in groups treated with DA-125 or DXR were observed 4 days after administration and returned to normal range 8 days after injection in groups of DA-125 18 mg/kg and DXR 12 mg/kg. The recovery of leukopenia induced in a group of DA-125 24 mg/kg took about 16 days after administration. The RBC counts, hemoglobin concentrations and hematocrit values also decreased in all drug treated groups on day 8 and recovered thereafter. The platelet counts of groups treated with DA-125 or DXR decreased on day 4 and recovered from day 8 of experiment. Local vascular irritation of DA-125 was also assessed in rabbits. The obtained results can be summarized as follows. 1. Thrombophlebitis was not induced even after daily intravenous administration of 0.4% solution of DA-125 or 0.2% solution of DXR for 7 days. 2. Macro- and microscopic observations revealed that the irritative activity of 0.4% solution of DA-125 in blood vessels was not so much different from that of saline when they were injected once a day into vein retroauricularis of rabbits for 7 days. 3. Mild inflammatory reaction was noted around vessels in rabbits treated with 0.2% solution of DXR after consecutive intravenous infusion for more than 5 days. 4. The potencies of vascular irritation of the test solutions were summarized in the following order; saline = 0.4% DA-125<0.2% DXR. These results indicated that DA-125 showed similar pattern of hematotoxicity with DXR but was less hematotoxic than DXR, and that 0.4% solution of DA-125 did not elicit unusual toxic properties when injected through intravenous route for clinical practice.

• Biomolecules & Therapeutics
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• v.1 no.1
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• pp.9-19
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• 1993

DA-125, a new anthracycline antibiotic, showed antitumor activity against animal tumors and human tumors. Therefore we studied the cardiotoxic potential of DA-125 in hamsters and rats as a part of safety research, and compared it with that of doxorubicin(DXR). In acute cardiotoxicity test model used hamsters DA-125 was administered intravenously at a dose of 6, 9, 12 mg/kg, and DXR at 3 mg/kg was given. The electrocardiogram(ECG) of hamsters was recorded for 30 minutes after administration. The DA-125 caused slight ECG alterations at a dose of 6 mg/kg. At a dose of 12 mg/kg DA-125 induced moderate to remarkable changes in ECG like decrease of heart rate, widening of PR interval and 07 interval, and A-V block in 3 out of 5 animals. The severity of ECG alteration at 12 mg/kg of DA-125 was similar to that at 3mg/kg of DXR and these changes caused by DA-125 and DXR recovered within 10 minutes after injection. In chronic cardiotoxicity test model used rats, DA-125 was administered intravenously once a week for three weeks at a dose of 6, 9mg/kg and DXR was given at a dose of 6mg/kg. Electrocardiogram was recorded every week from the start of administration to 2 weeks after the last administration and the animals were sacrificed for histological heart examination at 1 week or 2 weeks after the last administration. DA-125 did not cause any abnormal changes in ECG and in histological heart examination due to administration, but DXR caused widening of ST segment, QRS complex, and QT interval from 1 week after administration and these changes were continued to necropsy. These alterations in ECG were accompanied by cardiac histological lesions such as vacuolation in myocardiac cells, interstitial edema and necrosis of myocytes. These results suggest that DA-125 is less cardiotoxic than DXR.

• Biomolecules & Therapeutics
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• v.5 no.2
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• pp.110-116
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• 1997

The present study was designed to evaluate the effects of a recombinant human granulocyte-colony stimulating factor (G-CSF) on leukopenia and tumor growth in mice treated with DA-125, an adri-amycin (ADM) derivative. In normal mice, single intravenous injection of DA-125 produced transient leukopenia accompanied with weight loss and splenic atrophy in a dose-related manner. However, subcutane-ous administration of G-CSF (5$\mu$g/head) for 5 consecutive days after DA-125 resulted in a significantly elevated nadir of leukocyte counts and facilitation of recovery from the leukopenia. To investigate the effect of G-CSF on antitumor effects of DA-125, ADM (12 mg/kg) or DA-125 (40 mg/kg) was administered to Colon-26 murine adenocarcinoma-bearing Balb/c mice with G-CSF. Regardless of treatment with G-CSF, DA-125 and ADM markedly retarded the growth of implanted tumor, though they failed to increase mean survival time of tumor-bearing mice. These results suggest that G-CSF is able to not only ameliorate, but reconstitute DA-125-induced myelosuppression without affecting its antitumor potential.

• YAKHAK HOEJI
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• v.43 no.5
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• pp.623-628
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• 1999

DA-125, a new antitumor agent, was compared with adriamycin, a known DNA intercalator, in terms of inhibitory mechanism of DNA replication by using replicating simian virus 40 (SV40) genome in vivo. In analyzing the SV40 DNA replication intermediates present in cells treated with DA-125, it was not observed to accumulate B-dimers of SV40 DNA which are prominent in adriamycin-treated cells. However, treatment with DA-125 induced dose-dependent formation of DNA-topoisomerase complex which is characteristic of topoisomerase poisons. In addition, DA-125 showed more efficient in inhibiting SV40 DNA replication than adriamycin. Therefore, on the basis of this observation, we suggest that DA-125, a derivative of adriamycin, inhibits DNA replication by blocking topoisomerase activity as a toposomerase poison although adriamycin blocks topoisomerase activity as a DNA intercalator.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1993.04a
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• pp.36-36
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• 1993

DA-125의 분광학적, 물리화학적, 물리적 특성을 규명하고 HPLC 및 Bioassay에 의한 정량법을 개발하였다. DA-125는 용액중에서 pH의존적 안정성을 나타내었으며, 원말의 안정성은 상대습도에 의한 영향을 크게 받았다. DA-125의 합성수율은 약 10％ 향상되었으며, 연구용 시료는 약 72g을 합성하였다. DA-125는 ADM 내성암주에 대해서도 상대적으로 매우 강한 세포독성을 나타냈으며, in vivo애서도 ADM보다 우수한 종양성장억제율과 연명율을 나타내었고 특히 장기생존수에서 ADM 투여군에서는 생존예가 없는 반면 DA-125 투여군에서는 7/8이 생존하는 우수한 결과를 나타냈다. DA-125의 일반약리작용은 ADM과 유사하였으나 작용은 보다 경미하였다.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1994.04a
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• pp.309-309
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• 1994

DA-125에 당류로서 Inositol, Dextrose, Iactose, Mannitol 및 Sorbitol을 첨가하여 DA-125 단독으로 용해한 시료와 비교 평가하였을 때 DA-125의 안정성에 큰 영향이 없었으며, 아미노산 중 L-lysine첨가시 안정성이 향상되는 컷으로 나타났다. 염류를 사용하였을 때는 NaCl, MgSO$_4$첨가시 안정성이 크게 증가하였으며, NaCl의 첨가 농도에 따른 안정성을 시험한 결과 NaCl의 농도 증가에 따라 DA-125의 안정성이 증가하는 것으로 나타났다. 또한 기타 안정화제로 Sodium Bisulfite 첨가시 안정성이 증가되었다. 안정성 시험 중 pH및 용액상태는 변화하지 않았다.

• The Korean Journal of Pharmacology
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• v.30 no.2
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• pp.227-242
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• 1994

The general pharmacological effects of a new anthracycline anticancer agent, DA-125 $[7-0-(2,\;6-dideoxy-2-fluoro-{\alpha}-L-talopyranosyl)-adriamycinone-14-{\beta}-alaninate{\cdot}HCI]$ were investigated in mice, rats, guinea pigs, rabbits and dogs. Intravenous administration of DA-125 presented no significant effects on the central and peripheral nervous systems of ICR mice except a decrease in the numbers of acetic acid-induced writhing response at a dose of 10 mg/kg. In anesthetized rats and dogs, DA-125 produced a transient depression of blood pressure and an increase in heart rate, but did not affect the peripheral blood flow in the isolated ear vessels of rabbits and the mechanical functions of the isolated hearts of guinea pigs. No significant effects were observed on the gastrointestinal functions and the contractilities of smooth muscle preparations obtained from guinea pig trachea, rabbit ileum, pregnant and non-pregnant uterus and vas deferens of rats. DA-125 Increased the contractility of the isolated ileum of guinea pigs in a dose range of $10^{-6}{\sim}10^{-9}g/ml$, and also increased, but weaker than adriamycin, the vascular permeability in rat skin. DA-125 had no effect on the kallikrein-induced increase in permeability and the permeability of the visceral organs. DA-125 did not adversely affect the liver function and the blood coagulation system, and did not induce hemolysis in vitro. It is concluded from the results that the general pharmachological effects of DA-125 are similar to or weaker than those of adriamycin, and that little adverse effects are anticipated with a therapeutic dose range.

• Archives of Pharmacal Research
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• v.27 no.1
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• pp.77-82
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• 2004

DA-125, a novel derivative of adriamycin, is known for its anti-cancer activity. In this study, the inhibitory mechanism of DA-125 on topoisomerase was investigated in the simian virus 40 (SV40) replicating CV-1 cell by studying the SV40 DNA replication intermediates and DNA-topoisomerase complexes. DNA-protein complexes that were formed in the drug-treated cells were quantitated by using a glass filter assay. SV40 DNA replication intermediates that were accumulated in the drug-treated CV-1 cell were analyzed in a high resolution gel. DA-125 did not accumulate B-dimers of SV40 DNA replication intermediates which were found in the adriamycin-treated CV-1 cells. DA-125 induced a dose-dependent formation of the DNA-protein complexes, while adriamycin did not. When adriamycin and etoposide (VP16) were added to the SV40-infected cells at the same time, adriamycin blocked the formation of the DNA-protein complexes induced by VP16 in a dose-dependent manner. However, DA-125 blocked the formation of the DNA-protein complexes induced by VP16 up to the maximum level of the DNA-protein complexes that were induced by DA-125 alone. Adriamycin and DA-125 did not inhibit the formation of the DNA-protein complexes that were caused by camptothecin, a known topoisomerase I poison. DA-125 is bifunctional in inhibiting topoisomerase II because it simultaneously has the properties of the topoisomerase II poison and the DNA intercalator. As a topoisomerase II poison, DA-125 alone induced dose-dependent formation of the DNA-protein complexes. However, as a DNA intercalator, it quantitatively inhibited the formation of the DNA-protein complexes induced by a strong topoisomerase II poison VP16. Furthermore considering that the levels of the DNA-protein complex induced by VP16 were decreased by DA-125 in terms of the topoisomerase II poison, we suggest that DA-125 has a higher affinity to the drug-binding sites of DNA than VP16 has.