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PubMed1994

Straw thermal stabilizer for embryo cryopreservation.

Embryo cryopreservation procedures have been highly developed to support in vitro fertilization techniques, but the clinical results have not met initial expectations. Many variables influence the outcome of the embryo cryopreservation procedure. Exposure to classical freezing media does not affect further embryo development. Therefore, the first crucial step seems to be embryo thermal behavior during the freezing/thawing procedure. With the aim of avoiding thermal oscillations to the embryos due to liquid nitrogen injection into the freezing chamber, we have developed a straw thermal stabilizer (STS) cryopreservation accessory that when adapted to a programmable biological freezer offers a more exact control of the straws temperature and also a greater reproducibility of the freezing process. The STS incorporates a seeding mechanism controlled by specially designed software. For the biological assays, 2-cell mouse embryos were cooled until seeding at -7 degrees C or frozen to -120 degrees C using 1.5 M 1,2-propanediol and 0.1 M sucrose. As control groups, embryos were either untreated or were exposed to cryoprotectants, developing to blastocyst at rates of 90.8 and 88.4%, respectively. The embryos cooled until seedling or subjected to the complete freezing procedure developed into blastocysts at rates of 95.7 and 82.8%, respectively, disregarding the effect of the cryoprotectant exposure. These results show a substantial improvement in cryopreservation with no loss in embryo development due to the seeding procedure.

Animals↗
PubMed1994

Developmental competence of bovine oocytes frozen at different cooling rates.

Experiments were conducted to determine the optimal cooling conditions for improving the developmental competence of in vitro-matured bovine oocytes when frozen in 1.6 M 1,2-propanediol. Bovine oocytes were cooled from 0 degree to -5.5 degrees C at 1 degree C/min, seeded, and then cooled to -30 degrees C at different cooling rates (0.3 degree, 0.6 degree or 0.9 degree C/min) and then plunged into LN2. When frozen-thawed oocytes were fertilized in vitro, the proportions of fertilization and developmental competence did not differ among the three groups frozen at different cooling rates. The findings indicated that a cooling rate of less than 1.0 degree C/min in the freezing procedure did not affect the developmental competence of postthaw in vitro-matured bovine oocytes.

Animals↗
PubMed1995

Ultrastructural changes in bovine oocytes cryopreserved by vitrification.

Oocytes recovered from abattoir-derived ovaries were exposed to a cryoprotectant solution (DAP213: 2 M DMSO, 1 M acetamide, 3 M propanediol, and 10% fetal calf serum in tissue culture medium 199) for less than 20 s and vitrified either at the germinal vesicle (GV) stage or after maturation in vitro (IVM). Survival was assessed by fertilization and culture in vitro to the blastocyst stage. To identify ultrastructural changes, some of the vitrified oocytes that were morphologically normal after thawing were immediately processed for transmission electron microscopy after DAP213 removal. Cleavage rates for vitrified IVM oocytes were 4.5 and 6.7% using one-step and three-step cryoprotectant dilution procedures, respectively. Four (3%) oocytes developed to the eight-cell stage with the three-step procedure, but none formed blastocysts. None of the GV oocytes cleaved, while 66.7% (78/117) of controls developed to the two-cell stage and 19.2% (15/78) of those became blastocysts. Vitrification induced profound ultrastructural modifications in microvilli, mitochondria, vesicle formation, and the ooplasm of GV oocytes, whereas these structures were generally better preserved in IVM oocytes. The integrity of cell organelles was relatively better maintained following the three-step than after the one-step procedure in both GV and IVM oocytes. Changes in the zona pellucida (ZP) of IVM oocytes due to vitrification were associated with fewer cortical granules in the ooplasm. Since previous work showed that short-term exposure to DAP213 did not cause ZP alterations in IVM oocytes, these findings suggest that ZP damage due to low temperatures may result from the premature release of cortical granules.

Acetamides↗
PubMed1995

Comparison of the efficacy of conventional slow freezing and rapid cryopreservation methods for bovine embryos.

Day 7 bovine morulae and early blastocysts were randomly assigned to one of four cryopreservation methods: (i) a modified conventional controlled slow freezing and stepwise dilution after thawing; and three methods which enable direct transfer of the embryo into the recipient upon thawing: (ii) conventional controlled slow freezing and a modification of a one-step procedure, (iii) vitrification with 6.5 M glycerol plus 6% BSA (w/v), and (iv) vitrification with 25% glycerol (v/v) and 25% propanediol (v/v). In a comparative in vitro study, the percentage of grade 1 and 2 embryos developing into expanded blastocysts in culture for cryopreservation methods 1-4 were, respectively, 53% (29/55), 33% (20/61), 44% (26/59), and 51% (17/33). Method 2 yielded a significantly lower survival rate than methods 1 (P < 0.1) and 4 (P < 0.05) and was excluded from a subsequent test of in vivo development. Pregnancy rates (Day 60) after transfer of embryos cryopreserved by methods 1, 3, and 4 were, respectively, 59% (20/34), 43% (17/40), and 24% (5/21). Method 4 yielded a significantly lower pregnancy rate than method 1 (P < 0.05). Method 3, however, did not yield a statistically different pregnancy rate (P > 0.1) when compared to method 1. Method 3 has considerable promise in providing a successful method for the cryopreservation of bovine embryos that (i) reduces the time required for equilibration and cooling, (ii) provides for simple and rapid one-step dilution of cryoprotectant after thawing, and (iii) enables more embryos to be thawed and transferred per unit time.

Animals↗
PubMed1996

Critical cooling and warming rates to avoid ice crystallization in small pieces of mammalian organs permeated with cryoprotective agents.

Measurements were made by differential scanning calorimetry on small pieces of rabbit kidney permeated with 2, 3-butanediol containing mainly the levo- and dextro-isomers. The critical cooling rates necessary to vitrify the pieces of organ, and the corresponding critical warming rates which are required to avoid crystallization in the vitrified samples, were determined. The dynamic method used for these determinations is described. The glass-forming tendency and the stability of the amorphous state were both greater in the kidney tissue samples than in the bulk cryoprotective solution. This result is discussed in the context of the lowering of the freezing point of water in emulsions and the promotion of supercooling in hydrogels and porous materials. In corresponding experiments with rat hearts impregnated with 1,2-propanediol, only the critical warming rate was reduced.

Animals↗
PubMed1996

Fertilization and development of frozen-thawed germinal vesicle bovine oocytes by a one-step dilution method in vitro.

The objective of this study was to evaluate in vitro fertilization and cleavage rates of frozen-thawed bovine oocytes at the germinal vesicle (GV) stage. In mouse oocytes, spindle microtubule reorganization after GV breakdown is particularly sensitive to cold and readily damaged by exposure to low temperatures, the damage becoming apparent only at the time of the first mitotic division. The effects of various permeating cryoprotective agents [1.8 M ethylene glycol (EG), 1.3 M ethylene glycol monomethyl ether (EME), and 1.6 M 1,2-propanediol (PROH)] and different concentrations of trehalose (T) and polyvinylpyrrolidone (PVP) on post-thaw developmental capacity were examined. When bovine GV oocytes were frozen slowly in mixtures of 1.8 M EG plus 5% PVP and 0.05 M T, almost 80% developed to metaphase II; 22.2% degenerated after in vitro maturation, and none of those that had been cryopreserved underwent parthenogenetic activation. The total fertilization rate was higher (P < 0.05) for oocytes frozen in a mixture of 1.8 M EG plus 0.05 M T or 0.1 M T than in a mixture of 1.8 M EG with or without 0.2 M T; however, there was no difference in the number of normally fertilized or polyspermic oocytes that had been frozen in various cryoprotective solutions. No significant difference was observed in subsequent development using EG, EME, and PROH for GV oocytes. The addition of 0.05 or 0.1 M trehalose to the freezing solution yielded significantly better cleavage and blastocyst rates than the solutions containing 0.2 M or no trehalose. For unfrozen controls, GV oocytes yielded significantly higher (P < 0.01) cleavage and blastocyst rates compared with frozen-thawed GV oocytes. It was found that 5% PVP had a beneficial effect compared with 10 or 20% concentrations for the development of blastocysts. Transfer of six blastocysts derived from frozen-thawed GV oocytes into three recipient heifers resulted in three pregnancies and the birth of one set of twins and one singleton calf.

Animals↗
PubMed1997

Cryopreservation of mature bovine oocytes following centrifugation treatment.

In vitro matured bovine oocytes were frozen slowly in 1.6 M 1,2-propanediol following centrifugation treatment for polarization of lipid droplets in the cytoplasm. After thawing, the survival of the oocytes was assessed morphologically and also by in vitro fertilization and culture. The polarization of cytoplasmic lipid droplets had a negative effect on the survival of frozen-thawed oocytes. Thus, this treatment did not improve the frequency of normal fertilization and development to blastocysts, compared with that of frozen control oocytes. However, the frequency of polyspermy and activation of lipid-polarized oocytes that survived after freezing-thawing and subsequent in vitro fertilization tended to be less than those of surviving control oocytes. In addition, the effect of centrifugation treatment was to produce a small but significant increase in the cleavage rate of oocytes that survived after freezing-thawing and the development rates to blastocysts of surviving lipid-polarized oocytes tended to increase, compared with those of surviving control oocytes. These results suggest that the freezing tolerance of the spindle and other organelles of in vitro matured bovine oocytes is associated with lipid droplets and may be improved by the polarization of cytoplasmic lipid droplets before cryopreservation.

Animals↗
PubMed1998

Cryopreservation of Rainbow Trout (Oncorhynchus mykiss) Blastomeres: Influence of Embryo Stage on Postthaw Survival Rate.

The cryopreservation of isolated fish blastomeres is likely to provide a valid alternative to embryo cryopreservation, the results of which are still discouraging. A repeatable technique for the cryopreservation of rainbow trout blastomeres has been established and the effect of embryonic developmental stage on freezing tolerance evaluated. Embryos at Ballard 6A, 6B, and 6C stages were dechorionated and left to dissociate in a Ca2+- and Mg2+-free medium. Cryoprotection was provided by step-wise addition of 1.4 M 1,2-propanediol. Cells were loaded into the middle of 250-µl straws and slowly frozen to -80 degreesC before being plunged into LN2. A low thawing rate was adopted, followed by step-wise removal of the cryoprotectant. Morphological evaluation was by microscopy and video recording. Metabolic activity and survival rate were determined by FDA and PI staining, by recovery of the ability to reassociate after 24 h culture in Leibovitz L15 + 2% Ultroser, and by measuring DNA synthesis in 6B cells by the method of BrdU incorporation. Survival rates were 53 +/- 9.3, 88 +/- 1.7, and 95 +/- 0.5% for stage 6A, 6B, and 6C cells, respectively. While 6A cells reassociated into clumps of cells, 6B and 6C cells formed holoblastic morulas in 24 h; proliferation of 6B cells was comparable to fresh control cells. The relationship between freezing tolerance and the physiological events occurring during early embryonic development is discussed in light of these results and conclusions are drawn that envisage the transfer of frozen-thawed blastomeres into recipient embryos. Copyright 1998 Academic Press.

Journal Article↗
PubMed1998

Glass-forming tendency and stability of aqueous solutions of diethylformamide and dimethylformamide

The glass-forming tendency on cooling and the stability of the wholly amorphous state on warming of aqueous solutions of diethylformamide and of dimethylformamide have been studied by calorimetry. With diethylformamide, only ice formation is observed except on warming at the lowest rate of 2.5 degreesC/min, where occasionally a hydrate forms also. The hydrate was observed up to 10 degreesC/min with 50% diethylformamide. With dimethylformamide hydrates form even at high warming rates. The last hydrate melts at -47.7 degreesC. The warming thermograms are much more complicated than for diethylformamide. For the glass-forming tendency on cooling, as well as for the stability of the wholly amorphous state on warming, these two compounds, at concentrations of 40, 45, or 50% (w/w) in water, are more efficient than glycerol and ethylene glycol, but less than 1,2-propanediol and levo-2,3-butanediol. On warming, they are comparable to DMSO. Pure diethylformamide could not be crystallized, whereas, conversely, pure dimethylformamide could not be vitrified. Curiously, the glass transition of aqueous solutions of diethylformamide increases and then decreases with the diethylformamide concentration in water, contrary to other cryoprotectants, for which it always increases or decreases. Diethyl- and dimethylformamide could be interesting cryoprotectants if they are not too toxic when added before cryopreservation, and in the case of dimethylformamide, if one can avoid damage due to its hydrates. Copyright 1998 Academic Press.

Journal Article↗
PubMed2000

Cryopreservation of mouse oocytes using a medium with low sodium content: effect of plunge temperature.

The effect of various combinations of plunge temperature and thawing protocol on the survival and viability of mouse oocytes was examined. The oocytes were frozen either in a standard freezing medium (ETFM, embryo transfer freezing medium) or in a low-sodium, choline-based freezing medium (CJ2), with 1.5 M 1,2-propanediol and 0.1 M sucrose, and using a conventional slow cooling method. The criteria used to assess survival were morphological state after thawing (intact or lysed), ability to become fertilized, and ability to develop to the two-cell, morula, and blastocyst stage in vitro. Oocytes frozen in CJ2 and plunged into liquid nitrogen (LN(2)) from -10, -20, or -33 degrees C remained intact and developed to the blastocyst stage at significantly higher rates than oocytes frozen in ETFM. For oocytes plunged into LN(2) from -33 degrees C, very rapid thawing (10 s in 30 degrees C water) was more detrimental than rapid or slow thawing (holding in air at room temperature for 10 or 30 s, respectively, prior to submersion in water at 30 degrees C for 10 s). By contrast, oocytes plunged into LN(2) from -10 or -20 degrees C survived better when thawing was very rapid or rapid than when thawing was slow. With the current protocol CJ2 was very effective over a wide range of plunge temperatures (-20 to -33 degrees C), although the optimal thawing protocol depended on the particular plunge temperature. Over 90% of oocytes surviving after slow cooling in CJ2 to -33 degrees C could be plunged to -196 degrees C with little or no further damage.

Animals↗
PubMed2001

Comparison of permeating and nonpermeating cryoprotectants for mouse sperm cryopreservation.

Mouse sperm has proven to be more difficult to cryopreserve than sperm of other mammalian species. Published reports show that only three cryoprotectant agents (CPAs), alone or combined, have been studied: glycerol and dimethyl sulfoxide (DMSO), as permeating agents, and raffinose, as a nonpermeating agent. To date, the most consistent results for mouse sperm cryopreservation have been achieved by use of raffinose/skim milk as cryoprotectant with rapid cooling at 20 degrees C per minute. In this study, we compared the cryoprotection provided by permeating (glycerol, formamide, propanediol, DMSO, adonitol) or nonpermeating (lactose, raffinose, sucrose, trehalose, d-mannitol) compounds for freezing mouse sperm. Different solutions were made using 3% skim milk solution as the buffer or extender in which all different cryoprotectant agents were dissolved at a concentration of 0.3 M, with a final osmolality of approx. 400 mOsm. Sperm samples from CB6F1 (hybrid) and C57BL/6J (inbred) mice collected directly into each CPA were frozen/thawed under identical conditions. After thawing and CPA elimination (centrifugation) raffinose (59%), trehalose (61%), and sucrose (61%) sustained the best motility (P = < 0.1) of the nonpermeating agents, whereas the best of the permeating agents was DMSO (42%). Membrane integrity was analyzed and showed that the simple exposure (prefreeze) to sugars was less harmful than the exposure to glycols. Coincidentally, sperm frozen in trehalose (41%), raffinose (40.5%), and sucrose (37.5%) were the samples less injured among all different postthawed CPA tested. The in vitro fertilization results demonstrated that hybrid mouse spermatozoa frozen with sugars (lactose 80%, raffinose 80%, trehalose 79% of two-cell embryos production) were more fertile than those frozen with glycols (glycerol 11%).

Animals↗
PubMed2001

Water crystallization within rat precision-cut liver slices in relation to their viability.

This study examined whether tissue vitrification, promoted by partitioning within the tissue, could be the mechanism explaining the high viability of rat liver slices, rapidly frozen after preincubation with 18% Me2SO or VS4 (a 7.5 M mixture of Me2SO, 1,2-propanediol, and formamide with weight ratio 21.5:15:2.4). To achieve this, we first determined the extent to which crystallization or vitrification occurred in cryoprotectant solutions (Me2SO and VS4) and within liver slices impregnated with these solutions. Second, we determined how these events were related to survival of slices after thawing. Water crystallization was evaluated by differential scanning calorimetry and viability was determined by histomorphological examination of the slices after culturing at 37 degrees C for 4 h. VS4-preincubated liver slices indeed behaved differently from bulk VS4 solution, because, when vitrified, they had a lower tendency to devitrify. Vitrified VS4-preincubated slices that were warmed sufficiently rapid to prevent devitrification had a high viability. When VS4 was diluted (to 75%) or if warming was not fast enough to prevent ice formation, slices had a low viability. With 45% Me2SO, low viability of cryopreserved slices was caused by cryoprotectant toxicity. Surprisingly, liver slices preincubated with 18% Me2SO or 50% VS4 had a high viability despite the formation of ice within the slice. In conclusion, tissue vitrification provides a mechanism that explains the high viability of VS4-preincubated slices after ultrarapid freezing and thawing (>800 degrees C/min). Slices that are preincubated with moderately concentrated cryoprotectant solutions (18% Me2SO, 50% VS4) and cooled rapidly (100 degrees C/min) survive cryopreservation despite the formation of ice crystals within the slice.

Animals↗
PubMed1997

Differential follicle counts as a screen for chemically induced ovarian toxicity in mice: results from continuous breeding bioassays.

Ovaries from National Toxicology Program Reproductive Assessment by Continuous Breeding (RACB) bioassays were used to directly compare differential ovarian follicle counts and reproductive performance for 15 chemicals. Ovaries of 10 animals per group from 16 studies in CD-1 mice and 1 study each in C3H and C57BL/6 mice were sectioned serially at 6 microm. Counts of small, growing, and antral follicles were obtained in every 10th section. For all follicle types, younger mice had more follicles than older mice, and CD-1 mice had more follicles than age-matched animals from either inbred strain. The in-life portion of the RACB protocols demonstrated that 9 of 15 chemicals altered reproductive outcome in one or both sexes of mice, with six agents affecting females (R. E. Morrissey et al., 1989, Fundam. Appl. Toxicol. 13, 747-777). Three of six female toxicants [2,2-bis(bromoethyl)-1,3-propanediol, BPD; ethylene glycol monomethyl ether, EGME; methoxyacetic acid, MAA] significantly decreased counts of small and/or growing follicles by 33 to 92% in CD-1 mice; EGME also reduced follicle counts in the other strains. Follicle counts were decreased in progeny of animals treated with EGME or its active metabolite, MAA. For BPD, reductions in follicle numbers were proportional to dose. In CD-1 mice, female toxicants di-N-hexyl phthalate, propantheline bromide, and tricresyl phosphate reduced reproductive performance but not follicle numbers. Counts were not affected by toxicants for which the susceptible sex could not be determined (bisphenol A, ethylene glycol, oxalic acid). Altered follicle counts without apparent reproductive impairment occurred in CD-1 mice at lower doses of BPD but were not observed for nontoxic chemicals. These data suggest that differential follicle counts (1) are a quantifiable endpoint of ovarian injury in conventional bioassays, and (2) in some instances, may provide a more sensitive indicator of female reproductive toxicity than fertility.

Age Factors↗
PubMed2001

Interfacial Behavior of Mixed Systems of Glycerylether-Modified Silicone and Polyoxyethylene-Modified Silicone.

Undecylglycerylether-modified silicone (GES; the glycerylether-type surfactant with a silicone segment and alkyl chains (carbon number, 11) as the hydrophobic portion) forms a molecular aggregate (M.A.) with a small amount of water. This M.A. is similar to the reversed hexagonal liquid crystal formed by alpha-mono long-chain alkylglycerylether (3-isooctadecyloxy-1,2-propanediol; GE). From the investigation of the phase behavior in the water/GES/polydimethylsiloxane (PDMS) ternary system, a wide three-phase region of water (W)+M.A.+oil (O) was observed. As this M.A. is insoluble in PDMS and easily orients in the interface between water and PDMS, the high water content silicone W/O emulsion using GES as a surfactant is well stabilized. However, as the PDMS content increased this W/O emulsion became less stable. In order to improve this stability, mixtures of GES and polyoxyethylene-modified silicone (PS) were applied to the silicone emulsion as co surfactant. By application of a PS with a methyl group at the end cap of the polyoxyethylene chain (PSM), the emulsion became most stable at a GES/PSM ratio of 1 : 2, and at the same time, the interfacial tension between the oil phase and the water phase became minimal. The reason for this was studied by the measurement of spin-lattice relaxation times (T(1)) of the alkyl chains of GES in the GES/PS/water system by (13)C NMR. We assumed that the W/O silicone emulsions were stabilized by the efficient orientation of the aggregates in the interface between the silicone phase and the water phase by using PSM as a cosurfactant. Copyright 2001 Academic Press.

Journal Article↗
PubMed2001

Accumulation of methylglyoxal in anaerobically grown Escherichia coli and its detoxification by expression of the Pseudomonas putida glyoxalase I gene.

Anaerobic glycerol fermentation by Escherichia coli strains expressing genes from the Klebsiella pneumoniae dha regulon showed that cell growth and 1,3-propanediol (1,3-PD) production are significantly inhibited when 5 g/L or higher of glycerol is initially present. One reason for this inhibition may be methylglyoxal (MG) accumulation. Assays of both intracellular and extracellular MG levels indicated an accumulation of MG in anaerobic glycerol fermentation of transgenic E. coli. Pseudomonas putida glyoxalase I was expressed in the transgenic E. coli to enhance MG detoxification. The activity of glyoxalase I in the transgenic E. coli with the P. putida glyoxalase I under anaerobic conditions was 12-fold higher than that in the control cells. Compared to the control cells, the transgenic cells with the P. putida glyoxalase I displayed a reduction of 35-43% in intracellular MG and a decrease of 30% in extracellular MG. These decreases were statistically significant (P>94). Furthermore, the expression of the P. putida glyoxalase I in the transgenic E. coli markedly improved cell growth and resulted in a 50% increase in 1,3-PD production.

Anaerobiosis↗
PubMed1999

Studies of pH regulation by Btn1p, the yeast homolog of human Cln3p.

Although the gene responsible for Batten disease, CLN3, was positionally cloned in 1995, the function of Cln3p and the molecular basis of the disease still remain elusive. We previously reported that the yeast Saccharomyces cerevisiae contains a homolog to Cln3p, designated Btn1p, and that the human Cln3p complemented the pH-dependent resistance to D-(-)-threo-2-amino-1-[p-nitrophenyl]-1, 3-propanediol in btn1-Delta yeast mutants. We have determined that yeast lacking Btn1p have an elevated ability to acidify media during growth that correlates with an elevated plasma membrane ATPase activity. Btn1p may be involved in maintaining pH homeostasis of yeast cells.

Cell Membrane↗
PubMed1999

Investigation of Batten disease with the yeast Saccharomyces cerevisiae.

The CLN3 gene, which encodes the protein whose absence is responsible for Batten disease, the most common inherited neurovisceral storage disease of childhood, was identified in 1995. The function of the protein, Cln3p, still remains elusive. We previously cloned the Saccharomyces cerevisiae homolog to the human CLN3 gene, designated BTN1, whose product is 39% identical and 59% similar to Cln3p. We report that yeast strains lacking Btn1p, btn1-Delta deletion yeast strains, are more resistant to d-(-)-threo-2-amino-1-[p-nitrophenyl]-1,3-propanediol (ANP), in a pH-dependent manner. This phenotype is complemented in yeast by the human CLN3 gene. In addition, point mutations characterized in CLN3 from individuals with less severe forms of Batten disease, when introduced into BTN1, altered the degree of ANP resistance. Severity of Batten disease due to mutations in CLN3 and the degree of ANP resistance in yeast are related when the equivalent amino acid replacements in Cln3p and Btn1p are compared. These results indicate that yeast can be used as a model for the study of Batten disease.

Cell Division↗
PubMed1991

Crisnatol mesylate: phase I dose escalation by extending infusion duration.

Crisnatol mesylate is a rationally designed cytotoxic arylmethylamino-propanediol with broad spectrum cytotoxic activity. A phase I study with an unconventional escalation scheme was developed using a constant drug infusion rate (mg/m2/hr) and prolonging the infusion duration from 6 to 96 hours. Sixty-five patients received crisnatol at doses from 18 mg/m2 in 6 hrs to 3400 mg/m2 in 72 hours. The dose-limiting toxicity in two of five patients at 2700 mg/m2 and two of three patients at 3400 mg/m2 was neurologic and consisted of a syndrome of confusion, agitation, and disorientation. Phlebitis mandated the use of a central line. The mean terminal phase half-life (T1/2 beta) was 3.3 hours with a total body clearance (CL) of 22.8 L/hr/m2 and a volume of distribution (Vdss) of 53 L/m2. The median steady-state peak plasma concentration (Css) at 2700 mg/m2/72 hours was 2.7 micrograms/ml and at 3400 mg/m2/72 hours was 3.8 micrograms/ml. No responses were seen. The maximum tolerated dose (MTD) on this schedule is 2700 mg/m2/72 hours in patients with no liver disease and good performance status.

Adolescent↗