Antitumor Activity Of Adriamycin Research Articles

Matrine enhances the efficacy of adriamycin chemotherapy in osteosarcoma cells by the STAT3 pathway.

Matrine and adriamycin have been extensively considered to be effective in anticancer therapies. However, the role of matrine in the antitumor activity of adriamycin against human osteosarcoma (OS) remains elusive. The aim of this study was to investigate the effect of matrine in OS chemotherapy of adriamycin. In the study, we found that matrine promoted the inhibitory effect of adriamycin against OS cell proliferation and growth. Wound healing and transwell assays showed that the inhibitory effect of adriamycin against migration and invasion of OS cells was significantly enhanced by matrine. For the underlying mechanism investigation, we showed that adriamycin reduced the protein level of PCNA, MMP-9, phosphorylated STAT3, and survivin, which was further intensified by the application of matrine. These results show that matrine could promote the therapeutic efficacy of adriamycin against human OS.

Bio-Medical Aspects of Purine Alkaloids

This review shortly summarized bio-medical activities of purine alkaloids, caffeine (caf), theophyline (top) and theobromine (tob). Caffeine potentiates the cytotoxicity of a variety of DNA domaging agents. Caffeine increased antitumor activity of some cancerostatic drugs. Caffeine inhibits the carcinogenic activity of cigarette smoke, significantly potentiating the therapeutic effect of acetaminophenol, cyclophosphoramide, enhances lipid oxidation, affects the central nervous system and alters cardiovascular system. Theophyline has expressive anti-inflammatory and antiasthmatic effect, and enhanced mobilization of lipid reduces the brain regional adenylate cyclase activity, facilitates glucose inhibition. Theophyline is muscle relaxant, vasodilator, diuretic and cardiac stimulant. Theobromine increases antitumor activity of adriamycin and doxorubicin, has expressive anti-inflammatory effect and it is classical diureticum. Several examples of caffeine with some organic substrates as well as with copper are also outlined. Increasing activity of the respective drugs in the present of the purine alkaloids can be ascribed to direct interaction as was proved by X-ray data of some caffeine adducts with organic substances as well as Cu(II) complexes.

Tumor Environment Changed by Combretastatin Derivative (Cderiv) Pretreatment That Leads to Effective Tumor Targeting, MRI Studies, and Antitumor Activity of Polymeric Micelle Carrier Systems

To evaluate effect of a vascular disrupting agent, a combretastatin derivative (Cderiv), on tumor targeting for polymeric micelle carrier systems, containing either a diagnostic MRI contrast agent or a therapeutic anticancer drug. Cderiv was pre-administered 72h before polymeric micelle MRI contrast agent injection. Accumulation of the MRI contrast agent in colon 26 murine tumor was evaluated with or without pretreatment of Cderiv by ICP and MRI. Significantly higher accumulation of the MRI contrast agent was found in tumor tissues when Cderiv was administered at 72h before MRI contrast agent injection. T(1)-weighted images of the tumor exhibited substantial signal enhancement in tumor area at 24h after the contrast agent injection. In T(1)-weighted images, remarkable T(1)-signal enhancements were observed in part of tumor, not in whole tumor. These results indicate that Cderiv pretreatment considerably enhanced the permeability of the tumor blood vessels. Antitumor activity of adriamycin encapsulated polymeric micelles with the Cderiv pretreatment suppressed tumor growth in 44As3 human gastric scirrhous carcinoma-bearing nude mice. Pretreatment of Cderiv enhanced tumor permeability, resulting in higher accumulation of polymeric micelle carrier systems in solid tumors.

Modulation by Melatonin of the Cardiotoxic and Antitumor Activities of Adriamycin

In this study, we investigated the effects of melatonin on adriamycin-induced cardiotoxicity both in vivo in rats and in vitro, and on the antitumor activities of adriamycin on MDA-231 and NCI breast cancer cells. Rats that received a single intraperitoneal injection of 25 mg/kg adriamycin showed a mortality rate of 86%, which was reduced to 20% by melatonin treatment (10 mg/kg, SC for 6 days). Melatonin attenuated adriamycin-induced body-weight loss, hemodynamic dysfunction, and the morphologic and biochemical alterations caused by adriamycin. Melatonin also reduced adriamycin-induced nuclear DNA fragmentation, as assessed by the comet assay. In addition, the antitumor activity of adriamycin could be maintained using lower doses of this drug in combination with melatonin. Melatonin treatment in the concentration range of 0.1-2.5 mM inhibited the growth of human breast cancer cells. In terms of oncolytic activity, the combination of adriamycin and melatonin improved the antitumor activity of adriamycin, as indicated by an increase in the number of long-term survivors as well as decreases in body-weight losses resulting from adriamycin treatment. These results indicate that melatonin not only protects against adriamycin-induced cardiotoxicity but also enhances its antitumor activity. This combination of melatonin and adriamycin represents a potentially useful regimen for the treatment of human neoplasms because it allows the use of lower doses of adriamycin, thereby avoiding the toxic side effects associated with this drug.

Reversal of multiple drug resistance in cholangiocarcinoma by the glutathione S-transferase-pi-specific inhibitor O1-hexadecyl-gamma-glutamyl-S-benzylcysteinyl-D-phenylglycine ethylester.

Cholangiocarcinoma is markedly resistant to chemotherapy and has a dismal prognosis, but its mechanism of drug resistance is unknown. This study examines whether glutathione S-transferase-pi (GSTP1-1) is involved in resistance to anticancer drugs in cholangiocarcinoma and whether GSTP1-1-specific inhibitors can overcome this resistance. First, immunohistochemical examination disclosed strong staining of all our 17 cholangiocarcinoma specimens for GSTP1-1, irrespective of histological type. Transfection of the GSTP1-1 antisense expression vector into a human cholangiocarcinoma cell line (HuCCT1) apparently decreased its intracellular GSTP1-1 concentration, and the sensitivity of transfectants to adriamycin (ADR), cisplatin, and alkylating agents such as melphalan and 4-hydroxyperoxycyclophosphamide (4-HC) was increased significantly, compared with that of mock transfectants. We next synthesized GSTP1-1-specific inhibitors by elongating the carbon chain of the ethylester at the N-terminal of gamma-glutamyl-S-benzylcysteinyl-phenylglycyl diethylester and performed a pharmacokinetic study on them. Of six GSTP1-1 inhibitors tested, O1-hexadecyl-gamma-glutamyl-S-benzylcysteinyl-d-phenylglycine ethylester (C16C2) showed the smallest volume of central compartment and smallest volume of distribution at steady state and the second smallest clearance, being the most effective inhibitor in vivo. The IC50 value of ADR or 4-HC for HuCCT1 cells decreased greater by treatment with C16C2 in a dose-dependent manner, paralleling the decrease in GSTP1-1 activity, than that of ADR or 4-HC alone. The antitumor activity of ADR or cyclophosphamide was clearly enhanced by combination therapy with C16C2 in a xenograft model. In conclusion, our results demonstrated that GSTP1-1 is a resistance factor for anticancer drugs in cholangiocarcinoma and that C16C2, a GSTP1-1-specific inhibitor, is a potent agent against the resistance.

Diethyldithiocarbamate may enhance the antitumor effect of adriamycin nanoparticle-lipiodol emulsion

Objective: To studied the effect of Diethyldithiocarbamate (DDC) on the antitumor activity of adriamycin (ADM) nanoparticle-lipiodol emulsion. Methods: The SD rats bearing liver carcinoma were divided into six groups and treated by saline, adriamycin, adriamycin nanoparticle-lipiodol emulsion, adriamycin liposome-lipiodol emulsion, DDC plus adriamycin nanoparticle-lipiodol emulsion, DDC plus adriamycin liposome-lipiodol emulsion respectively. The volume of the tumors, tumor growth rate (G%) and life prolonging rate PL% in six groups were determined. Results: The values of the IC50 (µg/ml) of adriamycin were reduced from 18.40 to 0.74 for the resistant cells SGC7901/CVR, and from 4.00 to 0.32 for the sensitive cells SGC7901/WT by pretreating the tumor cells with DDC. The tumor growth rate (G%) and life prolonging rate PL% increased significantly (P<0.05) in the DDC pretreated groups than adriamycin nanoparticle-lipiodol or adriamycin liposome-lipiodol emulsion groups. Conclusion: The antitumor effect of adriamycin can be enhanced by inhibiting the superoxide dismutase (SOD) in tumor cells by DDC.

Effects of methylxanthine derivatives on antitumor activity and toxic side effect of adriamycin induced by inhibition of DNA biosynthesis

The antitumor activity of adriamycin (ADR) was enhanced by combination with theobromine or pentoxifylline. Theobromine increased the concentration of ADR in the tumor without any effects on that in the heart and the liver. The influence of the combination of theobromine or pentoxifylline with ADR on the lipid peroxide level (indicating the ADR-induced side effect) and on DNA biosynthesis (indicating the side effect and antitumor activity) were examined. When ADR was administered into mice, the lipid peroxide level in the liver and the heart increased. However, the combination of theobromine or pentoxifylline did not enhance the ADR-induced increment of the lipid peroxide level in the liver, and moreover, it inhibited that in the heart. The decrease of DNA biosynthesis in the liver and the heart, induced by ADR, were not enhanced by combination with theobromine or pentoxifylline. On the other hand, the combination of theobromine with ADR significantly increased the inhibition of DNA biosynthesis in the tumor. These findings indicate that the combination of theobromine or pentoxifylline with ADR have no effect on the side effects of ADR in the liver and the heart, with the increase of antitumor activity of ADR in the tumor, and it is suggested that these drugs will be of value as a biochemical modulator of ADR.

Potentiation of antitumor and antimetastatic activities of adriamycin by a novel N-alkylated dihydropyridine, AC394, and its enantiomers in colon cancer-bearing mice

We have previously shown that a series of N-alkylated 1,4-dihydropyridines potentiate the therapeutic efficacy of vincristine in vincristine-resistant P388 leukemia. The purpose of this study was to investigate the ability of one of the compounds, AC394, and its enantiomers to potentiate the antitumor activity of adriamycin against colon cancer cells in vitro and in vivo. The effects of AC394 on potentiation of adriamycin cytotoxicity and enhancement of its accumulation were evaluated using colon 26, HCT-15 and MCF-7 cells. Furthermore, the activities of AC394 and its enantiomers were compared. We also studied the combined effects of (+)-AC394 and adriamycin on subcutaneously (s.c.)-implanted and liver metastasis tumor models. AC394 potentiated the cytotoxicity of adriamycin and enhanced its accumulation in colon cancer cells (colon 26 and HCT-15), which are known to express P-GP (P-glycoprotein) intrinsically. Enhancement of adriamycin accumulation by AC394 was found in s.c.-implanted colon 26 cells in vivo. Although both enantiomers of AC394 showed equal activity in vitro, (+)-AC394 was more effective than (-)-AC394 given orally. (-)-AC394 was found to be cleared more rapidly from the plasma than (+)-AC394. Thus, (+)-AC394 was evaluated for further study. Administration of (+)-AC394 significantly potentiated the antitumor activities of adriamycin in human colon cancer HCT-15 cells implanted s.c. Furthermore, in the liver metastasis model using colon 26 cells, a model completely resistant to adriamycin, the combination therapy of adriamycin with (+)-AC394 produced superior antitumor effects over adriamycin alone. A newly synthesized N-alkylated 1,4-dihydropyridine derivative, (+)-AC394, showed superior effects on the potentiation of adriamycin antitumor and antimetastatic activities in vivo. These results suggest that this combination may have therapeutic efficacy not only against primary colon cancers but also against metastatic liver cancer.

The effects of theanine, as a novel biochemical modulator, on the antitumor activity of adriamycin.

We studied the effects of theanine, a component of green tea leaves, on the antitumor activity of adriamycin (ADR) from the biochemical modulation view point. In vitro, theanine inhibited the ADR efflux from Ehrlich ascites carcinoma cells and maintained the ADR concentration in tumor cells. Theanine enhanced the inhibitory effect of ADR on tumor growth by 2.1-fold in vivo, and increased 2.9-fold the ADR concentration in the tumor, compared to the ADR alone group. An increase in ADR concentration was not observed in normal tissues, such as the heart and liver. Theanine did not enhance, rather tended to normalize the increase of lipid peroxide level and reduction of glutathione peroxidase activity as indicators of the ADR-induced side toxicity.

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We previously reported that caffeine inhibited adriamycin efflux in Ehrlich ascites carcinoma cells and it would be of value as biochemical modulator of adriamycin. In this study, the transport of adriamycin was investigated, in vitro, as a part of a study to clarify the mechanism of adriamycin efflux inhibition by caffeine, using metabolites of caffeine. The mechanism of the effect of caffeine on adriamycin antitumor activity, in vivo, was also studied.1, 3, 7-Trimethyluric acid did not inhibit adriamycin efflux on tumor cells in vitro, and did not enhance the antitumor activity of adriamycin in vivo. Furthermore, 1, 7-dimethylxanthine, which is the major caffeine metabolite in human, promoted adriamycin efflux. However, theobromine would be of value as biochemical modulator of adriamycin from in vitro and in vivo study. Moreover, when the temperature of incubation was 20°C, the inhibition of adriamycin efflux by caffeine did not observed, It suggest that some enzymes system in the cell will be related to adriamycin efflux. However, since ouabain had no effect on the adriamycin efflux, Na+, K+-ATPase do not concern with adriamycin efflux. And in medium without glucose, there were no effects of caffeine. It suggested that energy which supply from glucose is needed to adriamycin transport. These results suggest that the effect of caffeine, as biochemical modulator, is not due to metabolite of caffeine. And the transport of adriamycin and effects of caffeine is considered to be related to some enzymes and to some energy consumptions in the cell.

Protection by salvianolic acid A against adriamycin toxicity on rat heart mitochondria

It was found that salvianolic acid A (Sai A) has potent antioxidant activity. The effects of Sai A on adriamycin-induced heart mitochondrial toxicity of rats in vitro and on adriamycin antitumor activity are investigated in this article. Malondialdehyde (MDA) formation and membrane rigidification of rat heart mitochondria intoxicated with adriamycin were significantly reduced by Sai A. In the electron spin resonance (ESR) studies, Sai A has no significant effect on the formation of adriamycin semiquinone radicals (AQ ⋅), while hydroxyl radicals generated by electron transfer from AQ ⋅ to H 2O 2 were scavenged by Sai A dose-dependently. On the other hand, Sai A was shown to have no effects on the antitumor activity of adriamycin in cultured L1210 ascitic tumor cells and in mice with P388 ascite tumor. These results indicate that Sai A protects against adriamycin induced heart mitochondrial toxicity of rats, while Sai A has no antagonizing effect on the antitumor activity of adriamycin.

Ascorbic acid and adriamycin toxicity

Adriamycin (ADR) is effective against a wide range of human neoplasms. However, its clinical use is compromised by serious cardiac toxicity, possibly through induction of peroxidation in cardiac lipids. Ascorbic acid, a potent antioxidant, was examined for effect in reducing ADR toxicity in mice and guinea pigs. Ascorbic acid had no effect on the antitumor activity of ADR in mice inoculated with leukemia L1210 or Ehrlich ascites carcinoma, but it significantly prolonged the life of animals treated with ADR. ADR elevated lipid peroxide levels in mouse heart, and ascorbic acid prevented the elevation. The significant prevention of ADR-induced cardiomyopathy in guinea pigs by ascorbic acid was proved by electron microscopy. Ascorbic acid and the derivatives may delay general toxicity of ADR and also prevent the cardiac toxicity. The results also suggest the clinical efficacy of the combined treatment of ADR and ascorbic acid or the derivatives.

Evaluation of Quinidine Effect on the Antitumor Activity of Adriamycin and Mitoxantrone in Adriamycin-Sensitive and -Resistant P388 Leukemia Cells

Utilizing the P388 murine leukemia cells sensitive (P388/S) and resistant (P388/ADR) to Adriamycin (ADR), we evaluated the effect of quinidine, an anti-arrhythmic agent, on the cytotoxic activity of ADR and Mitoxantrone (MITO), both in vitro as well as in vivo. Quinidine enhanced the cytotoxicity of both ADR and MITO in P388/S and P388/ADR cells, as assessed by the decrease in color intensity of formazan crystal in the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. A dose dependent inhibition of 3H-thymidine and 3H-uridine incorporation was observed when the P388/S and P388/ADR cells were exposed to quinidine alone. A non-toxic concentration of quinidine (5 microM) enhanced the DNA biosynthesis inhibition induced by ADR (55 to 65%) and MITO (37 to 44%) in P388/ADR cells, indicating reversal of resistance, while in P388/S cells only a minimal increase in DNA biosynthesis inhibition was observed. The combination of quinidine at doses of 50 to 100 mg/kg significantly potentiated the antitumor activity of ADR and MITO in P388/ADR bearing mice, whereas the potentiation of ADR and MITO antitumor response was lower in P388/S bearing mice. Quinidine increased the cellular levels of ADR by 53 to 126% in P388/ADR cells in vitro, but failed to indicate such elevated levels of cellular ADR in P388/S cells. This enhanced intracellular accumulation of ADR in P388/ADR cells, explains the therapeutic efficacy of ADR and MITO in P388/ADR, both in vitro as well as in vivo. Results suggest the efficacy of quinidine to ameliorate the antitumor effects of ADR and MITO in drug resistant tumor cells.

Bepridil Enhances Adriamycin-Induced DNA Biosynthesis Inhibition in Human Myeloid Leukemia Cells

The utilization of drug response modulators, based on their physico-chemical properties to augment the cytotoxic response of anticancer drugs is now gaining importance. We present in this communication, investigations performed to assess the antitumor activity of Adriamycin (ADR), on chronic myeloid leukemia (CML) cells, and the effect of bepridil, a calcium channel blocker on the ADR cytotoxicity. Inhibition of 3H-thymidine incorporation into DNA was used as an index of the cytotoxic effects of drugs when utilised alone or in combination. The combination of bepridil (1 and 5 micrograms/ml) and ADR (5 and 10 micrograms/ml) indicated a significant (P less than 0.001) enhancement in the DNA biosynthesis inhibition in CML cells, as compared to those samples exposed to ADR alone. The observed inhibition of DNA biosynthesis was found to be totally reversible, partially reversible and completely irreversible when the CML cells were exposed to bepridil alone, ADR alone and ADR plus bepridil, respectively. Bepridil was found to be highly lipid soluble at physiological pH, and this property could be responsible for the modulation of the ADR activity observed in this study. Results obtained, though preliminary due to the small sample size, clearly indicate a necessity for a detailed evaluation of bepridil effects, which would lead to higher therapeutic gains in anticancer chemotherapy in the clinic.

Effects of Fluosol-DA and oxygen breathing on adriamycin antitumor activity and cardiac toxicity in mice.

Tumor growth delays were obtained in the MX1 human breast carcinoma xenograft treated with various combinations of Adriamycin (doxorubicin), Fluosol-DA, and carbogen breathing (95% oxygen/5% carbon dioxide). Adding carbogen breathing (6 hours) or Fluosol-DA (Green Cross, Osaka, Japan) and air breathing to this drug treatment did not change the tumor growth delay observed. When 2 hours of carbogen breathing was delivered immediately after injection with Fluosol-DA and Adriamycin, a tumor growth delay of almost 36 days was observed, which was a significant increase from the tumor growth delay obtained with Adriamycin alone (P less than 0.01). Increasing the carbogen breathing time to 6 hours immediately after drug administration resulted in a tumor growth delay of about 43 days which was not statistically significantly different from the tumor growth delay seen with the complete treatment and 2 hours of carbogen breathing, but was different from the drug alone (P less than 0.005). A morphologic evaluation of Adriamycin cardiotoxicity in combination with Fluosol-DA and carbogen breathing was carried out. There was only mild cardiotoxicity in all treatment groups. There was a trend towards increased cardiotoxicity of Adriamycin as the treatment dose was increased from 1 to 4 mg/kg/dose, reaching statistical significance (P less than 0.05) for the Adriamycin (4 mg/kg/dose) + Fluosol-DA + carbogen breathing group when compared to the three treatment groups at 1 mg/kg/dose Adriamycin. The results of these studies indicate that there may be a therapeutic gain by the use of Fluosol-DA and carbogen breathing in combination with Adriamycin chemotherapy.

Specific reduction of toxic side effects of adriamycin by induction of metallothionein in mice.

The effect of preinduction of metallothionein (MT) by bismuth (Bi) compounds on the toxic side effects and antitumor activity of adriamycin (ADR) was investigated in mice. Preinduction of MT by oral administration of bismuth subnitrate (BSN) significantly decreased the lethal toxicity, cardiotoxicity and bone marrow toxicity observed with a single subcutaneous injection of ADR. A significant increase in the concentration of cardiac MT was observed in mice treated with BSN. The MT level in the heart was significantly correlated with the protective effect of BSN against the cardiotoxicity of ADR. In tumor‐bearing mice, pretreatment with BSN did not affect the antitumor activity of ADR, although its cardiotoxicity was significantly depressed. The ability of BSN to reduce specifically the toxicity of ADR may be ascribed to the fact that Bi induces MT in the target tissue of ADR toxicity but not in a tumor. The protective effect of MT against the toxicity of ADR, which is believed to act as an anticancer agent by generating active oxygen, can be assumed to be due to its ability to scavenge free radicals or inhibit their formation.

Prevention of Adriamycin Cardiotoxicity by Niacin, Isocitrate or N-acetyl-cysteine in Mice: A Morphological Study

Adriamycin is known to produce treatment limiting cardiotoxicity. We studied the effect of niacin, isocitrate, and N-acetyl-cysteine on cumulative adriamycin-induced cardiotoxicity in NMRI mice. Pathologic grading of the hearts indicated a significant reduction in myocardial injury. In addition, according to median survival and weight changes there was a significant decrease in toxicity. As demonstrated in Ehrlich ascites tumor, coadministration of N-acetyl-cysteine may interfere with the antitumor activity of adriamycin. In contrast, niacin and isocitrate did not show significant inhibition of antineoplastic activity. Our experiments suggest a promising role of niacin and isocitrate as potential cardioprotectors in the course of chemotherapy with adriamycin.

In vivo effects of adriamycin or N-trifluoroacetyladriamycin-14-valerate on a mouse lymphoma

The antitumor activity of adriamycin (ADR) and its analog N-trifluoroacetyladriamycin-14-valerate (AD32) was studied in vivo in a solid form of the transplantable mouse B cell lymphoma DBA3. At the selected single dose of 15 mg/kg of ADR, and 80 mg/kg of AD32, both drugs had comparable effects in overall tumor control. These two dosages were used throughout the experiments, which were designed to elucidate some of the antitumor mechanisms of action of the tested compounds. The recovery kinetics of clonogens were studied using the agar diffusion chamber technique. In ADR-treated tumors, maximal reduction of the survival fraction of colony-forming cells (DC-cfu) was observed at 18 hr post-injection. Over the next 6 hr the number of DC-cfu increased 3.9-fold and returned to pre-treatment levels. Since cell division or cell loss, measured with flow cytometry or with the [ 125I ]-iododeoxyuridine assay respectively, cannot explain rebound of clonogens in treated tumors, the changes of DC-cfu strongly suggests the presence of a repair of ADR-induced damage in cells left in situ over a 24-hr period. This event was shown at time-intervals when significant levels of ADR were still detectable by HPLC in tumor tissues. The appearance and disappearance of ADR-induced DNA-protein crosslinks and protein-associated DNA single-strand breaks, established by the DNA alkaline elution technique, coincided temporally with the rebound of DC-cfu, suggesting repair of ADR damage at the molecular level. In AD32-treated tumors, maximal decrease of the survival fraction of DC-cfu was present at 12 hr post-treatment. There was only a gradual return to pre-treatment levels over the next 1.5 days. While the rebound of DC-cfu cannot be explained by selective cell loss, flow-cytometric data showed a synchronous cell cohort passing through the cell-cycle phases at 12–48 hr post-treatment, contributing to cell replication. DNA alterations induced by AD32 were identical with those caused by ADR. In partial contrast to the findings with ADR, their removal could indicate replacement of damaged cells by newly generated undamaged cells and/or ‘repair’ of DNA. In conclusion, the results suggest that AD32 has several potential therapeutic advantages over its parent compound: (1) AD32 did not induce an efficient and clearly discernible repair of tumor cells, whereas a repair mechanism, responding to a high toxic dose of ADR, could be present in ADR-treated tumors; (2) the decrease in the number of DC-cfu in tumors treated with AD32 lasted over 2 days, as compared to only 12 hr in ADR-treated tumors; (3) synchronization of a cell cohort, which might be utilized in drug combination treatments, was induced by AD32.

Mechanism of adriamycin cardiotoxicity: Evidence for oxidative stress

Adriamycin is a widely used anticancer agent but the cumulative dose-dependent cardiotoxicity severely limits the use of Adriamycin in the treatment of neoplastic diseases. Recent evidence suggests that Adriamycin forms reactive free radical species which may oxidize cellular components and produce the cardiomyopathy. Sulfhydryl donors and antioxidants have been effective in preventing acute Adriamycin cardiotoxicity in animal models presumably by scavenging the free radicals generated by Adriamycin. The sulfhydryl donors, namely cysteamine and N-acetyl cysteine, do not interfere with Adriamycin's antitumor activity. The results from these studies give considerable hope that the chronic cardiotoxicity from Adriamycin may be attenuated in people, thereby givinh additional therapeutic benefit from this antitumor agent.

Effect of sulfhydryl-containing compounds on the antitumor effects of adriamycin

The lethality of single doses of adriamycin (ADR) in male mice has been reported to be antagonized by concurrent administration of the sulfhydryl compounds cysteamine (CYS) or N-acetylcysteine (NAC). The present investigation was undertaken to determine whether CYS and NAC also have an effect on the antitumor activity of ADR. The life span of male mice bearing a transplantable Ehrlich ascites carcinoma was significantly increased by ADR administered intraperitoneally for 4 successive days at sublethal dosages of 1.5 or 2.5 mg/kg/day. CYS or NAC (50 and 100 mg/kg ip, respectively) administered 1 hr before and 7 hr after ADR treatment did not inhibit the antitumor activity of ADR and further increased the life span of these tumorbearing animals. The uptake of ADR by Ehrlich ascites cells in vitro was not affected by CYS or NAC. ADR-induced inhibition of [ 3H]thymidine incorporation into DNA of Ehrlich ascites cells in vitro was also not affected by CYS or NAC. The mechanism of sulfhydryl-induced protection against the cardiotoxicity of ADR appears not to interfere with the antitumor activity of ADR.