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© 2002 American Society for Clinical Oncology Hepatic Drug Targeting: Phase I Evaluation of Polymer-Bound DoxorubicinByFrom the Cancer Research UK Institute for Cancer Studies, University of Birmingham, Department of Physics and Nuclear Medicine, City Hospital National Health Service Trust, and Department of Nuclear Medicine, Queen Elizabeth Hospital, University Hospital Birmingham National Health Service Trust, Birmingham; Department of Nuclear Medicine, Christie Hospital, Withington, Manchester; and Cancer Research UK, London, United Kingdom. In memory of Professor Tom Connors.Address reprint requests to D.J. Kerr, MD, University of Oxford, Department of Clinical Pharmacology, Radcliffe Infirmary, Woodstock Rd, Oxford OX2 6HE, United Kingdom; email: david.kerr{at}clinpharm .ox.ac.uk.
PURPOSE: Preclinical studies have shown good anticancer activity following targeting of a polymer bearing doxorubicin with galactosamine (PK2) to the liver. The present phase I study was devised to determine the toxicity, pharmacokinetic profile, and targeting capability of PK2. PATIENTS AND METHODS: Doxorubicin was linked via a lysosomally degradable tetrapeptide sequence to N-(2-hydroxypropyl)methacrylamide copolymers bearing galactosamine. Targeting, toxicity, and efficacy were evaluated in 31 patients with primary (n = 25) or metastatic (n = 6) liver cancer. Body distribution of the radiolabelled polymer conjugate was assessed using gamma-camera imaging and single-photon emission computed tomography. RESULTS: The polymer was administered by intravenous (IV) infusion over 1 hour, repeated every 3 weeks. Dose escalation proceeded from 20 to 160 mg/m2 (doxorubicin equivalents), the maximum-tolerated dose, which was associated with severe fatigue, grade 4 neutropenia, and grade 3 mucositis. Twenty-four hours after administration, 16.9% ± 3.9% of the administered dose of doxorubicin targeted to the liver and 3.3% ± 5.6% of dose was delivered to tumor. Doxorubicin-polymer conjugate without galactosamine showed no targeting. Three hepatoma patients showed partial responses, with one in continuing partial remission 47 months after therapy. CONCLUSION: The recommended PK2 dose is 120 mg/m2, administered every 3 weeks by IV infusion. Liver-specific doxorubicin delivery is achievable using galactosamine-modified polymers, and targeting is also seen in primary hepatocellular tumors.
TARGETING DRUGS TO organs or compartments harboring sites of disease is a major goal in pharmacology, with a view to increasing the therapeutic potential of a given drug dose with the capacity for decreased side effects. Cytotoxic anticancer drugs are particularly appropriate for this approach since their successful application is often prevented by the level of systemic toxicity they induce. In 1975, Ringsdorf1 introduced the concept of the targeted drug carrier in which water-soluble polymers, modified with both targeting agents and drugs, could be used to deliver the drugs to appropriate disease sites. This approach has seen extensive development in vitro and in animal models, although the approach has not previously been evaluated in man. Polymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) are particularly useful as targeted drug carriers because of their versatile chemistry and good biocompatibility. Such molecules have been used successfully in animals to deliver antibiotics and anticancer agents targeted with antibodies,2-4 proteins,3 or simple sugars.5-7 One approach showing particular promise involves the synthesis of copolymers of HPMA containing the topoisomerase II inhibitor doxorubicin and N-linked galactosamine, which binds to the hepatic asialoglycoprotein receptor (ASGPR).5 Linkage of the drug to the carrier via a tetrapeptide spacer (Gly-Phe-Leu-Gly; Fig 1), designed for cleavage by lysosomal cathepsins, was shown to release free doxorubicin within the liver, permitting the drug to increase concentration in its site of action, the nucleus.8 This produced superior anticancer activity in a range of animal tumor models compared with conventional doxorubicin solution.9
Here we report a phase I clinical and pharmacokinetic study of galactosamine-targeted polyHPMA-doxorubicin (known as PK2). Three objectives were addressed: (1) identify the toxicity associated with intravenous (IV) infusion of PK2, (2) determine efficiency of hepatic targeting by radioimaging with 123I-PK2, and (3) assess the antineoplastic efficacy of PK2.
Characteristics of Polymers PK2 was synthesized using standard protocols.10 The lyophilized product contained 7.5 wt% doxorubicin and 2.0 wt% galactosamine and had an overall average molecular weight of 27,100 (polydispersity 1.38). An analog was also prepared, containing in addition methacryloyltyrosinamide (1 mol%) to permit radioiodination. A matched control polymer known as PK1, containing doxorubicin but no galactosamine, was also prepared, together with the corresponding methacryloyltyrosinamide-containing imaging analog. The imaging analogs were iodinated with 123I-iodide in the presence of carrier iodide, using a protocol described elsewhere.11 The drug was purified by gel permeation chromatography (Sephadex G25) immediately before IV administration.
Patients and Clinical Protocol Pretreatment evaluation included a complete clinical history, physical examination, ECG, chest x-ray, computed tomography (CT) scan of accessible target lesions, and a multiple-gated acquisition scan to assess left ventricular ejection fraction (LVEF). A threshold of 50% was set for entry onto and persistence in the trial. LVEF measurement was repeated after three cycles and at the end of treatment (Fig 2). Patient no. 25 (treated at 120 mg/m2) had a history of controlled atrial fibrillation and was removed from the trial after three cycles because of falling LVEF, although no other patient appeared to be hemodynamically compromised by the treatment. Complete blood cell counts and differential blood chemistry were graded using the National Cancer Institute common toxicity criteria. Possible dose-limiting toxicities (DLTs) were defined as grade 3 diarrhea, mucositis, or thrombocytopenia, grade 4 neutropenia, or any other toxicity higher than grade 2, except alopecia and increase in transaminase levels. Objective responses were recorded according to standard World Health Organization criteria and had to be confirmed after at least 4 weeks.
Cohorts of three patients were treated with PK2 at doses of 20, 40, 80, and 160 mg/m2 (doxorubicin-equivalent), with a 1-week interval between individual patient entry. No intrapatient dose escalation was allowed. Dose escalation proceeded if there was minimal or moderate toxicity associated with the previous dose level until DLT supervened. If a DLT occurred in one of the initial three patients at any dose level, then an additional three patients were enrolled at the same dose level. Dose escalation was discontinued if DLT was observed in at least three of six patients, which defined the maximum-tolerated dose (MTD).12 The recommended dose was to be the best tolerated dose immediately below the MTD. Details are summarized in Table 1.
Administration of PK2 and Sampling Procedures Thirty-one patients were enrolled onto the PK2 study with primary hepatoma (n = 23) or other liver malignancy (metastatic colorectal carcinoma, n = 5; cholangiocarcinoma, n = 2; and metastatic carcinoma of unknown origin, n = 1). PK2 and 123I-PK2 (for imaging cycles only) were administered simultaneously in 0.9% saline by IV infusion every 3 weeks. Treatment was continued to a maximum of six cycles unless there was significant toxicity or evidence of disease progression which would necessitate discontinuation of therapy. Initial patients (nos. 1 through 5) were infused at a rate 4.16 mL/min (2.0 mg doxorubicin-equivalent/mL), although pain on infusion necessitated a change to a slower infusion (2 mL/min) and/or a 1.0-mg/mL solution for subsequent patients. Blood samples were taken immediately before treatment, at 0, 5, 15, 30, 60, and 90 minutes, at 2, 4, 6, 12, 24, 48, and 72 hours, and at 8 days relative to the end of infusion. Urine was collected in three samples (0 to 4 hours, 4 to 12 hours, and 12 to 24 hours). At the end of the study, six patients were administered the recommended dose of PK2 x 24-hour infusion, to determine whether this would change the distribution parameters or liver targeting of the drug. Blood samples were collected from these patients according to the schedule above, timed from both the start and end of infusion.
Chromatographic Analysis of Serum and Urine Samples Levels of 123I were measured in samples of plasma and urine by gamma scintigraphy in a well counter (Cobra Quantum; Canberra Packard, Pangbourne, United Kingdom), and urine samples were separated by Sephadex G25 chromatography to determine the component of free iodide.
Imaging Procedures for Determination of Polymer Distribution In a parallel study, four patients with primary colorectal carcinoma were administered PK1, a doxorubicin-polymer conjugate identical in every way to PK2 but for the absence of galactosamine. PK1 was administered at a dose of 280 mg/m2 (doxorubicin-equivalent), the recommended dose for phase II studies, and patients were subject to the same imaging procedures as for PK2. The images obtained were used as controls to determine the influence of galactosamine on liver targeting and biodistribution of PK2.
Dose Escalation and Assessment of Toxicity Recruiting sequential cohorts of three patients, PK2 was dose-escalated from the starting level (20 mg/m2, measured in doxorubicin-equivalents per square meter of body surface area) to the MTD (160 mg/m2). DLT consisted of severe fatigue (grade 3, two patients), grade 4 neutropenia (two patients), and oral ulceration (grade 3, one patient). Overall, 19 patients were treated with 120 mg/m2 to gain experience at this level, the recommended dose for any future trials. Side effects at this dose level included moderate but tolerable myelosuppression, alopecia, fatigue, and mucositis (Table 2). Other hematologic toxicities were grade 2 or lower, except for one occurrence of grade 4 thrombocytopenia in one patient treated at 120 mg/m2 (see below). Fifteen patients showed symptoms of anemia at enrollment, but none showed any drug-related deterioration during the study period. Twelve patients, including three who had been given previous chemotherapy, showed slight falls in platelet number on study, although these individuals were usually enrolled with a platelet count at the low end of the normal range. Of three patients who were enrolled with grade 1 thrombocytopenia, one progressed to grade 2 and one to grade 4.
Concentration of PK2 in Bloodstream and Urine Blood levels of the 123I-labelled analog of PK2 were estimated by gamma counting of plasma samples, and doxorubicin levels were measured directly by HPLC for free and polymer-bound doxorubicin. Only very low levels of non–polymer-bound doxorubicin (less than 0.1% plasma total) were found in the bloodstream. Profiles of plasma concentration-time for PK2 are shown in Fig 3. Levels of PK2 determined by gamma counting were indistinguishable from results generated by HPLC, and all patients administered PK2 by short infusion showed plasma clearance kinetics that fitted an open, two-compartment model. The pharmacokinetic parameters obtained for patients treated at doses of 20, 40, 80, and 120 mg/m2, and for a single patient treated at 160 mg/m2, are summarized in Table 3. PK2 seems to have linear kinetics, with approximately 25% being excreted intact in urine. The first dose level has a disproportionately low plasma area under the plasma concentration/time curve and high urinary excretion rate, which could imply saturable renal clearance. However, because there are no dose levels between 20 and 40 mg/m2, it was not possible to fully explore this hypothesis.
Targeting to Tumor and Parenchymal Liver Tissue Sequential gamma-camera imaging of PK2 distribution showed high levels of radioactivity in the hepatic region. Initial levels of radioactivity in the bladder and kidneys were followed by a rapid decline, consistent with renal excretion of the polymer (Fig 4A). In order to assess the relative contribution of polymer-bound galactosamine to hepatic targeting, similar imaging studies were performed with 123I-PK1, an otherwise identical HPMA copolymer that lacks the galactosamine moiety. In these patients, the level of liver uptake was much lower (Fig 4B), and the polymer showed a general distribution within the body, without concentration in any specific organ or tissue.
Image analysis of radioactivity distribution allowed quantitation of the hepatic targeting of PK2 (16.9% ± 3.9% total dose). Image registration, which allowed superimposition of SPECT and CT scans (Fig 5), revealed that the majority of the radioactive polymer was associated with areas of normal liver (Fig 6), with lower accumulation in areas of hepatic tumor (mean, 3.3% ± 5.6% total delivered dose; Fig 7).
Influence of Duration of Infusion on Plasma Profile of PK2 Six patients were administered PK2 at 120 mg/m2, crossing over in consecutive cycles from a 1-hour to a 24-hour infusion, to evaluate any effects on distribution kinetics. The plasma profile of PK2 after 24-hour infusion was compared with short infusion in the same patients. In each case, the plasma concentration rose throughout the 24-hour infusion period and then fell with the same alpha and beta half-lives and clearance parameters as seen at the end of the short infusion protocol (Table 3). This behavior was unaffected by the order of consecutive cycles given by 24-hour and short infusion. Although the peak levels achieved were always lower using the 24-hour infusion, the area under the plasma concentration/time curve was the same as for the short infusion. These observations suggest there would be no significant increases in hepatic targeting using an extended infusion protocol, and this was verified by comparing planar images of individual patients taken 24 hours after the end of consecutive cycles of drug administration, given by long and short infusion protocols (data not shown).
Targeting to Peripheral Metastases
Antitumor Activity
The ASGPR is expressed at high density on normal hepatocytes and is easily accessible from the bloodstream because of the permeability of the sinusoidal hepatic endothelium. It therefore represents an excellent target for receptor-mediated drug delivery and is known to have a high affinity for clusters of galactose residues.13 Results presented here indicate that it is possible to deliver galactosamine-targeted polymer conjugates selectively to the liver of cancer patients (15% to 20% of total delivered dose) after IV infusion. In contrast, the control polymer PK1, which bears no galactosamine, shows a general body distribution with no significant accumulation in the liver. Even 24 hours after administration, PK1 still displays a relatively high concentration in the bloodstream, with no discernible accumulation in any organs or tissues. The MTD of PK2 was found to be 160 mg/m2, which was associated with a toxicity profile characteristic of the linked cytotoxic agent doxorubicin, namely myelosuppression and mucositis, although there was perhaps more evidence of fatigue with PK2. The recommended dose for further trials to determine efficacy is 120 mg/m2. This is significantly higher than the conventional dose of 70 mg/m2 for non–polymer-bound doxorubicin, administered in solution by brief IV infusion. Interestingly, the MTD identified for the related polymer PK1 (320 mg/m2)14 was a good deal higher than that for PK2, emphasizing the significance of the galactosamine targeting moiety in determining the biodistribution and toxicology of the drug. As the polymer is toxicologically inert, these data imply that the final arbiter of toxicity is the quantity of doxorubicin delivered to compartments containing sensitive stem cells, eg, bone marrow and mucosal crypts. The existence of extrahepatic receptors for galactose has been reported,15 although they seemed to have little influence on the overall pattern of deposition of PK2. Hence, it is difficult to know whether the differential toxicity of PK2 is mediated through its liver targeting or through accumulation in less obvious sites. The appearance of fatigue as one of the DLTs is interesting but difficult to explain. Fatigue in cancer patients is multifactorial,16 and one might speculate that targeted delivery of doxorubicin to the liver may be associated with hepatic dysfunction leading to fatigue. The only patient who showed grade 1 transaminitis also showed grade 2 fatigue, and the only patient who showed grade 2 transaminitis also had grade 3 fatigue. However, despite meeting the entry criteria, this latter patient had several disease-related toxicities at enrollment (disease-related pain, insomnia) that may have influenced subsequent assessment of fatigue. The other reports of fatigue were not associated with any evidence of transaminitis or clinical signs of hepatitis, so it is difficult to reconcile the observed toxicity with an obvious mechanistic association. Uptake of PK2 into hepatic tumors (3.3% ± 5.6% total delivered dose) was significantly above background (Fig 7) but five-fold lower than levels observed in normal liver (Fig 6). This may well reflect a known decreased level of ASGPR expression in hepatoma compared with normal liver,17 particularly in poorly differentiated disease.18 Patients with metastatic colorectal cancer also showed significant tumor uptake of PK2, similar to that observed in a murine model of colorectal metastasis.19 Since ASGPR expression is a property of differentiated hepatocytes, it is considered unlikely that the receptor will be expressed by metastatic colorectal carcinoma cells. It is possible that accumulation of PK2 within tumor tissue may involve another component, perhaps resulting from relatively high permeability of tumor vasculature coupled with poor lymphatic drainage. This mechanism is thought to mediate nonspecific accumulation of macromolecules within tumor tissue, and is termed the enhanced permeability and retention effect.20,21 The enhanced permeability and retention effect is thought to represent the main mechanism of tumor accumulation of the nontargeted drug conjugate, PK1.14 Although the amount of drug delivered to tumor tissue was only about 20% of that localized to normal hepatic parenchyma, the calculated concentration of intratumoral doxorubicin (assuming that 100% of polymer-bound doxorubicin would be released as free drug at the tumor site) is 24.9 ± 15.9 µmol/L at a dose of 120 mg/m2 (Fig 7B). This is substantially higher (12- to 50-fold) than the level of doxorubicin previously measured in tumor biopsies after IV administration of the non–polymer-bound drug (0.5 to 2.0 µmol/L, depending on tumor type).22 Most cytotoxic drugs have steep dose-response curves and, although doxorubicin has minimal clinical activity against hepatoma, the advantage obtained by generating significantly higher tumoral drug concentrations with the polymer makes it worth investigating in phase II efficacy studies. There were no signs of saturation of the ASGPR with increasing drug dose. This was surprising, since studies in mice have found partial saturation of uptake after IV bolus injection of 0.68 mg/kg total PK25 (corresponding to a dose below the starting dose used in this study). Saturation of the receptor at these doses in vivo is compatible with the rate of galactose-mediated endocytosis reported in isolated rat hepatocytes (4 x 106 molecules per cell per hour23,24). This rate of uptake corresponds to about 9.6 x 1017 molecules of PK2 per liver per hour in a 1.5-kg human liver containing 1.6 x 108 hepatocytes/g, or about 6 mg of doxorubicin per liver per hour. Expression of the ASGPR shows considerable interspecies variation, however,25 and estimates of Km vary from 4 nmol/L for glycosylated albumin in mice26 to 6.5 µmol/L for asialo-orosomucoid in rats.13 In humans, there are estimates of the ASGPR being expressed at levels of 0.9 to 1.2 µmol/L in normal liver in vivo,27,28 and it is possible that the receptor has a greater rate of endocytic activity in humans than in rodents. Nevertheless, other targeting mechanisms could play a role in hepatic delivery of PK2. Apart from ASGPR targeting, one possible alternative explanation for the liver uptake could involve phagocytosis by the reticuloendothelial system, although the low level of spleen uptake argues against nonspecific phagocytosis. However the hepatic Kupffer cells are known to express "galactose particle" receptors, reported to have very high affinity for particles above 5 to 15 nm in diameter.29 Unimolecular colloids of polyHPMA (42 kd, bearing 1.5 mol% Gly-Leu-Phe-nitroaniline side chains) have an average diameter of 8.4 nm30; hence, it is feasible that Kupffer cell uptake could contribute to the hepatic targeting seen here. In either case, the hepatic targeting seems to be mediated by galactosamine since the galactosamine-free PK1 conjugate shows no liver targeting. Clear evidence of tumor-selective targeting was discerned in one patient with a metastatic hepatoma deposit in his shoulder. Planar imaging 24 hours after drug administration showed selective accumulation of radioactivity in the metastasis, indicating tumor targeting of PK2. This study has demonstrated that targeting the anticancer agent doxorubicin using polymers bearing galactosamine can effectively target the liver and can achieve greater drug levels in tumors than using nongalactosylated polymers or free doxorubicin. PK2 shows evidence of clinical activity. Of the 18 patients treated with advanced liver cancer, there was evidence of cytoreduction or decreased tumor markers in three patients with hepatoma, and two patients remain in partial remission at the time of writing, over 26 and 47 months after cessation of treatment. These results are remarkably similar to those of an early trial that administered galactosylated albumin bearing the anthracycline daunorubicin to 11 patients with primary hepatoma, which achieved one complete remission.31 It is clear that the approach is worthy of further consideration for treatment of hepatocellular cancer. The galactosamine-targeted polymer is mainly delivered to regions of normal liver, so third-generation polymeric cytotoxics should be designed for efficient diffusion of the free drug through tissues to mediate an effective "bystander" effect, coupled with an intrinsic selectivity for toxicity to tumor cells. Finally, this study also demonstrates the feasibility of targeting low molecular weight agents selectively to normal liver, raising the possibility of using this approach for treatment of diseases such as cirrhosis, hepatic malarial infection, Wilson’s disease, and viral hepatitis.
Supported by Cancer Research UK, London, United Kingdom. We are grateful to Pharmacia & Upjohn (Milan, Italy) for supplying the polymeric drugs, to Sally Andrews for expert technical support, and to Sarah Armstrong for excellent co-ordination of the clinical trial.
1. Ringsdorf H: Structure and properties of pharmacologically active polymers. J Polym Sci Polym Symp 51: 135-153, 1975 2. Ulbrich K, Strohalm J, Subr V, et al: Polymeric conjugates of drugs and antibodies for site-specific drug delivery. Macromol Symp 103: 177-192, 1996 3. Flanagan PA, Duncan R, Subr V, et al: Evaluation of protein-N-(2-hydroxypropyl)methacrylamide copolymer conjugates as targetable drug-carriers: 2. Body distribution of conjugates containing transferrin, antitransferrin receptor antibody or anti-Thy 1.2 antibody and effectiveness of transferrin-containing daunomycin conjugates against mouse L1210 leukemia in vivo. J Control Release 18: 25-37, 1992 4. Rihova B: Antibody-targeted polymer-bound drugs. Folia Microbiol (Praha) 40: 367-384, 1995[Medline] 5. Seymour LW, Ulbrich K, Wedge SR, et al: N-(2-Hydroxypropyl)methacrylamide copolymers targeted to the hepatocyte galactose-receptor: Pharmacokinetics in DBA2 mice. Br J Cancer 63: 859-866, 1991[Medline] 6. Duncan R, Seymour LCW, Scarlett L, et al: Fate of N-(2-hydroxypropyl)methacrylamide copolymers with pendent galactosamine residues after intravenous administration to rats. Biochim Biophys Acta 880: 62-71, 1986[Medline] 7. Seymour LW: Soluble polymers for lectin-mediated drug targeting. Adv Drug Deliv Rev 14: 89-111, 1994[CrossRef] 8. Wedge SR, Duncan R, Kopeckova P: Comparison of the liver subcellular distribution of free daunomycin and that bound to galactosamine targeted N-(2-hydroxypropyl)methacrylamide copolymers, following intravenous administration in the rat. Br J Cancer 63: 546-549, 1991[Medline] 9. Duncan R, Seymour LW, Flanagan PA, et al: Preclinical evaluation of polymer-bound doxorubicin. J Control Release 19: 331-342, 1992[CrossRef] 10. Rihova B, Bilej M, Vetvicka V, et al: Biocompatibility of N-(2-hydroxypropyl) methacrylamide copolymers containing Adriamycin: Immunogenicity, and effect on hematopoietic stem-cells in bone-marrow in vivo and mouse splenocytes and human peripheral blood lymphocytes in vitro. Biomaterials 10: 335-342, 1989[CrossRef][Medline] 11. Julyan PJ, Seymour LW, Ferry DR, et al: Preliminary clinical study of the distribution of HPMA copolymers bearing doxorubicin and galactosamine. J Control Release 57: 281-290, 1999[CrossRef][Medline] 12. Cassidy J, Bissett D, Kerr DJ: Methodological aspects of phase I studies of novel anticancer agents. Int J Cancer 1: 195-199, 1992
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Schwartz AL, Fridovich SE, Lodish HF: Kinetics of internalization and recycling of the asialoglycoprotein receptor in a hepatoma cell line. J Biol Chem 257: 4230-4237, 1982 24. Schwartz AL, Fridovich SE, Rup D, et al: Characterization of the asialoglycoprotein receptor in a hepatoma line. J Cell Biol 91: 220, 1981 (abstr) 25. Chang TM, Chang CL: Hepatic-uptake of asialoglycoprotein is different among mammalian species due to different receptor distribution. Biochim Biophys Acta 942: 57-64, 1988[Medline] 26. Nishikawa M, Ohtsubo Y, Ohno J, et al: Pharmacokinetics of receptor-mediated hepatic uptake of glycosylated albumin in mice. Int J Pharm 85: 75-85, 1992[CrossRef] 27. Virgolini I, Muller C, Angelberger P, et al: Quantification of human hepatic binding protein (HBP) via 99mTc-galactosyl-neoglycoalbumin (NGA) liver scintigraphy. Wien Klin Wochenschr 103: 458-461, 1991[Medline] 28. Virgolini I, Nuller C, Angelberger P, et al: Functional liver imaging with 99Tcm-galactosyl-neoglycoalbumin (NGA) in alcoholic liver cirrhosis and liver fibrosis. Nucl Med Commun 12: 507-517, 1991[Medline] 29. Schlepper-Schafer J, Hulsman D, Djovkar A, et al: Endocytosis via galactose receptors in vivo: Ligand size directs uptake by hepatocytes or liver macrophages. Exp Cell Res 165: 494-506, 1986[CrossRef][Medline] 30. Ulbrich K, Konak C, Tuzar Z, et al: Solution properties of drug carriers based on poly[N-(2-hydroxypropyl)methacrylamide] containing biodegradable bonds. Macromolecular Chemie 188: 1261-1272, 1987 31. Ceulemans F, Baurain R, Geubel A, et al: Pilotage des anthracyclines et hepatomes. Pathol Biol 35: 61-68, 1987[Medline] Submitted June 4, 2001; accepted November 26, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2, age at least 18 years, life expectancy greater than 12 weeks, WBC count 
3 x 109 cells/L, absolute neutrophil count of 
), 40 (
), 80 (•), 120 (
and 160 mg/m2 (
). Mean values are shown, with error bars representing ± SD.
), 40 (
