Intraperitoneal Administration Of Doxorubicin Research Articles

Novel derivative of nicotinic acid ameliorates doxorubicin-induced cardiac injury via regulation of redox homeostasis

Introduction: Doxorubicin (DOX) is an anthracycline antibiotic with considerable significance in clinics as an anticancer agent, which is limited by its cardiotoxicity, though. A large number of possible therapeutic strategies for reducing cardiotoxicity with doxorubicin have been studied. However, none of them fully meets the requirements of clinical practice. The aim of the study: to evaluate the cardioprotective effects of a new original heterocyclic compound, a pyridine-3-carboxylic acid derivative potassium 5-hydroxynicotinate. Materials and Methods: Cardiac injury was induced by intraperitoneal administration of doxorubicin (DOX) at a dose of 20 mg/kg. After 48 hours, the parameters of left ventricular contractility and StTTI coefficient were assessed on isolated heart in the Langendorff system under the conditions of 480 beats per minute for 11 seconds. Additionally, specific markers of myocardial injury were determined. The lipid peroxidation products and SOD activity were measured as well to challenge whether the compound is able to reduce oxidative stress. Results: The study showed that pretreatment by potassium 5-hydroxynicotinate (35 mg/kg, 48 h) attenuated DOX-induced damage, resulting in a significant decrease in the StТТI coefficient to 3.3 values and in the restoration of the antioxidant activity of enzymes. Conclusion: The obtained data totally demonstrate the protective effects of potassium 5-hydroxynicotinate in DOX-induced cardiomyopathy. A significant role in potassium 5-hydroxynicotinate-mediated cardioprotection is, apparently, related to the reduction of oxidative stress and down-regulation of the level of intracellular calcium.

Dynamics of morphological changes in the heart of rats after serial systemic administration of Doxorubicin

Along with a good antitumor effect, Doxorubicin has a systemic effect with damage to vital organs, in particular the heart. The lack of a unified approach to dosing and the frequency of administration of Doxorubicin in the experiment prompts the search for an optimal model of Doxorubicin cardiomyopathy. The aim of the study was to develop a method of serial administration of Doxorubicin in medium therapeutic doses in an experiment and to evaluate the cardiotoxic effect of the drug. 42 female Wistar rats were included in the study. The control group consisted of 7 intact rats. The experimental group consisted of 35 rats who received systemic chemotherapy with Doxorubicin at a dose of 5 mg/kg once a week for 5 weeks. On days 7th, 14th, 21st, 28th, 35th, the hearts of experimental animals were taken for morphological examination. Histomorphometrically determined: the diameter of cardiomyocytes (in the middle part) and the transverse diameter of their nucleus, the width of the interstitial space (endo- and perimysia). The data of histomorphological and histomorphometric examination of the myocardium testified that all animals of the experimental group had a circulatory disorder in the heart muscle at the level of hemomicrocirculation. Such changes led to cardiomyocyte hypotrophy, interstitial edema and fibrosis. During systemic chemotherapy, the animals showed marked changes in the myocardium, such as expansion of the endomysial zone, due to capillary congestion and edema, in comparison with animals of the intact group. At the end of the experiment, the animals of the experimental group retained the expansion of the endomysial zone, mainly due to interstitial fibrosis. Such changes indicate myocardial hypoxemia with damage and death of cardiomyocytes, activation of interstitial and replacement collagen formation. The obtained morphological data indicate the development of dilated cardiomyopathy in experimental animals. Serial intraperitoneal administration of Doxorubicin at a dose of 5 mg/kg once a week for 5 weeks causes morphological changes in the myocardium of experimental animals, similar to changes in the heart of people undergoing chemotherapy with this drug.

The effect of bendamine on the intensity of lipid peroxidation and the activity of the antioxidant defense system of blood in rats in experimental doxorubicin-induced cardiomyopathy

Experimental studies obtained in recent years indicate the urgency of developing drugs of complex action to prevent the development of cardiovascular disease in dogs. This requires a much deeper study of the pathogenesis of heart failure, including cardiomyopathy. The aim of the study was the effect of bendamine on the intensity of lipid peroxidation and the activity of the antioxidant defense system of blood in rats in experimental doxorubicin-induced cardiomyopathy. To reproduce heart failure in rats, an experimental model was used by intraperitoneal administration of doxorubicin at a dose of 2.5 mg/kg 3 times a week for two weeks. The study was performed on white sexually mature young male Wistar rats weighing 180–200 g, which were kept on the standard diet of the institute vivarium of the State Research Control Institute of Veterinary Drugs and Feed Additives. For the study, three groups of rats of 6 animals in each were formed: control group – intact animals; experimental group R1, in which animals were simulated doxorubicin-induced cardiomyopathy by intraperitoneal administration of doxorubicin; experimental group R2, in which animals after injection of doxorubicin, intragastrically administered the drug “Bendamine” at a dose of 20 mg/kg. According to studies, doxorubicin intoxication in rats enhances LPO processes, as indicated by an increased content of lipid hydroperoxides by 47.4 %, diene conjugates – by 21.4 % and TBA-active products – by 24.9 % for animals of the control group. Doxorubicin cardiomyopathy in rats has a decrease in the activity of antioxidant enzymes in the blood of animals. In particular, the activity of catalase decreases by 36.9 % (P ≤ 0.001), and the activity of SOD – by 20.3 % (P ≤ 0.001). In the study of the activity of the glutathione link of the antioxidant defense system, similar changes were found as in the study of the activity of catalase and SOD. The use of the drug “Bendamine” in the rats of the experimental group helped to inhibit the excessive formation of lipid peroxidation products and increase the activity of both enzymatic and non-enzymatic parts of the antioxidant system.

Influence of the preparation “Bendamin” on the indicators of antioxidant protection of rat myocardium in experimental modeling of heart failure

The aim of this study was to investigate the effect of Bendamin on the antioxidant status of rats in experimental doxorubicin-induced cardiomyopathy. The studies were performed on white sexually mature young male of Vistar line rats weighing 180–200 g, which were kept on a standard diet of the Institute Vivarium of the State Research Institute of Veterinary Drugs and Feed Additives. Animals were divided into 3 groups of 6 animals in each: control group – intact animals; experimental group R1, in which animals were simulated with doxorubicin-induced cardiomyopathy by intraperitoneal administration of doxorubicin at a dose of 2.5 mg/kg 3 times a week for two weeks; experimental group R2, in which animals were injected with the drug “Bendamin” at a dose of 20 mg/kg after injection of doxorubicin. The data obtained indicate that the introduction into the experimental animals of the experimental group of doxorubicin is accompanied by intensification in the myocardium of the processes of free radical oxidation. The increase in diene conjugates was found to be 32.7% and TBK-active products increased by 37.6% compared to the control group of rats. Doxorubicin was also found to cause inhibition of the glutathione system of the animal's antioxidant protection after administration to rats. After administration of the drug “Bendamin”, rats of the second experimental group were suppressed with lipid peroxidation under the conditions of doxorubicin intoxication. In the rats of the second experimental group, the level of intermediates and end products is likely to decrease, so in the rat myocardial homogenate the level of diene conjugates decreased by 16.8% and the level of TBA-active products by 20.8% compared to the first experimental group. who had clinical signs of cardiomyopathy caused by doxorubicin administration. The use of the drug “Bendamin” in rats of the second experimental group contributed to the enhancement of the enzymatic and non-enzymatic element of the antioxidant system, protecting the structural and functional integrity of cell bioembranes. The results of the studies enrich the pharmacological characteristics of the drug “Bendamin”, indicate its sufficiently clear protective effect on the myocardium in experimental doxorubicin cardiomyopathy and is a convincing proof of the feasibility of the drug in veterinary practice.

Impact of corvitin and alpha-ketoglutarate on heart morphology, expression and activity of matrix metalloproteinases 2/9 in the heart of rats with doxorubicin-induced cardiomyopathy

The anthracycline anticancer drug doxorubicin is an effective and frequently used chemotherapeutic agent for various malignancies but it causes acute ventricular dysfunction, and also induces cardiomyopathy and heart failure. One of the mechanisms of cardiotoxicity of doxorubicin is oxidative stress, which stimulates myocardial remodeling. Matrix metalloproteinases MMP2 and MMP9 play a key role in this process. Despite extensive research, the expression and activity of these enzymes in the doxorubicin-damaged heart and the effect of antioxidants on these indicators have not been sufficiently studied. The aim of this work was to study the possible cardioprotective effect of the antioxidant drugs corvitin and alpha-ketoglutarate in rats with doxorubicin-induced cardiomyopathy. Cardiomyopathy in rats was induced by intraperitoneal administration of doxorubicin at the dose of 2.5 mg/kg body weight weekly for 28 days. Animals were divided into four groups: group 1 (control) received saline injections (2.5 mL/kg); group 2 – injections of doxorubicin, 3 – corvitin (5 mg/kg) 60 minutes before doxorubicin administration, 4 – doxorubicin and 1% solution of alpha-ketoglutarate in drinking water ad libitum. Heart weight and shape indexes, the ratio of muscle to connective tissues, and heart histology were examined 7 days after the end of drug administration. Activity of MMP2 and MMP9, their intracellular distribution in myocardial tissues were evaluated by gelatin-zymography and immunohistochemistry. It was found that doxorubicin cardiomyopathy in rats was accompanied by a decrease in heart weight index, adaptive change of heart shape from ellipsoid to globular, increase of connective tissue content. Administration of doxorubicin results in profound lesion of the cardiomyocytes of the atria and ventricle, manifested by excessive cytoplasmic expression of MMP2 and MMP9 and an increase their activity in the heart. Antioxidants corvitin and alpha-ketoglutarate have insufficient regenerative effect on mass and shape indexes of heart however, exhibit potent cardioprotective effect by regulation of expression and activity of MMP2 and MMP9.

Doxorubicin Exposure Causes Subacute Cardiac Atrophy Dependent on the Striated Muscle-Specific Ubiquitin Ligase MuRF1.

Background Anthracycline chemotherapeutics, such as doxorubicin, are used widely in the treatment of numerous malignancies. The primary dose-limiting adverse effect of anthracyclines is cardiotoxicity that often presents as heart failure due to dilated cardiomyopathy years after anthracycline exposure. Recent data from animal studies indicate that anthracyclines cause cardiac atrophy. The timing of onset and underlying mechanisms are not well defined, and the relevance of these findings to human disease is unclear. Methods and Results Wild-type mice were sacrificed 1 week after intraperitoneal administration of doxorubicin (1-25 mg/kg), revealing a dose-dependent decrease in cardiac mass ( R2=0.64; P<0.0001) and a significant decrease in cardiomyocyte cross-sectional area (336±29 versus 188±14 µm2; P<0.0001). Myocardial tissue analysis identified a dose-dependent upregulation of the ubiquitin ligase, MuRF1 (muscle ring finger-1; R2=0.91; P=0.003) and a molecular profile of muscle atrophy. To investigate the determinants of doxorubicin-induced cardiac atrophy, we administered doxorubicin 20 mg/kg to mice lacking MuRF1 (MuRF1-/-) and wild-type littermates. MuRF1-/- mice were protected from cardiac atrophy and exhibited no reduction in contractile function. To explore the clinical relevance of these findings, we analyzed cardiac magnetic resonance imaging data from 70 patients in the DETECT-1 cohort and found that anthracycline exposure was associated with decreased cardiac mass evident within 1 month and persisting to 6 months after initiation. Conclusions Doxorubicin causes a subacute decrease in cardiac mass in both mice and humans. In mice, doxorubicin-induced cardiac atrophy is dependent on MuRF1. These findings suggest that therapies directed at preventing or reversing cardiac atrophy might preserve the cardiac function of cancer patients receiving anthracyclines.

Antioxidant activity of Spirulina platensis alleviates doxorubicin-induced oxidative stress and reprotoxicity in male rats

Male infertility is a common side effect of doxorubicin (DOX) that substantially impairs the quality of life of young cancer survivors. Therefore, the current work was designed to evaluate the possible antioxidant and gonado-protective effects of Spirulina platensis (S. platensis) in DOX-treated rats. Intraperitoneal administration of DOX (3 mg/kg b.wt.) once weekly for 5 weeks significantly decreased the levels of testicular catalase, superoxide dismutase and glutathione peroxidase. Moreover, it significantly decreased serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels, as well as sperm motility and sperm count. Additionally, DOX treatment significantly increased the testicular malondialdehyde concentration and the percent of sperm abnormalities and resulted in marked cystic dilation of seminiferous tubules with extensive separation, dissociation of germinal cells from the basement membrane and arrested spermatogenesis. Oral administration of S. platensis at a dose of 300 mg/kg daily for 5 weeks mitigated DOX-induced oxidative stress, testicular damage, hormone alterations and spermiogram abnormalities via its potent antioxidant activity. S. platensis may represent a potential therapeutic option to protect testicular tissue during DOX treatment.

Dendrimer-doxorubicin conjugates exhibit improved anticancer activity and reduce doxorubicin-induced cardiotoxicity in a murine hepatocellular carcinoma model.

Hepatocellular carcinoma (HCC) is the 2nd leading cause of cancer-related deaths every year globally. The most common form of treatment, hepatic arterial infusion (HAI), involves the direct injection of doxorubicin (DOX) into the hepatic artery. It is plagued with limited therapeutic efficacy and the occurrence of severe toxicities (e.g. cardiotoxicity). We aim to improve the therapeutic index of DOX delivered via HAI by loading the drug onto generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers targeted to hepatic cancer cells via N-acetylgalactosamine (NAcGal) ligands. DOX is attached to the surface of G5 molecules via two different enzyme-sensitive linkages, L3 or L4, to achieve controllable drug release inside hepatic cancer cells. We previously reported on P1 and P2 particles that resulted from the combination of NAcGal-targeting with L3- or L4-DOX linkages, respectively, and showed controllable DOX release and toxicity towards hepatic cancer cells comparable to free DOX. In this study, we demonstrate that while the intratumoral delivery of free DOX (1 mg/kg) into HCC-bearing nod scid gamma (NSG) mice achieves a 2.5-fold inhibition of tumor growth compared to the saline group over 30 days, P1 and P2 particles delivered at the same DOX dosage achieve a 5.1- and 4.4-fold inhibition, respectively. Incubation of the particles with human induced pluripotent stem cell derived cardiomyocytes (hiPSC CMs) showed no effect on monolayer viability, apoptosis induction, or CM electrophysiology, contrary to the effect of free DOX. Moreover, magnetic resonance imaging revealed that P1- and P2-treated mice maintained cardiac function after intraperitoneal administration of DOX at 1 mg/kg for 21 days, unlike the free DOX group at an equivalent dosage, confirming that P1/P2 can avoid DOX-induced cardiotoxicity. Taken together, these results highlight the ability of P1/P2 particles to improve the therapeutic index of DOX and offer a replacement therapy for clinical HCC treatment.

Protective effect of a direct renin inhibitor in acute murine model of cardiotoxicity and nephrotoxicity

This study aimed to investigate the possible protective effects of aliskiren against doxorubicin (DXR)-induced cardiorenal injury and to identify the mechanisms involved. Intraperitoneal administration of DXR (15 mg/kg, body weight, as a single dose) caused significant induction in the levels of angiotensin I, caspase-3, lactate dehydrogenase (LDH), lipid peroxidation malondialdehyde (MDA), urea, and creatinine. Concomitant decline in the levels of albumin and total protein in plasma, reduction in reduced glutathione (GSH), and antiperoxidative enzyme superoxide dismutase (SOD) levels followed by ultrastructural alterations in the myocardial and renal tissues were also observed. Oral administration of aliskiren (100 mg/kg, for a period of 14 days) significantly prevented all these DXR-induced adverse effects and maintained the rats near to normal status. However, telmisartan (10 mg/kg) pretreatment has shown slight protection in DXR-induced renal injury as evidenced by broadening of podocyte foot process and narrowing of slit pore diameter. The results of aliskiren were compared with telmisartan which was used as reference in this study. These results suggested that aliskiren has protective effects against acute model of DXR-induced cardiotoxicity and nephrotoxicity, implying that plasma renin activity plays a role in DXR-induced cardio-renal injury.

GW24-e3067 Animal model for unloading the rat hearts of end-stage dilated cardiomyopathy

ObjectivesTo create a model of minicking VAD by unloading rats with HF (heart failure) after dilated cardiomyopathy in rats.MethodsHeart failure (HF) was induced by the intraperitoneal administration of doxorubicin (total...

Amelioration of doxorubicin-induced myocardial oxidative stress and immunosuppression by grape seed proanthocyanidins in tumour-bearing mice

We have investigated the protective effects of grape seed proanthocyanidins on doxorubicin-induced toxicity in tumour-bearing mice. The intraperitoneal administration of doxorubicin (2 mg kg(-1) every other day, cumulative dosage for 18 mg kg(-1)) significantly inhibited the growth of sarcoma 180, and induced myocardial oxidative stress with decreased superoxide dismutase and glutathione peroxidase activity while increasing malondialdehyde formation in the heart or serum. Doxorubicin-induced myocardial oxidative stress also reduced lactate dehydrogenase and creatine kinase activity in the heart and elevated their levels in the serum. Doxorubicin also affected immune functions of tumour-bearing mice with significantly decreased interleukin-2 (IL-2) and interferon-gamma (INF-gamma) production, and slightly decreased natural killer (NK) cell cytotoxicity, lymphocyte proliferation and CD4+/CD8+ ratio. It markedly increased the percentages of cytotoxic T cells (CD3+CD8+), helper T cells (CD3+CD4+), IL-2R+CD4+, and IL-2R+ cells as compared with untreated tumour-bearing mice. The intragastric administration of proanthocyanidin (200 mg kg(-1) daily) significantly inhibited tumour growth, and increased NK cell cytotoxicity, lymphocyte proliferation, CD4+/CD8+ ratio, IL-2 and INF-gamma production. Moreover, proanthocyanidin strongly enhanced the anti-tumour effect of doxorubicin and the above immune responses, and completely eliminated myocardial oxidative stress induced by doxorubicin. In conclusion, intragastric administration of proanthocyanidin could enhance the anti-tumour activity of doxorubicin and ameliorate doxorubicin-induced myocardial oxidative stress and immunosuppression in tumour-bearing mice.

Intracoronary Infusion of Skeletal Myoblasts Improves Cardiac Function in Doxorubicin-Induced Heart Failure

Background Skeletal myoblast transplantation is promising for the treatment of end-stage heart failure. Direct intramyocardial injection is useful for local cell delivery but may not be effective in global dissemination of cells into the heart, which would be advantageous in treating generalized cardiac dysfunction as in dilated cardiomyopathy. We hypothesized that intracoronary infusion of myoblasts would disseminate cells more effectively, leading to functional improvement in global heart failure. Methods and Results Heart failure was induced by the intraperitoneal administration of doxorubicin (total dose 15 mg/kg) in rat. One million primary skeletal myoblasts were then infused via the coronary arteries of an excised, failing doxorubicin-treated heart. After incubation under increased intracoronary pressure, the hearts were subsequently transplanted into syngeneic recipients. For the control group, doxorubicin-treated hearts were infused with medium only and transplanted. Four weeks after transplantation, Langendorff perfusion demonstrated that both maximum dP/dt (2797.6±103.3 versus 2326.9±133.1 mm Hg/s, P =0.01) and minimum dP/dt (−2067.4±88.1 versus −1718.8±91.3 mm Hg/s, P =0.02) were improved in myoblast-transplanted hearts compared with medium-infused hearts. This was associated with a sharper slope of the left ventricular developed pressure-volume curve and a reduced slope of the end-diastolic pressure-volume relation in the myoblast-transplanted hearts. Immunohistochemistry for skeletal myosin heavy chain showed that globally disseminated myoblasts had survived and differentiated into multinucleated myotubes that had aligned with the cardiac fiber axis within host myocardium. No significant myocardial infarction was observed. Conclusions We demonstrated the feasibility and efficiency of skeletal myoblast transplantation via the intracoronary route as a promising strategy for improving cardiac function in global heart failure.

Intracoronary infusion of skeletal myoblasts improves cardiac function in doxorubicin-induced heart failure.

Skeletal myoblast transplantation is promising for the treatment of end-stage heart failure. Direct intramyocardial injection is useful for local cell delivery but may not be effective in global dissemination of cells into the heart, which would be advantageous in treating generalized cardiac dysfunction as in dilated cardiomyopathy. We hypothesized that intracoronary infusion of myoblasts would disseminate cells more effectively, leading to functional improvement in global heart failure. Heart failure was induced by the intraperitoneal administration of doxorubicin (total dose 15 mg/kg) in rat. One million primary skeletal myoblasts were then infused via the coronary arteries of an excised, failing doxorubicin-treated heart. After incubation under increased intracoronary pressure, the hearts were subsequently transplanted into syngeneic recipients. For the control group, doxorubicin-treated hearts were infused with medium only and transplanted. Four weeks after transplantation, Langendorff perfusion demonstrated that both maximum dP/dt (2797.6+/-103.3 versus 2326.9+/-133.1 mm Hg/s, P=0.01) and minimum dP/dt (-2067.4+/-88.1 versus -1718.8+/-91.3 mm Hg/s, P=0.02) were improved in myoblast-transplanted hearts compared with medium-infused hearts. This was associated with a sharper slope of the left ventricular developed pressure-volume curve and a reduced slope of the end-diastolic pressure-volume relation in the myoblast-transplanted hearts. Immunohistochemistry for skeletal myosin heavy chain showed that globally disseminated myoblasts had survived and differentiated into multinucleated myotubes that had aligned with the cardiac fiber axis within host myocardium. No significant myocardial infarction was observed. We demonstrated the feasibility and efficiency of skeletal myoblast transplantation via the intracoronary route as a promising strategy for improving cardiac function in global heart failure.

Effect of intraperitoneal chemotherapy and fibrinolytic therapy on tumor implantation in wound sites.

Failure of surgical treatment for gastrointestinal cancers is often caused by recurrence of the tumor in traumatized peritoneal surfaces. This study examined the effect of intraperitoneal administration of doxorubicin and recombinant tissue plasminogen activator (rt-PA), a fibrinolytic agent, on incidence and volume of postoperative tumor implants in peritoneal wounds. Prior to randomization, a surgical wound was created on the right parietal peritoneum of 110 BDIX rats and 6 x 10(5) DHD/K12 colon cancer cells were inoculated intraperitoneally (ip). The control group was given an intraperitoneal injection of saline. Five groups received 1 mg/kg of ip doxorubicin at different times postoperatively: at the end of surgery (D0), 3 hr after surgery (D + 3), postoperative day 1 (D1), postoperative day 3 (D3), and postoperative day 7 (D7). In a second set of experiments, five groups of rats received, in addition to postoperative doxorubicin, 5 mg/kg of intraoperative ip rt-PA. Incidence and volume of tumor implants in peritoneal wounds were assessed for each group 20 days after the tumor inoculation. All rats of the control group (incidence = 100%) developed tumor implants in peritoneal wounds. Mean (SD) volume was 16.2 (4.7) mm3. When administered at D0, D + 3, and D1 intraperitoneal doxorubicin reduced significantly the incidence and volume of tumor implants in wounds. Postoperative administration of doxorubicin at D3 and D7 did not affect significantly the incidence and the volume of tumor implants in peritoneal wounds. When rt-PA was administered intraoperatively, ip injection of doxorubicin at any postoperative timing decreased significantly the incidence and volume of tumor implants. In conclusion, ip doxorubicin administered before postoperative D3 may act on tumor cell implanted in peritoneal wounds. Delayed (D3, D7) ip administration of doxorubicin does not prevent the development of tumor implants in peritoneal wounds. Intraoperative administration of rt-PA may significantly increase the efficacy of delayed ip chemotherapy.

Anti-Tumor Effect of Cisplatin, Carboplatin, Mitoxantrone, and Doxorubicin on Peritoneal Tumor Growth After Intraperitoneal and Intravenous Chemotherapy: A Comparative Study

Tumor growth was studied in a peritoneal tumor model in the rat after intravenous and intraperitoneal administration of doxorubicin (4 mg/kg), mitoxantrone (2.5 mg/kg) and cisplatin (4 mg/kg) and after intraperitoneal administration of carboplatin (20 mg/kg). All treatments delayed tumor growth and intraperitoneal treatment was more effective initially than intravenous treatment for all drugs tested. Regrowth occurred between 2 and 7 weeks after treatment and was less pronounced after intravenous treatment. Tumor sizes in cisplatin treated rats 7 weeks after treatment were comparable after intraperitoneal and intravenous treatments. Intraperitoneal carboplatin even with a dose 5 times higher than cisplatin resulted in a less tumor growth delay in all stages of the treatment, compared to cisplatin. All cytostatic drugs, except carboplatin, induced loss of body weight. Weight loss was similar for intraperitoneal and intravenous treatment with both cisplatin and mitoxantrone while for doxorubicin the weight loss was significantly higher after intravenous treatment than after intraperitoneal therapy. Considering the "therapeutic index", defined as the ratio of tumor growth delay to weight loss, cisplatin had the highest "therapeutic index", 1.5 (intraperitoneal) and 1.7 (intravenous) compared to 0.3 (intraperitoneal) and 0.6 (intravenous) for Mitoxantrone and 0.4 (intraperitoneal) and 0.5 (intravenous) for doxorubicin. This indicated that cisplatin was the most favorable drug to use in this peritoneal tumor model for both intraperitoneal and intravenous treatment. The tumor growth delay was initially more pronounced after intraperitoneal cisplatin compared with intravenous.