No abstract

There is evidence that a putative glioma tumor suppressor locus resides on the long arm of chromosome 19. We present data on 161 gliomas from 156 patients, which were studied by microsatellite analysis for loss of heterozygosity (LOH) on chromosome 19. Eight loci on the long arm and 2 loci on the short arm of chromosome 19 were examined. LOH on 19q was observed in 3/19 astrocytomas (WHO grade II), 12/27 anaplastic astrocytomas (WHO grade III), 16/76 cases of glioblastoma multiforme WHO (grade IV), 4/9 oligodendrogliomas (WHO grade II), 3/5 anaplastic oligodendrogliomas (WHO grade III), 5/9 mixed oligo-astrocytomas (WHO grade II) and 8/10 anaplastic oligo-astrocytomas (WHO grade III). While 31 of the tumors with LOH on chromosomal arm 19q exhibited allelic loss at every informative locus, 20 tumors showed terminal or interstitial deletions. In contrast to astrocytomas and glioblastomas, tumors with an oligodendroglial component had predominantly lost the entire long arm of chromosome 19. The common region of overlap in gliomas was located on 19q13.2-q13.4 between the markers D19S178 and D19S180. Our data confirm the involvement of a putative tumor suppressor gene on chromosomal arm 19q in gliomas and assign this gene to 19q13.2-q13.4.

The pharmacokinetics of intraperitoneally (i.p.) injected mitoxantrone was determined in plasma and peritoneal dialysate taken from five patients presenting with cancer confined to the peritoneal cavity over a sampling period of 1 week. The drug was given through a Tenckhoff catheter as a 15-min infusion and the peritoneal dialysate was removed after a dwell time of 4 h; the doses delivered varied between 20 and 50 mg/m2. Dose-limiting local toxicity was moderate. The HPLC technique used for mitoxantrone determinations proved to be sensitive within the range of 0.3-4,000 ng/ml. Median values obtained for the pharmacokinetic parameters of mitoxantrone in peritoneal dialysate were: t1/2 beta (distribution), 56.4 min (range, 16.8-235.8 min); t1/2 gamma (elimination), 128 h (range, 28.3-171.0 h); Vdss (volume of distribution at steady state), 24.8 l (range, 17.0-232.5 l); delta'ss (volume of distribution at steady state corrected for the body surface area in square meters), 14.4 l/m2 (range, 10.6-129.2 l/m2); and clearance, 0.25 l/h (range, 0.16-0.59 l/h). For plasma the median values were: t1/2 alpha (absorption), 58.8 min (range, 45.6-87.0 min); t1/2 beta (distribution), 2.5 h (range, 1.4-6.3 h); t1/2 gamma (elimination), 44.1 h (range, 9.1-91 h); Vdss, 2,152 l (range, 352-19,733 l); delta'ss, 1,345 l/m2 (range, 220-11,606 l/m2); and clearance, 117 l/h (range, 51-1,609 l/h). After 168 h the median plasma concentration was 1 ng/ml. The median peak concentration in peritoneal dialysate was 490 ng/ml. Considering the moderate toxicity observed and the concentrations achieved in the peritoneal dialysate, removal of the dialysate after certain dwell times seems reasonable to be a reasonable approach for the optimization of i.p. treatment with mitoxantrone.

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

A new tumor model for testing and comparing the effect of different forms of treatment on liver tumors is described. Single tumors were induced in the liver of rats by the implantation of small pieces taken from a subcutaneously growing tumor. Tumor growth was determined by measuring the weight of the implanted tumors after the animals had been killed. In this way, weight curves for treated and untreated tumors could be defined. The weight of untreated liver tumors increased exponentially with time (tumor weight in milligrams = 1 + e(t-0.31)/5). In addition, tumor growth defined as the geometric mean of three perpendicular diameters was determined. Tumor-diameter curves showed a linear increase with time in the untreated groups (tumor diameter in millimeters = 0.4 t + 1.90). The model was tested by assessing the effect of intraperitoneally injected cisplatin. The dose chosen produced a marked delay in tumor growth. On the basis of the weight gain shown by the treated animals and tumor growth delay, a therapeutic index can be defined, thus enabling to compare quantitatively different forms of treatment according to their antitumor effect and toxicity.