Rapid tumor cell proliferation after induction chemotherapy in oropharyngeal cancer

Tumor cell kinetics were studied in vivo in a series of 97 patients with oropharyngeal cancer. The duration of S phase (tS), the labeling index (LI), and the potential doubling time (Tpot) were obtained by flow cytometry measurements of a tumor biopsy obtained after intravenous injection of 200 mg 5-bromodeoxyuridine to the patient. The mean LI was 9.7% (standard deviation [SD], 5.4), the mean tS was 10.1 hours (SD, 3.6), and the mean Tpot was 4.6 days (SD, 3.5). No significant relationship was found between the Tpot or LI and the size of the tumor, nodal status, histological grade, or the site of the primary within the oropharynx. Conversely, aneuploid tumors had longer tS (P<.001), higher LI (P<.001), and shorter Tpot (P<.05) than the diploid tumors. The mean LI and Tpot of the tumors obtained after induction chemotherapy were significantly higher and shorter, respectively, than those measured before any treatment. The data strongly suggest that rapid tumor cell proliferation frequently occurs in oropharyngeal cancer which had responded poorly to chemotherapy.     

Gastric lipase: evidence of an adaptive response to dietary fat in the rabbit

In the rabbit, the stomach is the only source of preduodenal lipase, and in humans, it is quantitatively the most important. Thus, the adaptive response of gastric and pancreatic lipases to dietary fat was studied in the adult rabbit. Effect of duration was studied by feeding rabbits 12% dietary fat for 1, 2, or 4 weeks or 2.7% for 2 weeks (control). To study the effects of the amount of fat, rabbits were fed the control diet (2.7% fat) or 6% and 12% dietary fat for 2 weeks. The influence of sunflower oil and butter was compared by feeding rabbits 12% dietary fat for 2 weeks. Approximately doubling (6% vs. 2.7%) the usual amount of dietary fat was sufficient to induce a maximum increase in gastric lipase activity in the fundus [+ 66.3% (units per gram tissue) or + 85.2% (units per milligram protein)] and the total stomach mucosa [+ 84.5% (units per mucosa)], whereas pancreatic lipase activity only significantly increased when rabbits were fed 12% dietary fat. A full adaptive response was observed for both gastric and pancreatic lipases after 2 weeks of diet. Triglyceride composition did not noticeably change the adaptive response of both lipolytic enzymes. The present results agree closely with those concerning lingual lipase in the rat and evidence that gastric lipase shows an adaptive response to moderate fat intake. The implications of these findings concerning humans are discussed.     

Pharmacological and preclinical toxicological studies of 1,2-diaminocyclohexane(isocitrato)platinum(II)

The antitumor activity of a new highly water-soluble platinum derivative, (1,2-diaminocyclohexane)(isocitrato)platinum(II) (NSC 350602; PHIC), was studied in L1210 leukemia cells inoculated into mice. PHIC was found to be active for i.p. graft-i.p. treatment, i.p. graft-i.v. treatment, and i.v. graft-p.o. treatment. A significant activity was observed on early and advanced L1210 leukemia even when the treatment was delayed 6 days after the graft. A comparison between the activities of PHIC, cisplatin (NSC 119875), and (4-carboxyphthalato)(1,2-diaminocyclohexane)-platinum(II) (NSC 271674; DACCP) for i.p. graft-i.p. treatment indicated that the highest activity was observed for divided doses rather than single dose in the case of PHIC and DACCP and not for cisplatin. Under these conditions, PHIC gave larger treated versus control survival time values or a greater number of surviving animals than did cisplatin and DACCP. No cross-resistance between PHIC and cisplatin could be detected in L1210 leukemia cells resistant to cisplatin. Mutagenicity studies on Salmonella typhimurium revealed that PHIC is far less mutagenic than cisplatin on TA100 and TA98 strains. Other pharmacological parameters, such as growth inhibition rate of cultured L1210 cells, penetration, and DNA binding in L1210 cells inoculated in mice, were compared for PHIC and cisplatin together with their in vitro rates of hydrolysis and platinum:DNA adducts. No nephrotoxicity was detected with PHIC at the maximum nonlethal dose level in mice in contrast to results with cisplatin. A preclinical study was conducted in baboons at 100, 150, and 200 mg/kg. No nephrotoxicity could be detected at a dose of 100 mg/kg without prehydration for six courses at 3-week intervals. At 200 mg/kg, an increase of blood creatinine was controlled by prehydration. Gastrointestinal toxicity was mild during the three regimens. Phase I clinical trials are under way.     

Cerebrospinal fluid amino acids in extrapyramidal disorders before and after L-DOPA treatment

Summary a) In 9 Parkinsonian patients and in 2 patients with other extrapyramidal syndromes cerebrospinal fluid amino acids have been determined by ion exchange chromatography.b) For 15 amino acids a statistically significant increase was found. It was most evident for citrulline, lysine, histidine and arginine.c) In 5 of the patients the lumbar puncture was repeated. Abnormalities persisted during oral L-DOPA treatment. No free L-DOPA could be detected in these cerebrospinal fluids.

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Zusammenfassung a) Die freien Aminosäuren des Liquor cerebrospinalis wurden säulenchromatographisch bei 9 Parkinson-Patienten und 2 Patienten mit extrapyramidalen Syndromen bestimmt.b) Die Ergebnisse zeigen statistisch signifikante Vermehrung von 15 Aminosäuren und insbesondere für Citrullin, Lysin, Histidin und Arginin.c) Nach oraler L-DOPA-Gabe (5 Patienten) persistieren die festgestellten Abweichungen. Freies L-DOPA konnte im Liquor nicht gefunden werden.