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Biomedical subjects

D S Alberts

Publications and source records attributed to D S Alberts.

At least 91 records · Page 5Linked to original sources
PubMed1996

Intraperitoneal mitoxantrone or floxuridine: effects on time-to-failure and survival in patients with minimal residual ovarian cancer after second-look laparotomy--a randomized phase II study by theSouthwest Oncology Group.

A randomized phase II study of intraperitoneal (ip) mitoxantrone or floxuridine (FUDR) was performed for the treatment of minimal residual epithelial ovarian cancer found at second-look laparotomy after initial platinum-based chemotherapy. Entry was to take place within 30 days of reassessment laparotomies, with documentation of peritoneal metastases either microscopic or gross with cytoreduction to less than or equal to 1 cm in largest diameter. Patients were stratified by the site of the largest disease present (microscopic to 0.5 cm maximum diameter versus greater than 0.5 to 1 cm maximum diameter), by time of registration (< 14 days versus up to 30), and by serum CA-125 (< or = 35 versus >35 units/ml) prior to randomization to either ip mitoxantrone 10 mg/m2 every 2 weeks X 9 or ip floxuridine (FUDR) 3 g (total dose)/ day X 3 days every 3 weeks X 6 cycles. Implantable ip systems and 1.5-2 liters of normal saline were used to deliver the drugs of 83 patients registered between December 1988 and January 1994; there were 6 pathology exclusions and 9 surgical exclusions, and 1 nonevaluable patient for a total of 39 evaluable on mitoxantrone and 28 on FUDR being evaluable. FUDR is the choice for further study because of a progression-free survival exceeding 15% at 1 year over mitoxantrone and a median overall survival of 38 months. It should be emphasized again that the goal of a randomized phase II selection design is to select a winner for phase III testing should there be a substantial difference between the treatments with respect to the primary endpoint. Comparative conclusions between the treatment arms should not be attempted due to the inherently much smaller sample sizes. This should reemphasize the limitations in a comparison of efficacy; however, the toxicologic differences still emerge quite clearly.

Adult↗
PubMed1996

Antitumor activity of combretastatin-A4 phosphate, a natural product tubulin inhibitor.

The tubulin-binding natural product combretastatin A-4 (CA-4) was tested for antitumor activity against fresh human tumors in vitro and 2 mouse tumors, both in vitro and in vivo. In colony forming assays using 10% fetal bovine serum, CA-4 was inhibitory in 27/40 human ovary cancers with a mean IC50 of 3.18 micrograms/mL for a 1-hour exposure (n = 35 specimens) and 0.27 microgramf1p4for a continuous exposure to CA-4 for 11-14 days (n = 5 specimens). Murine B-16 melanoma and P-388 leukemia were also highly sensitive to CA-4 in vitro with an identical IC50 value of 0.0007 micrograms/mL for continuous drug exposure for 8 days. Comparable in vitro cell culture studies performed in serum concentrations higher than 10%, revealed a significant loss of cytotoxic potency. Using the same reversed-phase HPLC technique as developed for paclitaxel, CA-4 was shown to bind to serum proteins (> or = 30,000 mw) > 99% and to albumin approximately 70%. CA-4 was only marginally active (25% increased lifespan) in DBA/2 mice bearing P-388 leukemia who were given doses of 100 mg/kg IP on either days, 1, 5 and 9 (p = 0.075 by Wilcoxon analysis) or on consecutive days 1-9 (p = 0.19 compared to control). A higher IP dose of 150 mg/kg on days 1, 5 and 9 did not delay subcutaneous B-16 melanoma tumor growth in C57/B1 mice. These findings demonstrate a substantial loss of antitumor efficacy for CA-4 in physiologic serum concentrations in vitro. No consistent antitumor activity was observed in two murine tumor models in vivo.

Animals↗
PubMed1996

Amplification of 19q13.1-q13.2 sequences in ovarian cancer. G-band, FISH, and molecular studies.

In this study of ovarian carcinoma, we extended previous findings by performing FISH using chromosome 19 paint and microFISH probes and patient samples with and without abnormalities of chromosome 19 identified by G-banding. Karyotype interpretations of der(19) were confirmed, while additional 19 translocations were also detected by FISH with 19WCP in some cases. Similar FISH studies of ovarian carcinoma cell lines found chromosome 19 abnormalities even after extensive in vitro culture. MicroFISH probes were generated by chromosome microdissection from two cases with hsr(19) and mapped to 19q13.2 and 19q13.1-.2, respectively. FISH with these microFISH probes alone or in combination with a 19WCP probe to four patient samples and seven cell lines showed that 65% of chromosome 19 structural abnormalities contained 19q13.1-q13.2 sequences, sometimes as large hsrs. Ovarian cancer cell lines showed amplification and overexpression of the AKT2 putative oncogene, but not the ERCC-2 DNA repair gene in this chromosomal region. In addition to AKT2, amplification and overexpression of other yet-unidentified genes in the 19q13.1-q13.2 region may contribute to ovarian carcinoma pathogenesis or progression.

Chromosome Aberrations↗
PubMed1996

WR-1065, the active metabolite of amifostine (Ethyol), does not inhibit the cytotoxic effects of a broad range of standard anticancer drugs against human ovarian and breast cancer cells.

Amifostine (WR-2721, Ethyol), a phosphorylated thiol, demonstrates the unique ability to protect normal but not tumour tissue from cytotoxic damage induced by radiation therapy and chemotherapy. This study tested the effect of amifostine's active metabolite, the free thiol, WR-1065, on the cytotoxicity of standard anticancer drugs against human A2780 ovarian and MCF7 breast cancer cell lines in vitro, using the well-characterised sulphorhodamine B assay. 50% inhibitory concentration (IC50) values were determined for each of 16 different anticancer drugs in the presence and absence of the highest nontoxic dose of WR-1065 from concentration-response curves constructed in triplicate and based on 18 replicate cell culture plates for each tested drug concentration. Pretreatment with WR-1065 had no statistically significant effect on the IC50 value of any of the 16 drugs tested against either the A2780 or MCF7 human tumour cells. These data expand upon previous reports showing that amifostine does not protect tumours from the cytotoxic effects of anticancer agents. The ability of amifostine to protect against dose-limiting toxicity to a variety of normal tissues without protection of tumour should enhance the efficacy ratio of a wide range of standard anticancer drugs.

Antineoplastic Agents↗
PubMed1996

Expression of the zinc finger gene EVI-1 in ovarian and other cancers.

The EVI-1 gene was originally detected as an ectopic viral insertion site and encodes a nuclear zinc finger DNA-binding protein. Previous studies showed restricted EVI-1 RNA or protein expression during ontogeny; in a kidney and an endometrial carcinoma cell line; and in normal murine oocytes and kidney cells. EVI-1 expression was also detected in a subset of acute myeloid leukaemias (AMLs) and myelodysplasia. Because EVI-1 is expressed in the urogenital tract during development, we examined ovarian cancers and normal ovaries for EVI-1 RNA expression using reverse transcription polymerase chain reaction (RT-PCR) and RNAase protection. Chromosome abnormalities were examined using karyotypes and whole chromosome 3 and 3q26 fluorescence in situ hybridisation (FISH). RNA from six primary ovarian tumours, five normal ovaries and 47 tumour cell lines (25 ovarian, seven melanoma, three prostate, seven breast and one each of bladder, endometrial, lung, epidermoid and histiocytic lymphoma) was studied. Five of six primary ovarian tumours, three of five normal ovaries and 22 of 25 ovarian cell lines expressed EVI-1 RNA. A variety of other non-haematological cancers also expressed EVI-1 RNA. Immunostaining of ovarian cancer cell lines revealed nuclear EVI-1 protein. In contrast, normal ovary stained primarily within oocytes and faintly in stroma. Primary ovarian tumours showed nuclear and intense, diffuse cytoplasmic staining. Quantitation of EVI-1 RNA, performed using RNAase protection, showed ovarian carcinoma cells expressed 0 to 40 times the EVI-1 RNA in normal ovary, and 0-6 times the levels in leukaemia cell lines. Southern analyses of ovarian carcinoma cell lines showed no amplification or rearrangements involving EVI-1. In some acute leukaemias, activation of EVI-1 transcription is associated with translocations involving 3q26, the site of the EVI-1 gene. Ovarian carcinoma karyotypes showed one line with quadruplication 3(q24q27), but no other clonal structural rearrangements involving 3q26. However, whole chromsome 3 and 3q26 FISH performed on lines with high EVI-1 expression showed translocations involving chromosome 3q26. EVI-1 is overexpressed in ovarian cancer compared with normal ovaries, suggesting a role for EVI-1 in solid tumour carcinogenesis or progression. Mechanisms underlying EVI-1 overexpression remain unclear, but may include rearrangements involving chromosome 3q26.

Blotting, Southern↗
PubMed1996

Disposition and metabolism of topically administered alpha-tocopherol acetate: a common ingredient of commercially available sunscreens and cosmetics.

Skin cancers are a serious health problem in the United States. One common method of skin cancer primary prevention is use of sunscreens. Research has been conducted to ascertain the role of active ingredients of sunscreen products in photoprotection and possible carcinogenesis. In contrast, little is known about the "other ingredients", listed or unlisted, on sunscreen product labels. One such ingredient is vitamin E. usually in the form of alpha-tocopherol acetate. Results of recent studies of skin carcinogenesis in an ultraviolet (UV) B mouse carcinogenesis model suggest that topically applied alpha-tocopherol acetate does not prevent and, under some conditions, enhances skin cancer development and growth, whereas the free unesterified from of alpha-tocopherol significantly reduces experimental UVB carcinogenesis. We have performed a Phase II cancer prevention study to evaluate whether topically applied alpha-tocopherol acetate is absorbed in human skin and metabolizes to the free or other forms. In this double-blind study, 19 men and women > 30 years of age who had at least three actinic keratoses on their forearms were randomly assigned to apply alpha-tocopherol acetate (125 mg/g) or difluoromethylornithine cream to their arms twice daily for three months. Blood samples and photographs and punch biopsies of actinic keratoses were obtained before and at the end of the study (Month 4). Plasma and skin concentrations of free alpha-tocopherol, alpha-tocopherol acetate, and gamma-tocopherol were analyzed by high-performance liquid chromatography at Month 4. The results of this report focus only on data obtained from the 11 participants randomized to the alpha-tocopherol acetate arm of the study. Topically applied alpha-tocopherol acetate was substantially absorbed in skin, with no evidence of conversion within skin to its unesterified form (i.e., free alpha-tocopherol). There was no evidence of systemic availability or biotransformation of topically applied alpha-tocopherol acetate. In summary, we have determined that alpha-tocopherol acetate is not metabolized to the free form of alpha-tocopherol in plasma or skin.

Administration, Topical↗
PubMed1996

Prevention of photocarcinogenesis by topical administration of pure epigallocatechin gallate isolated from green tea.

Topical application of purified (-)-epigallocatechin-3-gallate (EGCG), a polyphenolic antioxidant isolated from green tea, inhibited photocarcinogenesis in BALB/cAnNHsd mice with no visible toxicity. Mice were treated with 0, 10, or 50 mg of EGCG in 200 microliters of acetone three times weekly for three weeks before ultraviolet (UV) treatments began and throughout the experiment. UV radiation consisted of five 30-minute exposures per week to banks of six FS40 Westinghouse sunlamps for 25 weeks. In the photocarcinogenesis study, mice received a total dose of approximately 2.1 x 10(6) J/m2. Skin cancer incidence in UV-irradiated mice was 96% at 28 weeks after the first UV treatment; EGCG at 10 or 50 mg reduced this incidence to 62% and 29%, respectively. UV-induced immunosuppression, assessed by the inability of UVB-irradiated mice to reject a syngeneic antigenic tumor, was not influenced by topical EGCG. Oral administration of 0, 100, or 500 mg of pure EGCG per liter of drinking water (approximately 0, 0.56, or 2.8 mg/day, respectively) did not decrease UV-induced skin tumor incidence, rate of primary tumor growth, or inability to reject antigenic tumors. Thus induction of skin tumors by UV radiation was significantly reduced by topical, but not by oral, administration of purified EGCG through a mechanism distinct from inhibition of photoimmunosuppression.

Administration, Topical↗
PubMed1996

Antiemetic efficacy of two different single intravenous doses of dolasetron in patients receiving high-dose cisplatin-containing chemotherapy.

This randomized, double-blind, parallel-group, multicenter study compared the antiemetic effectiveness, safety, and tolerability of two different intravenous (i.v.) doses of dolasetron mesylate (0.6 and 1.8 mg/kg) in cancer patients receiving their first course of high-dose cisplatin-containing chemotherapy (> or = 75 mg/m2). Efficacy was assessed by recording the timing, number, and severity of emetic episodes in the 24 h following high-dose cisplatin. Safety was evaluated by monitoring adverse events, vital signs, clinical laboratory parameters, and electrocardiograms. Of the 62 patients enrolled in the study, 29 received 0.6 mg/kg of dolasetron mesylate and 33 received 1.8 mg/kg. Patients who received dolasetron mesylate 1.8 mg/kg consistently experienced a greater degree of antiemetic control than those who received 0.6 mg/kg. Complete responses were achieved by 55% of patients who received 1.8 mg/kg compared with 31% for the 0.6-mg/kg group. The 1.8-mg/kg group achieved a significantly (p = 0.039) higher complete/ major response rate than the 0.6-mg/kg group (77% vs 55%, respectively) and a significantly (p = 0.004) longer time to the first emetic episode (> 24 h vs 13.5 h, respectively). More than 80% of patients were either satisfied or very satisfied with dolasetron treatment. The most common adverse events were mild to moderate in intensity, consistent with other studies, and included headache (24.1% of patients) and diarrhea (4.8%). These results demonstrated that a single 1.8-mg/kg i.v. dose of dolasetron mesylate provided effective antiemetic activity in a majority of patients given high-dose cisplatin for the first time and should be evaluated further in clinical trials.

Antiemetics↗
PubMed1996

Inhibitory effect of six green tea catechins and caffeine on the growth of four selected human tumor cell lines.

Green tea is an aqueous infusion of dried unfermented leaves of Camellia sinensis (family Theaceae) from which numerous biological activities have been reported including antimutagenic, antibacterial, hypocholesterolemic, antioxidant, antitumor and cancer preventive activities. From the aqueous-alcoholic extract of green tea leaves, six compounds (+)-gallocatechin (GC), (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), (-)-epigallocatechin gallate (EGCG) and caffeine, were isolated and purified. Together with (+)-catechin, these compounds were tested against each of four human tumor cells lines (MCF-7 breast carcinoma, HT-29 colon carcinoma, A-427 lung carcinoma and UACC-375 melanoma). The three most potent green tea components against all four tumor cell lines were EGCG, GC and EGC. EGCG was the most potent of the seven green tea components against three out of the four cell lines (i.e. MCF-7 breast cancer, HT-29 colon cancer and UACC-375 melanoma). On the basis of these extensive in vitro studies, it would be of considerable interest to evaluate all three of these components in comparative preclinical in vivo animal tumor model systems before final decisions are made concerning which of these potential chemopreventive drugs should be taken into broad clinical trials.

Caffeine↗
PubMed1996

A phase II trial of piroxantrone in endometrial cancer: Southwest Oncology Group study 8918.

A phase II trial of the new anthrapyrazole piroxantrone was carried out by the Southwest Oncology Group in patients with advanced metastatic or recurrent endometrial cancer. A two-stage statistical design targeted accrual of 20 eligible patients. The starting dose of piroxantrone was 150 mg/m2 in patients without prior radiation therapy (RT) and 120 mg/m2 in patients with prior RT. There were 15 eligible patients, six of whom had received prior hormonal therapy while nine patients had not received prior hormonal therapy. Eight patients had received prior RT while seven patients had not received any prior RT. One to seven cycles of piroxantrone were administered. Dose escalation was feasible in four patients. No grade 5 toxicity was experienced by any patients. Most of the grade 4 (granulocytopenia in one) and grade 3 (leukopenia in three, granulocytopenia in three, anemia in two and thrombocytopenia in one) toxicity was related to myelosuppression. Grade 3 non-hematologic toxicities were nausea, fatigue and SGOT elevation. There was one partial response for a response rate of 7% (95% CI 0.2-32%) and median survival was 11 months (95% CI 3-13 months). The study was prematurely terminated due to lack of patient accrual.

Adult↗
PubMed1996

The measurement of adenoma occurrence.

Adenomatous polyps are regarded as the dominant precursor lesion of colon cancer. For four decades the occurrence of adenomas has been investigated, both in observational studies and in controlled, randomized cancer-prevention studies. During this period, little consensus has been reached with regard to the data that should be reported in such studies. The emerging consensus on the methods of analysing the results does not have a firm biostatistical basis, and does not deal appropriately with the phenomenon of colonoscopy avoidance. We review a simple biostatistical method that is appropriate, and apply it to a selected recent series of studies. Our finding is that there are common patterns of adenoma occurrence across these studies, with a rate of 0.3-0.4 per year in the first year following polypectomy, dropping to 0.1-0.15 in subsequent years. The method of analysis also serves to highlight exceptions to this pattern.

Adenoma↗
PubMed1996

Future development of amifostine in cancer treatment.

Amifostine selectively protects normal, but not tumor, tissue from the cytotoxic damage induced by radiation therapy and chemotherapy. In a broad range of preclinical and phase II and III clinical studies, amifostine has been shown to substantially reduce anticancer drug-induced neutropenia, thrombocytopenia, nephrotoxicity, neurotoxicity (including ototoxicity and peripheral neuropathy), musculoskeletal toxicity, cardiotoxicity, and mutagenicity. Based on the rapidly expanding clinical trials database, there is strong rationale to design phase II and III studies of amifostine as a cytoprotective agent in patients with early and/or advanced breast, bladder, cervix, head and neck, small cell and non-small cell lung, ovarian, and rectal cancers, as well as melanoma, pediatric sarcomas, and lymphomas, including Hodgkin's disease. In this article, we have attempted to survey recently completed and ongoing phase II and III clinical studies and suggest specific designs for future clinical trials to establish the ultimate role of amifostine as a broad-spectrum cytoprotective agent.

Adult↗
PubMed1996

New carotenoid values for foods improve relationship of food frequency questionnaire intake estimates to plasma values.

Carotenoid consumption is of great interest in disease prevention studies. Until recently, carotenoid food composition data have not been available from a single laboratory source with high validity/reliability characteristics. With the availability of a new carotenoid food composition data base, we examined the impact of the new data base on the intake estimates as measured by a food frequency questionnaire and on the relationship of those estimates to plasma values to ascertain what, if any, improvement is achieved through use of the new values. Plasma samples were available for 162 healthy adults participating in cancer prevention studies at the Arizona Cancer Center, including men and women, smokers and nonsmokers. A single laboratory analyzed plasma samples for beta-carotene, alpha-carotene, lutein, and lycopene. All subjects had completed a modified version of the Block food frequency questionnaire, which calculates carotenoids using a literature-based algorithm. A new carotenoid composition data base using recently published data (A.R. Mangels et al., J. Am. Diet. Assoc., 93: 284-296, 1993) was then directly substituted for the Block data base. There were high correlations between intake estimates derived from the two data bases for all four carotenoids (range, r = 0.76-0.96). Average intake estimates based on the Mangels et al. data base were significantly higher for beta-carotene and lycopene; however, correlations between intakes and plasma values were significantly different only for beta-carotene (r = 0.44 for Mangels versus 0.32 for Block, P = 0.015).

Aged↗
PubMed1996

A phase I study of etoposide phosphate plus paclitaxel.

Etoposide phosphate (Etopophos; Bristol-Myers Squibb Company, Princeton, NJ) is a water-soluble derivative of etoposide, a semisynthetic podophyllotoxin that is important in the treatment of a variety of malignancies, including lung cancer, germ cell tumors, non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute leukemia, etc. Because etoposide is poorly water soluble, it must be dissolved in a polysorbate 80-based solvent mixture, which is moderately allergenic and requires a large volume of saline for administration. Etoposide phosphate is water soluble and is rapidly converted in vivo to etoposide by endogenous phosphatases. Because it is water soluble, etoposide phosphate can be administered in volumes much smaller than those required with etoposide therapy, permitting rapid intravenous administration in the outpatient setting. We recently reported the results of a phase I study using etoposide phosphate on a bolus, daily x 5 schedule. Like others, we demonstrated that etoposide phosphate has pharmacokinetic properties virtually identical to those of etoposide. Our dose-finding study indicated that etoposide phosphate can be used in doses up to 100 mg/m2/d x 5 every 3 weeks in patients who have not had extensive prior chemotherapy, and that a dose of 75 mg/m2 would be appropriate for patients who had undergone multiple prior therapies or who had prior radiotherapy. The dose-limiting toxicity was neutropenia. Paclitaxel, a microtubule-stabilizing agent, is active against a variety of solid and hematopoietic malignancies that overlap with those against which etoposide is active. Because the mechanisms of action of these two agents differ, it is logical to suppose that the combination of the two agents might produce some additive effect when used to treat cancers that respond to both individual agents. We therefore undertook a phase I study using paclitaxel as a 3-hour infusion in combination with a 5-minute infusion of etoposide phosphate daily x 3 every 21 days. We used the 3-hour paclitaxel schedule because it has been shown to be less myelotoxic than longer infusions at the same doses. Our goal in this ongoing study is to determine the maximum tolerated doses of the two drugs in combination, to determine the toxicities of the regimen, and to assess its anticancer activity.

Adult↗
PubMed1996

Evaluation of proliferating cell nuclear antigen as a surrogate end point biomarker in actinic keratosis and adjacent, normal-appearing, and non-sun-exposed human skin samples.

The incidence of nonmelanoma skin cancer, including both squamous cell carcinoma and basal cell carcinoma, is a significant health problem in the United States. Actinic keratosis (AK), the precursor of cutaneous squamous cell carcinoma, is a major risk factor for nonmelanoma skin cancer. In addition, AKs are tissue targets for the identification of biomarkers for use in chemopreventive studies. The biomarker addressed in this study is epidermal cell proliferation, as quantitated by proliferating cell nuclear antigen (PCNA). Shave biopsies were obtained from AKs, tissue immediately adjacent to AKs, normal-appearing, upper-medial arm skin, and non-sun-exposed skin from 19 subjects. When any degree of PCNA staining was considered positive (semiquantitative 1-4 scale), there was a significant difference and a progressively increasing mean PCNA labeling index (LI) in the total epidermis (basal and suprabasal layers), beginning with non-sun-exposed buttock skin, with the lowest LI (2.5 + or - 1.6%), followed by upper-medial arm skin (12.3 + or - 7.4%; P = 0.0015), skin adjacent to AKs (19.2 + or - 12.2%; P = 0.0218), and finally, AKs with the highest LI (34.6 + or - 20.1%; P = 0.0017). This same pattern was observed when the epidermis was separated into basal and suprabasal layers, with the exception of a nonsignificant result for upper-medial arm skin compared with adjacent skin in the basal layer (P = 0.3981). PCNA LIs were also analyzed separately by staining intensity (i.e., scores of 1-4). The PCNA LI in skin with varying degrees of sun damage and/or histological atypia is a candidate surrogate end point biomarker for skin cancer chemoprevention studies.

Aged↗
PubMed1996

Reproducibility of the measurement of colonic proliferation using bromodeoxyuridine across laboratories.

Although measures of colonic cell proliferation are being used as potential intermediate markers in chemoprevention studies, measurement standardization is still ongoing. This study was designed to assess the reproducibility of the labeling index quantification, as measured by bromodeoxyuridine, across four laboratories experienced in its use. Each institution submitted 10 slides, with one circled area of each slide to be scored. Each site followed its standard procedures for scoring colonic crypts; no attempts to standardize these procedures were made. There was high concordance among the laboratories on whether scorable crypts were present on a particular slide, but only two pairs of laboratories demonstrated agreement statistically greater than that predicted by chance. The overall difference among the sites on the number of scorable crypts was marginally significant (P = 0.083), and there was a highly significant overall difference in the magnitude of the labeling index (P < 0.0001). Sites 1 and 2 tended to have similar results, as did sites 3 and 4, most likely due to common training. Even with these discrepancies, high correlation (r > 0.75) was observed among the reported labeling index values for each pair of laboratories. Without standardized training, these laboratories may differ in the crypts considered appropriate for counting and in whether cells are counted as labeled or unlabeled. These results suggest that standardized training in scoring across all sites performing labeling index determinations is required to assure reproducibility across sites or studies. These results may also help explain discrepancies in the average values of the labeling index reported in the literature.

Analysis of Variance↗
PubMed1996

Safety of autotransplants with high-dose melphalan in renal failure: a pharmacokinetic and toxicity study.

Melphalan (MEL) is probably the most effective chemotherapeutic agent in multiple myeloma (MM) with a clear dose-response effect. It can be escalated without excessive toxicity to 200 mg/m2, a myeloablative dose requiring hematopoietic stem cell support. Patients with marked renal insufficiency, not an infrequent finding in MM, have either received reduced doses or have been excluded from therapy with high-dose MEL. A prospective study was performed to evaluate the relationship between MEL pharmacokinetics and renal function in 20 patients with MM. Six patients had severe renal insufficiency (creatinine clearance, <40 ml/min), including five on chronic hemodialysis. Three patients with severe renal impairment first received a low test dose of MEL (16 mg/m2) for pharmacokinetic studies. All patients received 200 mg/m2 MEL divided into two equal doses of 100 mg/m2 i.v. on 2 consecutive days, followed by the administration of peripheral blood stem cells. MEL pharmacokinetics, performed after the first dose of 100 mg/m2, was not adversely affected by impaired renal function. The median half-life (t1/2), area under the concentration curve, and clearance of MEL were 1.1 h, 5.5 mg h/liter, and 27.5 liter/h, respectively, in patients with a creatinine clearance of <40 ml/min compared to 1.9, 7.9, and 23.6 for the others. Renal insufficiency also had no apparent negative impact on the quality of peripheral blood stem cell collections and did not adversely affect posttransplant engraftment, transfusion requirements, incidence of severe mucositis, or overall survival. However, it was associated with longer durations of fever (P = 0. 0005) and hospitalization (P = 0.004). No transplant-related deaths were observed. Plasma t1/2 and area under the concentration curve differed by a factor of 10 and MEL clearance by a factor of 5 between patients with the lowest and highest values. These large variations in MEL elimination could not be explained by patient or disease characteristics. We conclude that renal failure does not require dose reduction of MEL in autologous transplant. Due to marked interindividual variation in MEL elimination, pharmacokinetically guided dosing as well as cellular pharmacology studies may be helpful in achieving a more uniform antitumor effect.

Adult↗