pirarubicin and Neoplasms

Here the author describes the tumor-selective delivery of a fluorescence photosensitizing agent and an antitumor agent, based on the polymer effect of an N-(2-hydroxypropyl)methacrylamide (HPMA) based copolymer, by utilizing the enhanced permeability and retention (EPR) effect seen in solid tumors. Firstly, the tumor distribution of the photosensitizer, zinc-protoporphyrin IX (ZnPP), was significantly increased by conjugation with the HPMA polymer (P-ZnPP). The P-ZnPP suppressed tumor growth by local generation of cytotoxic singlet oxygen, and the tumor tissue was visualized by fluorescence upon light irradiation. Subsequently, a two-step mechanism for tumor selectivity was observed for the cytotoxic anthracycline, pirarubicin (THP), which conjugated the HPMA-based copolymer via a hydrazone bond (P-THP). The EPR-dependent accumulation of P-THP and the tumor-selective release of THP in the tumor tissues led to highly tumor-selective toxicity. Rapid cell uptake of THP compared to other anthracyclines, and deeper P-THP penetration of the tumor cell spheroid were attributed to the superior antitumor activity of P-THP. The molecular weight of P-THP affected its antitumor activity; oligomeric P-THP derivatives with higher molecular weights, DP-THP and SP-THP, showed even higher antitumor activity. P-THP was effective for both implanted tumor and autochthonous tumor models. These results indicate that nano-sized anticancer drugs based on polymer effect are promising clinical therapeutics.

Topics: Animals; Anthracyclines; Antineoplastic Agents; Doxorubicin; Drug Delivery Systems; Drug Development; Humans; Hydrogen-Ion Concentration; Methacrylates; Molecular Targeted Therapy; Molecular Weight; Neoplasms; Photosensitizing Agents; Polymers; Protoporphyrins

Autologous bone marrow transplantation (ABMT) and peripheral blood stem cell transplantation (PBSCT) are increasingly used to support high-dose chemotherapy for solid tumors of childhood. In this review we described practical aspects of myeloablative chemotherapy rescued by ABMT, PBSCT or combination of ABMT and PBSCT for the treatment of children with high-risk solid tumor, involving our experiences in 15 cases. Indication, method of harvesting bone marrow and peripheral blood stem cells, cryopreservation, transplantation, selection of anti-neoplastic agents for preconditioning, nutritional and G-CSF support, engraftment and outcomes for prognosis were discussed. In comparing the engraftment of stem cells between ABMT and PBSCT, the acceleration of platelet and erythrocyte recovery is less impressive, although there is a tendency to more rapid recovery of granulocyte in PBSCT group. The outcomes are distinctly improved only in patients who showed complete remission after induction chemotherapy, radiation and surgical excision. A better prognosis will be conferred especially in neuroblastoma and entities of small round cell tumor. It is noteworthy that relapses can occur as distant metastasis considerable years after complete clinical remission. This may be largely contributed by contaminated malignant cells in both harvested bone marrow and peripheral blood stem cells. There is no significant difference between the relapse rates after ABMT and PBSCT.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Carboplatin; Child; Combined Modality Therapy; Cryopreservation; Doxorubicin; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Kidney Neoplasms; Neoplasms; Neuroblastoma; Rhabdomyosarcoma; Wilms Tumor

Doxorubicin is an essential component of the treatment of aggressive lymphoma, childhood solid tumors, bone and soft tissue sarcomas, and breast cancer and additional indications are emerging. On the other hand, daunorubicin has occupied the central position of interest in the treatment of acute leukemia. Epirubicin has a spectrum very similar to doxorubicin but lesser toxicity. The ability to protect against cardiotoxicity with ICRF-187 further enhances clinical interest in exploiting modifications in doze intensity to therapeutic advantage. Idarubicin has at least equivalent activity to daunorubicin and doxorubicin in leukemia. New areas of research in relation to anthracycline antibiotics include introduction of new the analogs, insight into mechanisms of resistance, the reversal of multidrug resistance in vitro, the protection of cardiac toxicity, and the study of other important biochemical reactions relevant to cytotoxicity. Orally active anthracyclines such as idarubicin and compounds which lack cross-resistance with the parent drugs or have other mechanisms for cytotoxicity are being developed. It is likely that these modifications will lead to an expanding therapeutic spectrum for these already widely useful drugs.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Cardiomyopathies; Carubicin; Doxorubicin; Drug Resistance; Epirubicin; Humans; Idarubicin; Menogaril; Molecular Structure; Neoplasms; Nogalamycin

Doxorubicin is an essential component of the treatment of aggressive lymphoma, childhood solid tumors, bone and soft tissue sarcomas, and breast cancer and additional indications are emerging. On the other hand, daunorubicin has occupied the central position of interest in the treatment of acute leukemia. Epirubicin has a spectrum very similar to doxorubicin but lesser toxicity. The ability to protect against cardiotoxicity with ICRF-187 further enhances clinical interest in exploiting modifications in doze intensity to therapeutic advantage. Idarubicin has at least equivalent activity to daunorubicin and doxorubicin in leukemia. New areas of research in relation to anthracycline antibiotics include introduction of new the analogs, insight into mechanisms of resistance, the reversal of multidrug resistance in vitro, the protection of cardiac toxicity, and the study of other important biochemical reactions relevant to cytotoxicity. Orally active anthracyclines such as idarubicin and compounds which lack cross-resistance with the parent drugs or have other mechanisms for cytotoxicity are being developed. It is likely that these modifications will lead to an expanding therapeutic spectrum for these already widely useful drugs.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Cardiomyopathies; Carubicin; Doxorubicin; Drug Resistance; Epirubicin; Humans; Idarubicin; Menogaril; Molecular Structure; Neoplasms; Nogalamycin

A Phase I study of intravenous (IV) bolus 4'-0-tetrahydropyranyladriamycin (Pirarubicin) was done in 55 patients in good performance status with refractory tumors. Twenty-six had minimal prior therapy (good risk), 23 had extensive prior therapy (poor risk), and six had renal and/or hepatic dysfunction. A total of 167 courses at doses of 15 to 70 mg/m2 were evaluable. Maximum tolerated dose in good-risk patients was 70 mg/m2, and in poor-risk patients, 60 mg/m2. The dose-limiting toxic effect was transient noncumulative granulocytopenia. Granulocyte nadir was on day 14 (range, 4-22). Less frequent toxic effects included thrombocytopenia, anemia, nausea, mild alopecia, phlebitis, and mucositis. Myelosuppression was more in patients with hepatic dysfunction. Pharmacokinetic analyses in 21 patients revealed Pirarubicin plasma T 1/2 alpha (+/- SE) of 2.5 +/- 0.85 minutes, T beta 1/2 of 25.6 +/- 6.5 minutes, and T 1/2 gamma of 23.6 +/- 7.6 hours. The area under the curve was 537 +/- 149 ng/ml x hours, volume of distribution (Vd) 3504 +/- 644 l/m2, and total clearance (ClT) was 204 + 39.3 l/hour/m2. Adriamycinol, doxorubicin, adriamycinone, and tetrahydropyranyladriamycinol were the metabolites detected in plasma and the amount of doxorubicin was less than or equal to 10% of the total metabolites. Urinary excretion of Pirarubicin in the first 24 hours was less than or equal to 10%. Activity was noted in mesothelioma, leiomyosarcoma, and basal cell carcinoma. The recommended starting dose for Phase II trials is 60 mg/m2 IV bolus every 3 weeks.

Topics: Adult; Aged; Agranulocytosis; Doxorubicin; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Neoplasms; Remission Induction; Stroke Volume

(2'' R)-4'-O-Tetrahydropyranyl Adriamycin (THP) is a new antitumor agent discovered among series of similar anthracycline compound synthesized by Umezawa et al. Phase I study revealed dose limiting factor of leukopenia with upper GI toxicity. Alopecia, cardiac failure and transient hepatic failure were extremely mild. Definite responses were demonstrated in acute leukemia, lymphoma, ovarian carcinoma, head and neck carcinoma, breast carcinoma and GU carcinoma. Pharmacokinetic studies revealed rapid cell uptake and outputs in bile (20%) and urine (8%) in 24 hours. Transfer to third spaces were poor but definite. In vivo a part of THP was converted to ADM in the liver, but not in other tissues including tumors. THP would be an extremely interesting compound, because of comparable spectrum of responses to various tumors with extremely low toxicity compared with other anthracycline compounds.

Topics: Acute Disease; Clinical Trials as Topic; Doxorubicin; Gastrointestinal Diseases; Humans; Leukemia; Lymphoma; Neoplasms

Pirarubicin (PIRA) is a semi-synthetic anthracycline derivative that is reported to have lesser toxicity and better clinical outcomes as compared to its parental form doxorubicin (DOX). However, long term use of PIRA causes bone marrow suppression and severe cardiotoxicity to the recipients. Herein, we have developed a biodegradable polymeric nano platform consisting of amphiphilic di-block copolymer methoxy polyethylene glycol-polylactic acid and a hydrophobic penta-block copolymer polylactic acid-pluronic L-61-polylactic acid as a hybrid system to prepare PIRA (& DOX) encapsulated nanoparticles (NPs) with an aim to reduce its off targeted toxicity and enhance therapeutic efficacy for cancer therapy. Prepared PIRA/DOX NPs showed uniform particle size distribution, high encapsulation efficiency and sustained drug release profile. Cytotoxicity evaluation of PIRA NPs against TNBC cells and mammospheres showed its superior anti-cancer activity over DOX NPs. Anti-cancer efficacy of PIRA/DOX NPs was found significantly enhanced in presence of penta-block copolymer which confirmed chemo-sensitising ability of pluronic L-61. Most importantly, encapsulation of PIRA/DOX in the NPs reduced their off targeted toxicity and increased the maximum tolerated dose in BALB/c mice. Moreover, treatment of EAC tumor harbouring mice with PIRA NPs resulted in higher tumor regression as compared with the groups treated with free PIRA, free DOX or DOX NPs. Altogether, the results conclude that prepared PIRA NPs exhibits an excellent anti-cancer therapeutic efficacy and has a strong potential for cancer therapy.

Topics: Animals; Cell Line, Tumor; Doxorubicin; Drug Delivery Systems; Mice; Nanoparticles; Neoplasms; Poloxamer; Polyesters; Polymers

Polymer nanomedicines with anti-tumor activity should exhibit sufficient stability during systemic circulation to the target tissue; however, they should release the active drug selectively in the tumor. Thus, choice of a tumor-specific stimuli-sensitive spacer between the drug and the carrier is critical. Here, a series of polymer conjugates of anti-cancer drugs doxorubicin and pirarubicin covalently bound to copolymers based on N-(2-hydroxypropyl)methacrylamide via various enzymatically cleavable oligopeptide spacers were prepared and characterized. The highest rate of the drug release from the polymer carriers in presence of the lysosomal protease cathepsin B was determined for the copolymers with Val-Cit-Aba spacer. Copolymers containing pirarubicin were more cytotoxic and showed higher internalization rate than the corresponding doxorubicin counterparts. The conjugates containing GFLG and Val-Cit-Aba spacers exhibited the highest anti-tumor efficacy in vivo against murine sarcoma S-180, the highest rate of the enzymatically catalyzed drug release, and the highest cytotoxicity in vitro.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Doxorubicin; Drug Carriers; Humans; Mice; Nanomedicine; Neoplasms; Polymers

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Hypoxia; Cell Line, Tumor; Cell Membrane; Cell Membrane Permeability; Cell Nucleus; Doxorubicin; Drug Delivery Systems; Drug Liberation; Humans; Hydrogen-Ion Concentration; Indocyanine Green; Nanoparticles; Neoplasms; Particle Size; Peptides; Photochemotherapy; Photothermal Therapy; Tissue Distribution; Tumor Microenvironment; Xenograft Model Antitumor Assays

Biomimetic design has been extensively investigated. The only FDA-approved biomimetic albumin-bound paclitaxel may not be beneficial to some treated patients due to rapid dissociation upon intravenous infusion and no substantial improvement in the drug's pharmacokinetics or biodistribution. Herein, we developed an alternative and injectable preformed albumin-bound anticancer drug delivery. We combined HSA, Kolliphor HS 15 (HS15), and pirarubicin (THP) via purely physical forces in a thin-film hydration method to obtain an albumin-bound complex of HSA-THP. The lack of any chemical reactions preserves HSA bioactivity, in contrast to the destroyed secondary structure within AN-THP (albumin nanoparticle of THP) for the harsh manipulation during preparation. In vitro, HSA-THP showed a significantly higher cellular uptake efficiency than THP, and the complex was more cytotoxic. In vivo, HSA-THP showed longer half-life than THP. It also exhibited greater tumor accumulation and tumor penetration via gp60- and SPARC-mediated biomimetic transport than THP and AN-THP. As a result, HSA-THP showed strong antitumor and antimetastasis efficacy, with relatively little toxicity. These results suggest the clinical potential of biomimetic tumor-targeted drug delivery.

Topics: Albumins; Animals; Antineoplastic Agents; Cell Line, Tumor; Doxorubicin; Drug Carriers; Drug Delivery Systems; Female; Humans; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasms; Polyethylene Glycols; Rats; Rats, Sprague-Dawley; Stearates

Stimuli-responsive drug delivery systems based on tumor microenvironment conditions show tremendous promise to enhance tumor-targeted delivery and drug release. Herein, a multifunctional peptide (P51) was developed for programmed delivery of the hydrophobic chemotherapeutic agent pirarubicin. P51 was prepared with a ligand-specific targeting for the cancer biomarker Arg-Gly-Asp (RGD), and three tumor microenvironment-sensitive release triggers, acid environment, reducing agent, and a specific enzyme. The peptides Cys-s-s-Cys (disulfide linkage) and Pro-Val-Gly-Leu-Ile-Gly correspond to the cleavage sites of a reducing agent (DTT) and an enzyme (MMP-2). The peptides act as a junction between Ser-Glu-Glu-Asp-Pro (a negatively charged sequence) and a 41-residue peptide containing an α-helix that has the capacity to encapsulate pirarubicin via electrostatic and hydrophobic interactions. These interactions can be disrupted by the acidic tumor microenvironment. Self-assembly of P51 and pirarubicin (P51-THP NPs) results into stable spherical nanoparticles in a single step. We have demonstrated that the acid environment, DTT, and MMP-2 stimulate the release of pirarubicin from P51-THP NPs and, more importantly, the efficiency of drug release is markedly increased when all three release triggers are present. In addition, more effective tumor targeting, antitumor effect, and reduced systemic toxicity of P51-THP NPs have been confirmed by in vitro and in vivo results.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Cell Line, Tumor; Doxorubicin; Drug Delivery Systems; Drug Liberation; Female; Humans; Mice; Mice, Nude; Nanoparticles; Neoplasms; Peptides; Tumor Microenvironment; Xenograft Model Antitumor Assays

Topics: Acrylamides; Antineoplastic Agents; Doxorubicin; Drug Carriers; Drug Screening Assays, Antitumor; HCT116 Cells; Humans; Neoplasms; Spheroids, Cellular

Topics: Animals; Antineoplastic Agents; Arginine; Disease Models, Animal; Doxorubicin; Female; Hydroxyurea; Macromolecular Substances; Male; Mice; Nanomedicine; Nanoparticles; Neoplasms; Nitric Oxide; Nitric Oxide Donors; Nitroglycerin; Permeability; Rats, Sprague-Dawley

Previously we showed that linear poly(N-(2-hydroxypropyl)methacrylamide) conjugates of pirarubicin (THP), LP-THP, with MW about 39 kDa, exhibited far better tumor accumulation and therapeutic effect than that of parental free THP. To improve the pharmacokinetics of LP-THP further, high-MW conjugate of poly(amido amine) (PAMAM) dendrimer grafted with semitelechelic HPMA copolymer (PHPMA) was synthesized [star polymer (SP); 400 kDa] and conjugated with THP via hydrazone bond-containing spacer (SP-THP). THP was conjugated to SP to form SP-THP via acid cleavable hydrazone bonding, which responds to acidic milieu of tumor tissue. As a consequence, it would release free THP, by active therapeutic principle. SP-THP exhibits larger hydrodynamic diameter (25.9 nm) in aqueous solution than that of LP-THP (8.2 nm) as observed by light scattering and size exclusion chromatography. Because of the larger size, the tumor AUC5h-72 h of SP-THP was 3.3 times higher than that of LP-THP. More importantly, released free THP was retained selectively in the tumor tissue for at least up to 72 h after administration of SP-THP. We found that SP-THP exhibited superior antitumor effect to LP-THP against both S-180 tumor-bearing mice in vivo, and with chemically AOM/DSS-induced colon tumor-bearing mice, most probably due to their different molecular size. In our comparison study of in vitro and in vivo behavior of SP-THP and LP-THP we concluded that SP-THP exhibited enhanced therapeutic efficacy not only in implanted tumor but also in orthotopic/spontaneous tumor despite its higher toxicity compared to LP-THP. Upon these findings further investigation using various tumors including transgenic, and metastatic tumors is going to be conducted soon.

Topics: Animals; Antineoplastic Agents; Berberine Alkaloids; Cell Line, Tumor; Dendrimers; Doxorubicin; Drug Carriers; HeLa Cells; Humans; Male; Melanoma, Experimental; Methacrylates; Mice; Mice, Inbred ICR; Neoplasms; Polymers

An effective chemotherapy for neoplastic diseases requires the use of drugs that can reach the site of action at a therapeutically efficacious concentration and maintain it at a constant level over a sufficient period of time with minimal side effects. Currently, conjugates of high-molecular-weight hydrophilic polymers or biocompatible nanoparticles with stimuli-releasable anticancer drugs are considered to be some of the most promising systems capable of fulfilling these criteria. In this work, conjugates of thermoresponsive diblock copolymers with the covalently bound cancerostatic drug pirarubicin (PIR) were synthesized as a reversible micelle-forming drug delivery system combining the benefits of the above-mentioned carriers. The diblock copolymer carriers were composed of hydrophilic poly[N-(2-hydroxypropyl)methacrylamide]-based block containing a small amount (∼ 5 mol %) of comonomer units with reactive hydrazide groups and a thermoresponsive poly[2-(2-methoxyethoxy)ethyl methacrylate] block. PIR was attached to the hydrophilic block of the copolymer through the pH-sensitive hydrazone bond designed to be stable in the bloodstream at pH 7.4 but to be degraded in an intratumoral/intracellular environment at pH 5-6. The temperature-induced conformation change of the thermoresponsive block (coil-globule transition), followed by self-assembly of the copolymer into a micellar structure, was controlled by the thermoresponsive block length and PIR content. The cytotoxicity and intracellular transport of the conjugates as well as the release of PIR from the conjugates inside the cells, followed by its accumulation in the cell nuclei, were evaluated in vitro using human colon adenocarcinoma (DLD-1) cell lines. It was demonstrated that the studied conjugates have a great potential to become efficacious in vivo pharmaceuticals.

Topics: Antineoplastic Agents; Cell Line, Tumor; Doxorubicin; Drug Delivery Systems; Humans; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Micelles; Nanoparticles; Neoplasms; Polymers

N-(2-Hydroxypropyl)methacrylamide copolymer containing hydrazide groups (PHPMA) conjugated with pirarubicin (THP) via a hydrazone bond (PHPMA-hyd-THP) is a drug conjugate that releases THP in the acidic milieu of a tumor. PHPMA-hyd-THP has an apparent Mw of 40,000 and a hydrodynamic diameter of 8.2±1.7nm but no apparent plasma protein binding. PHPMA-hyd-THP possesses two mechanisms of selectivity toward solid tumors and has potent antitumor action. The first one is drug accumulation in tumors that depends on the enhanced permeability and retention (EPR) effect, which results in a 4-20 times higher concentration of drug in the tumor than in normal tissues such as the heart, lung, and intestine. This accumulation in tumor tissue is in great contrast to that of conventional low-Mw THP. The second one is pH-dependent release of drug from PHPMA-hyd-THP: this conjugate released free THP more efficiently at a lower pH, which exists in tumors, and exerts cytotoxic activity. Free THP is known for its much faster uptake into tumor cells compared with doxorubicin. Thus, in our in vitro study, PHPMA-hyd-THP showed a higher cytotoxicity at the lower pH of tumor tissue than at the neutral pH of normal tissue. Furthermore, much more THP was liberated from the conjugate in acidic tumor tissue than in normal tissue. The EPR effect-dependent accumulation of PHPMA-hyd-THP and tumor-selective THP release in the tumor tissues led to highly tumor-selective drug accumulation, which continued for more than 72h, whereas the lowest free drug concentration was detected in normal tissues at 24h and no longer at a later time. In conclusion, we determined in our study here that the acid-cleavable PHPMA-hyd-THP conjugate had an excellent antitumor effect without appreciable adverse effects.

Topics: Acrylamides; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Doxorubicin; Drug Carriers; HeLa Cells; Humans; Male; Mice; Neoplasms; Polymers; Tissue Distribution; Tumor Burden

Pirarubicin (THP), an analogue of doxorubicin, has exhibited promising activities against acute leukemia, malignant lymphoma, and several solid tumors. However, the cumulative cardiotoxicity limits its wide application in chemotherapy.. To provide an alternative strategy for reducing the cardiotoxicity, a novel THP liposome powder (L-THP), comprising distearoylphosphatidylcholine, distearoylphosphatidylglycerol, cholesterol, and lactose was appropriately prepared based on the physicochemical properties of THP. And L-THP was characterized and evaluated. Comparative studies on pharmacokinetic and biodistribution behaviors between L-THP and commercialized THP injection were performed in normal mice through intravenous administration.. When L-THP was reconstituted in a proper amount of normal saline for injection, it had a mean diameter of around 220.0 nm, a zeta potential of about -33.0 mV, and a high THP entrapment efficiency of more than 93.1%. Pharmacokinetics study showed that heart accumulation of THP could be reduced by 81.2% for L-THP.. These results suggest that our L-THP might greatly reduce the cardiotoxicity, thus improving the therapeutic index of THP. Meanwhile, further preclinical studies are warranted to define the cardiotoxicity and the therapeutic efficacy of L-THP.

Topics: Animals; Antineoplastic Agents; Doxorubicin; Drug Carriers; Drug Stability; Excipients; Liposomes; Male; Mice; Neoplasms; Particle Size; Powders; Solubility; Tissue Distribution

The objective of the present study was to evaluate the relationship between the pharmacokinetic parameters of pirarubicin and of its metabolite doxorubicin measured in plasma and whole blood, and the hematologic toxicity of this drug, in order to evaluate the predictability of changes in white blood cells (WBC) by single measurement of drug concentrations. This pharmacokinetic-pharmacodynamic relationship was studied in a total of 45 patients with different tumor types treated by combined chemotherapy containing pirarubicin, administered as short infusion (10+/-2 min) at doses ranging from 50 to 90 mg. In 45 courses performed in 24 patients, we established the relationship between the half-product of pirarubicin level in whole blood at the end of the infusion and the duration of this infusion, which represents an estimate of the area under the time x concentration curve (AUC(PIRA,wb,ei) = C(PIRA,wb,ei) x duration of infusion/2), the age of the patients and the relative fall in WBC counts. These results allowed us to establish a predictive formula in order to anticipate the number of WBC that the patient will obtain about 12 days after treatment, at the nadir of the counting. WBCnadir = 0.032404 x Age + 2.005 + WBCinitial x e(-0.009316 x AUC(PIRA,wb,ei) + 4.202265), WBC being expressed as x 10(3) cells/microl and AUC(PIRA,wb,ei) in ng/ml x h. In a second step, the validation of the prediction was carried out in 43 courses from 21 patients treated in the same conditions, for which WBC(predicted nadir) was compared by linear regression to WBCcounted. We obtained a highly significant correlation: r = 0.656; p<0.0001). Therefore, we show in this paper that the hematological toxicity, especially the WBC nadir count, can be predicted from single-sample blood HPLC analysis. This rapid and easy prediction of leukopenia can help the clinician in anticipating important hematological toxicities and in deciding to start early prophylactic treatment with hematopoietic growth factors.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Doxorubicin; Female; Humans; Leukocyte Count; Leukopenia; Male; Middle Aged; Neoplasms

Pirarubicin (4'-O-tetrahydropyranyldoxorubicin, THP-Adriamycin) is a new anthracycline antibiotic that has recently been developed because its reduced cardiac toxicity is associated with an antitumour efficacy similar to that of doxorubicin. Pirarubicin is characterised by strong haematological toxicity, which has been shown to be correlated with pharmacokinetic parameters, especially the area under the time-concentration curve. To obtain routine pharmacokinetic evaluations of pirarubicin for dose monitoring we developed a limited sampling strategy relying on three blood samples taken at the end of the infusion and at 12 and 24 h post-infusion. The characteristics of interindividual variability were assessed on the first courses of treatment performed in 18 patients; the model was then validated on 10 independent first courses of treatment performed in 10 other patients. The main pharmacokinetic parameters (half-lives, total volume of distribution, total plasma clearance) were estimated in the test group by maximum-likelihood estimation using all samples and by Bayesian estimation using three samples. The concordance between the two estimates was correct (the bias and precision for clearance were 2.3% and 12.1%, respectively), which shows that this limited sampling strategy can be used in routine drug monitoring.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bias; Blood Specimen Collection; Doxorubicin; Drug Monitoring; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Models, Statistical; Neoplasms; Probability; Reproducibility of Results

The pharmacokinetic monitoring of anthracycline-containing regimens is warranted because of the important toxicity of these drugs and because pharmacokinetic-pharmacodynamic relationships have been clearly established. We studied the pharmacokinetics of the new anthracycline pirarubicin in 80 courses of treatment performed in 27 patients, using a limited sampling protocol we had previously validated. We observed (for 47 of these courses) a significant correlation between the leucocyte cell kill and the pirarubicin area under the time x concentration curve, but the most significant correlation was obtained using the plasma concentration of doxorubicin, a metabolite of pirarubicin, at the end of the infusion. On the basis of this value, it is possible to predict for pirarubicin haematological toxicity in a way that can help the clinician in identifying patients at risk for toxicity.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Cell Survival; Doxorubicin; Drug Monitoring; Female; Half-Life; Humans; Leukocytes; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms; Reproducibility of Results

The cytotoxic activities of several natural and semisynthetic anthracyclines against L1210 leukemia and two human colon tumor cells (Colon 4, HT 29) in vitro were examined after short (1 h) and long (7 days) incubation times and correlated with the water/octanol partition coefficients and the DNA-binding affinity of the compounds. Analysis of equation in which cytotoxicity against L1210 (1-h incubation) was parabolically related to the partition coefficient revealed an almost exclusive correlation (r = 0.80) between the cytotoxicity and the parameters, and this correlation was only slightly improved by addition of DNA-binding affinity (r = 0.85). On the other hand, cytotoxic activities displayed after continuous incubation were partially related to both partition coefficients (parabolic dependence) and DNA-binding affinities (linear dependence). In this case the correlation between the activity and partition coefficient (r = 0.67) was significantly improved by addition of DNA-binding affinity (r = 0.90). Similar results were also obtained for human colon tumor cells although the corresponding correlation coefficients were generally of lower value, indicating that cytotoxic activity of anthracyclines against these primary resistant cells may be influenced by additional factors not yet determined.

Topics: Animals; Antibiotics, Antineoplastic; Chemical Phenomena; Chemistry, Physical; Colonic Neoplasms; DNA; Humans; Leukemia L1210; Molecular Structure; Neoplasms; Regression Analysis; Structure-Activity Relationship; Tumor Cells, Cultured

Topics: Doxorubicin; Humans; Neoplasms

Topics: Antineoplastic Agents; Doxorubicin; Female; Humans; Injections; Male; Middle Aged; Neoplasms

Tetrahydropyranyladriamycin (THP-adriamycin) is an anthracycline analogue currently under development in Europe and Japan. Preclinical studies suggest that it may have greater activity and less cardiac toxicity than doxorubicin. We conducted a phase I clinical and pharmacologic study of THP-adriamycin given as a weekly 15-min infusion for 3 weeks, followed by 1 week of observation. Therapy was associated with minimal acute toxicity. The dose-limiting toxicity was neutropenia, usually maximal during the 4th week after treatment; alopecia was rare. The maximum tolerated dose was 25 mg/m2; for phase II studies using this schedule, a dose of 20 mg/m2 weekly for 3 weeks is recommended. Pharmacokinetic studies revealed a triphasic elimination of the parent compound with alpha, beta, and gamma half-lives of 5.6 min, 1.4 h, and 9.3 h, respectively. THP-adriamycin was rapidly taken up by blood cell components, with concentrations in red blood cells (RBCs), lymphocytes, and polymorphonuclear cells exceeding those in plasma. In all, less than 10% of the compound was eliminated in the urine within 24 h.

Topics: Chromatography, High Pressure Liquid; Doxorubicin; Drug Evaluation; Half-Life; Humans; Infusions, Intravenous; Neoplasms; Time Factors

A Phase I trial of pirarubicin (4'-O-tetrahydropyranyl-doxorubicin) was undertaken to study its toxicity and to gain preliminary knowledge of its efficacy. The dose was escalated by increments of 10 from 30 to 70 mg/m2. Out of 20 patients, 19 were evaluable for toxicity and response to treatment. Hematologic toxicity was dose limiting and dose related. Other adverse effects included nausea and vomiting, hair loss, and stomatitis. No acute cardiotoxicity was encountered. In 2 patients with metastatic breast cancer who had not been pretreated with cytostatic agents, a partial remission was achieved lasting for 5 months. In 6 patients, tumor parameters did not change for a median of 3 months, and 11 patients suffered progressive disease.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Dose-Response Relationship, Drug; Doxorubicin; Drug Evaluation; Female; Humans; Male; Middle Aged; Naphthacenes; Neoplasms

To investigate the features of acute cardiotoxicity caused by the anticancer agents, adriamycin (ADM), THP-adriamycin (THP), epirubicin (epi-ADM) and mitoxantrone (MIX), Holter electrocardiograms were recorded before and after administration of these drugs and some of the electrocardiographic parameters were analyzed. The heart rate tended to increase after ADM administration, but other agents had no effect. The basic rhythm was sinus rhythm in many cases except for only one case in which intermittent atrial fibrillation developed after ADM administration. These agents had no effects on the specialized conduction system. With regard to supraventricular premature beats, no increase in preexisting supraventricular premature beats was observed, but there was a slight tendency for the fresh appearance of supraventricular extrasystoles after administration of these agents. On the other hand, ventricular premature beats tended to increase in number and severity after ADM therapy. The other three agents induced no significant increase in ventricular extrasystoles. Development of ST-T changes was seen after the administration of ADM and THP, but epi-ADM and MIX produced no significant changes. In conclusion, epi-ADM and MIX were less cardiotoxic than ADM and THP.

Topics: Adult; Aged; Doxorubicin; Electrocardiography; Epirubicin; Female; Heart; Heart Rate; Humans; Male; Middle Aged; Mitoxantrone; Monitoring, Physiologic; Neoplasms

We have studied the pharmacokinetics and metabolism of pirarubicin (4'-O-tetrahydropyranyldoxorubicin) in six patients included in an EORTC phase II study. Pirarubicin was injected as an i.v. bolus of 5 min on 3 consecutive days at a dose of 20 mg/m2 per day. Blood samples were collected at regular times after each injection. Urine was collected over 12 h periods for 3 days and then over 24 h periods. Pirarubicin and metabolites were extracted on Sep-pak cartridges, and analyzed by HPLC with fluorometric detection. Unchanged pirarubicin followed three similar plasma concentration curves, which could be fitted by a two-compartment model with successive half-lives of 22.0 min and 12.7 h. Total plasma clearance of the drug was 90 l/h/m2 and total volume of distribution 1380 l/m2. Doxorubicin was the main metabolite in plasma after an injection of pirarubicin; its concentration was lower than that of pirarubicin but progressively increased from day to day and exceeded the level of pirarubicin 8 h after the 3rd injection of the drug until the end of the blood sampling. Pirarubicinol and doxorubicinol were also metabolites of pirarubicin in plasma; pirarubicinol followed similar plasma concentration curves during the 3 days of treatment whereas doxorubicinol progressively increased from day to day. Total urinary excretion represented about 6% of the dose injected. The same metabolites as in plasma were found in urine. Whereas the total amount of pirarubicin and pirarubicinol was the same in urine during the 24 h after each injection, the amounts of doxorubicin and doxorubicinol excreted increased from day to day, so that doxorubicin became progressively the main compound in urine after the end of the treatment. The progressive accumulation of pirarubicin metabolites (doxorubicin and doxorubicinol) after the repetitive injections of pirarubicin are probably due to the protracted half-lives of these compounds as compared to that of pirarubicin.

Topics: Adult; Aged; Chromatography, High Pressure Liquid; Doxorubicin; Drug Evaluation; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasms; Ovarian Neoplasms; Uterine Neoplasms

The pharmacokinetic properties of THP and ADM were comparatively studied in the same patients with various cancers. The concentration of ADM in either plasma or blood cells was higher than that of THP from 5 minutes to 24 hours after administration. The metabolites of ADM such as aglycones were detected in plasma until 3 hours after administration, but these were never detected in blood cells. By contrast, the metabolites of THP were detected until 24 hours after administration. These results suggested that THP was metabolized in tissues and excreted into urine and that the rate of metabolism and excretion of THP was faster than that of ADM. Distribution volumes (V1, V2, and V3) of THP were larger than those of ADM. The above results strongly suggested that THP would be easily transferred into the tissues, but that in the case of slower transferring tissues with lower K13 values, ADM rather than THP would be easily transferred to the tissues. These pharmacokinetic properties suggested that the toxicity of THP might be diminished compared with that of ADM.

Topics: Aged; Chromatography, High Pressure Liquid; Doxorubicin; Female; Humans; Injections, Intravenous; Kinetics; Male; Middle Aged; Neoplasms

THP-ADM is a new antitumor agent which belongs to the anthracycline family. This agent has shown a high therapeutic index compared with the mother compound, Adriamycin, in preclinical and clinical studies. This time, a pharmacokinetic study of THP-ADM was performed and the following characteristics of this agent were clarified. Short t1/2 was noted compared with that of Adriamycin in a 3-compartment open model. Leukocyte concentration of THP-ADM was much higher than that of plasma or red blood cells. Renal excretion over 48 hours was 9% and biliary excretion over the same period was 20%. Tissue concentration revealed high THP-ADM and low Adriamycin in all tissues excluding the liver. In liver tissue, a high concentration of Adriamycin and a low concentration of THP-ADM was observed. A small amount of Adriamycin was noted in the plasma following THP-ADM administration. The Adriamycin was most likely related to the small amount of existing Adriamycin in THP-ADM or conversion of THP-ADM to Adriamycin in the liver tissue or both. Poor penetration of THP-ADM was noted into the third space.

Topics: Doxorubicin; Humans; Kinetics; Liver; Liver Neoplasms; Neoplasms; Stomach Neoplasms

A Phase II Study of (2''R)-4'-O-tetrahydropyranyladriamycin (THP) in patients with various solid tumors was carried out by 44 cooperative study institutions. Seven hundred fifty-six patients administered the drug intravenously were entered into this study. Of these, 499 patients were evaluated for objective responses. THP was given mainly at a dose of 40 to 60 mg/body every 3 to 4 weeks or 20 to 30 mg/body once a week. Response rates were 18.8% for head and neck cancer, 13.1% for stomach cancer, 21.4% for breast cancer, 22.2% for bladder cancer, 30% for renal pelvic and urinary tract tumor, 26.8% for ovarian cancer and 24.2% for uterine cancer. Overall response rate was 15.4% including 10 complete responses and 67 partial responses. Adverse reactions were similar to those previously reported in the phase I study, including gastrointestinal toxicities and myelosuppression. Alopecia and stomatitis, which are major side effects of other anthracyclines, were rather mild. Incidence of ECG changes was 2.8% and no congestive heart failure was observed.

Topics: Adult; Aged; Alopecia; Anorexia; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Female; Humans; Infusions, Parenteral; Leukopenia; Male; Middle Aged; Nausea; Neoplasms

A phase I trial of a new anthracycline derivative, 4'-O-tetrahydropyranyldoxorubicin (THP), was conducted in 54 patients with various advanced solid tumors and malignant lymphomas. Starting dose was 5 mg/m2 i.v. and dose escalations were made by a modified Fibonacci search scheme. There were 40 evaluable courses. The dose-limiting toxic effect was leukopenia which was dose-related and reversible. The maximum tolerated dose for a single i.v. injection was estimated to be 55 mg/m2. The median nadir day for leukopenia was day 12 with recovery occurring 13 days (median) after reaching the nadir. Thrombocytopenia was less commonly observed than leukopenia. Other toxic effects were mild gastrointestinal disturbances, fever and general malaise. Ventricular extrasystole was observed in a case of pancreatic cancer who received 5 mg/m2 of the drug. There were no cases with alopecia, or with hepatic or renal dysfunction. With regard to objective tumor response, CR was observed in 2 cases with NHL, and MR in 2 cases with lung cancer, and 1 case each with breast cancer and NHL. Response occurred at a dose of more than 35 mg/m2. The recommended dose schedule for phase II trial is 35-45 mg/m2 by single i.v. injection at 3-4-week intervals.

Topics: Aged; Anorexia; Breast Neoplasms; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Female; Humans; Infusions, Parenteral; Leukopenia; Lung Neoplasms; Lymphoma; Male; Middle Aged; Nausea; Neoplasms; Stomach Neoplasms; Thrombocytopenia

To investigate the detailed acute cardiotoxicity of the anthracycline antibiotics, adriamycin (ADM) and a tetrahydropyranyl derivative (THP-ADM), Holter ECG was recorded and some of the electrocardiographic parameters were analyzed. The basic rhythm was sinus rhythm in many cases except only one case which developed intermittent atrial fibrillation after the administration of ADM. No effect on the specialized conduction system was observed in either ADM or TH-PADM. In relation to the supraventricular premature beat, no increase of the pre-existing supraventricular extrasystole and fresh appearance of the supraventricular extrasystole were observed after the administration of these drugs. On the other hand, the ventricular premature beat was tended to increase after ADM administration, and the mode of appearance of the ventricular extrasystole was very dangerous and life-threatening. For example, short-run type and R on T type ventricular extrasystole were recorded. THP-ADM induced no significant increase of the ventricular extrasystole. The developed ST-T changes were seen after the administration of these drugs, but the patients complained neither the symptoms of heart failure nor stenocardia. In conclusion. THP-ADM had less cardiotoxicity than ADM.

Topics: Adolescent; Adult; Aged; Arrhythmias, Cardiac; Atrial Fibrillation; Breast Neoplasms; Cardiac Complexes, Premature; Doxorubicin; Electrocardiography; Female; Heart; Humans; Lung Neoplasms; Lymphoma; Male; Middle Aged; Neoplasms

A phase II clinical trial of a new anthracycline, 4'-O-tetrahydropyranyladriamycin (THP-ADM), was performed in thirty-one patients with advanced malignant tumors refractory to standard chemotherapies. The dosage of THP-ADM was 40 mg/m2 by iv bolus injection repeated every 3 weeks. Of 3 evaluable patients with non-Hodgkin's lymphoma, one achieved partial remission. A minor response was noted in one out of 7 patients with gastric cancer and one out of 5 patients with ovarian cancer. Leukopenia less than 4 X 10(3)/cmm and thrombocytopenia less than 100 X 10(3)/cmm were seen in 81% and 19% of cases, respectively. Mild gastrointestinal toxicities including nausea and vomiting and anorexia were observed in about one third of the patients. Mild hair loss occurred in 2 patients (6%). No ECG abnormalities on clinical sign of cardiotoxicity were seen.

Topics: Aged; Breast Neoplasms; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Female; Humans; Lymphoma; Male; Middle Aged; Neoplasms; Ovarian Neoplasms; Stomach Neoplasms

The phase I study of a new anthracycline, 4'-o-tetrahydropyranyl adriamycin, was performed. A dose-limiting factor was leukopenia while thrombocytopenia was less frequent and a maximum tolerated dose was determined as 54 mg/m2. Mild gastrointestinal toxicities including anorexia, nausea and vomiting occurred in about half of the patients, while very minimal alopecia was seen in only one patient. A recommended dose for phase II study was established: 40 mg/m2 at 3-week intervals.

Topics: Adult; Aged; Alopecia; Digestive System; Doxorubicin; Drug Evaluation; Female; Humans; Leukopenia; Male; Middle Aged; Neoplasms; Thrombocytopenia