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Biomedical subjects

N Kubota

Publications and source records attributed to N Kubota.

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

Pollinosis etiologic relationship between excessive IL-4 production and down-regulation of the inflammation-suppressive system.

Previous findings suggest a bi-directional relationship between the immune and endocrine systems, which may expand to a major inflammation-regulatory mechanism, although its mechanism is largely unknown, especially in the human body. Lymphokine and neuroendocrine peptide hormones have been identified as two major groups of immunologic mediators. The particularly pivotal molecules among them are interleukin (IL-1), considered to be a mediator of inflammation, and ACTH, whose activation is induced by IL-1. Among the important functions of lymphokines related to atopic inflammation is the regulation of IgE secretion from B cell through the action of IL-4, produced from the Th2 subset stimulated by IL-1, as a switch factor. IL-4 is the major IgE secretagogue. IL-4 is, moreover, a potent suppressive stimulant of IL-1 secretion. In this study, we tested the hypothesis whether a immunologic interaction exists in patients with allergic rhinitis to Japanese cedar pollen. We performed immunohistochemical staining of IL-1 beta, interleukin 1 receptor (IL-1r) and interleukin-4 (IL-4) in the nasal tissue, and evaluated serum levels of the biochemical mediators involved in the inflammation-regulatory mechanism: IL-1 beta, IL-4, interleukin 1 receptor antagonist (IL-1ra), IgE, cortisol, and ACTH before, during, and after allergen-provoked rhinitis in pollinosis sufferers. Our morphological study showed that, even before the pollen season, large amounts of IL-4 and IL-1r, exclusive of IL-1 beta, were produced in the nasal tissue of patients with seasonal pollinosis. IL-1-positive cells were observed in small amounts in the same tissue, but the quantity was probably enough to cause secretion of intrinsic IL-4 to produce sufficient IgE for atopic inflammation. Upon immunoenzymatic measurement of serum IL-4, even before the pollen season, almost all atopic patients also showed a higher IL-4 level than controls. Serum IgE data also showed a high level before the pollen season in atopic patients. This evidence suggests that atopic patients have already set the first step of inflammatory event not only in the nasal epithelium but also generally even before inhaling proper quantity and quality of the allergen. On the other hand, although atopic patients had inflammation, they did not show an extremely high value of serum IL-1, regarded as inflammatory lymphokine, compared with non-atopic individuals. In contrast, a higher serum level of IL-1ra was observed before and during the pollen season in atopic patients, subsiding to normal level after the season. Serum levels of both cortisol and ACTH did not show a high value in atopic patients during the season. These results demonstrate that excessive IL-4 production of atopic patient causes down-regulated transformation of IL-1 and up-regulated secretion of IL-1ra generally, followed by failure to increase secretion of ACTH from hypophysis and cortisol generally, resulting in defective performance of a specifically useful function of the anti-inflammatory mechanism.

Adrenocorticotropic Hormone↗
PubMed1996

Results of surgery for paralytic esotropia due to abducens palsy.

The surgical effects of three methods, transposition of the vertical rectus muscles, Jensen's procedure, and resection (advancement) of the lateral rectus muscle, were compared among 109 cases of paralytic esotropia due to abducens palsy. These procedures were combined with recession of the medial rectus muscle in about half the cases. Of the 109 cases, 22 were followed up for 4 years or longer. Results were similar, provided that the following protocols for surgery were adhered to: in cases of complete paralysis, transposition of the vertical rectus muscles was done, and in cases of incomplete paralysis, resection (advancement) of the lateral rectus muscle was performed. With both procedures, results were improved if recession of the medial rectus muscle was carried out at the same time.

Abducens Nerve↗
PubMed1996

Long-term results of surgery for superior oblique palsy.

The results one month after surgery in 159 cases of superior oblique palsy were compared according to the method of surgery with the results 4 years or longer after surgery. There were 141 cases of congenital palsy and 18 cases of acquired palsy, for a total of 159 cases. Our study showed that surgery on the oblique muscle provided long-lasting effects, while recession of the superior rectus muscle or recession of the contralateral inferior rectus muscle could cause late overcorrection. When performing surgery on the rectus muscle, careful attention must be paid to suturing the muscle.

Humans↗
PubMed1995

Molecular cloning and expression of serum calcium-decreasing factor (caldecrin).

We previously reported on the purification of a serum calcium-decreasing factor, referred to as caldecrin, from porcine pancreas, that is thought to be a serine protease (Tomomura, A., Fukushige, T., Noda, T., Noikura, T., and Saheki, T. (1992) FEBS Lett. 301, 277-281). In the present study, we purified caldecrin from rat pancreas and determined its primary structure by cDNA cloning. The predicted caldecrin protein is presumed to be synthesized as a preproenzyme of 268 amino acids with a signal peptide of 16 amino acids and an activation peptide of 13 amino acids, and is, with the exception of a central region, almost identical to the reported rat pancreatic elastase IV sequence. The caldecrin gene is selectively expressed in the pancreas, as judged by Northern blot analysis. After expression in BMT-10 cells, immunoreactive caldecrin was found in the culture supernatant, and it inhibited the parathyroid hormone-stimulated 45Ca release from cultured fetal long bones. Catalytic site mutants were synthesized in a baculovirus system, and recombinant mutants also decreased the serum calcium level of mice. These data implicate caldecrin, a protease closely related to elastase IV, in the regulation of blood calcium levels.

Amino Acid Sequence↗
PubMed1995

Protective effect of coenzyme Q10 on cultured skeletal muscle cell injury induced by continuous electric field stimulation.

The protective effect of coenzyme Q10 (CoQ10) on continuous electric field stimulation-induced muscular injury was investigated in cultured cells established from neonatal rat femoral muscles. After cultivation for 9 days, skeletal muscle cells contracted and relaxed rhythmically for 4 hr in response to continuous electric field stimulation (power, 5 V; duration, 5 msec; amplitude, 3 Hz). After the onset of the stimulation, lactate and lactate dehydrogenase (LDH) release and intracellular Ca2+ contents ([Ca2+]i) at relaxation increased gradually. In contrast, the intracellular ATP contents decreased. The addition of 5 microM CoQ10, but not alpha-tocopherol and radical scavengers, to the culture medium protected the cells against these biochemical changes after the stimulation. Verapamil, an inhibitor of Ca2+ channels, also attenuated the increase in [Ca2+]i at relaxation and LDH. These results suggested that one of the causal mechanisms of muscular injury is an increase in [Ca2+]i due to the excess entry of extracellular Ca2+, and that CoQ10 can protect skeletal muscle cells against such undesirable biochemical changes.

Adenosine Triphosphate↗
PubMed1995

A comparison of biological effects of modulated carbon-ions and fast neutrons in human osteosarcoma cells.

PURPOSE: To compare the biological effects of a 135 MeV/u carbon-ion beam and 13 MeV fast neutron beam using human osteosarcoma cells. METHODS AND MATERIALS: We have studied the clonogenic cell survival, recovery of potentially lethal damage (PLD) in plateau phase cells, and spheroid cure in multicellular spheroid after irradiation at various positions in the plateau and spread out Bragg peak (SOBP) of a 135 MeV/u carbon-ion beam and with 13 MeV neutrons. The carbon beam had a 4-cm range in water and a range filter was used to produce a 3-cm extended-peak region. The reference radiation was 137Cs gamma-rays. RESULTS: The relative biological effectiveness (RBE) values for 10% survival level of plateau phase cells for carbon-ions at the position of plateau, proximal peak, midpeak, and distal peak within the SOBP, and neutrons were 1.71, 2.48, 2.63, 3.47, and 2.29, respectively. Corresponding RBE values at 1% level were 1.64, 1.93, 2.06, 2.49, and 2.05. The extent of recovery from PLD was reduced after carbon-ions at proximal peak, midpeak, and distal peak, and neutrons, although not substantially reduced after carbon-ions at plateau. The RBE values for 50% spheroid cure level of spheroids for carbon-ions at the position of plateau, proximal peak, midproximal peak, middistal peak, and distal peak within the SOBP, and neutrons were 1.69, 1.88, 1.87, 1.94, 2.03, and 1.90, respectively. CONCLUSIONS: The biological parameters measured all indicate an approximately comparable biological effectiveness between 75-80 KeV/microns carbon-ions of the SOBP and 13 MeV neutrons in the human tumor model studied in vitro.

Carbon↗
PubMed1995

Antitumor activities of a new indolocarbazole substance, NB-506, and establishment of NB-506-resistant cell lines, SBC-3/NB.

The novel anticancer glucosyl derivative of indolo-carbazole (NB-506), an inhibitor of DNA topoisomerase I, exhibited strong in vitro cytotoxicity against various human cancer cell lines. In order to elucidate its cytotoxic mechanisms, we established nine NB-506-resistant sublines with different resistance ratios from human small cell lung cancer cells (SBC-3/P) by stepwise and brief exposure (24 h) to NB-506. Among them, SBC-3/NB#9 was 454 times more resistant to NB-506 than the parent cell line. The SBC-3/NB#9 cells showed cross-resistance only to topoisomerase I inhibitors, such as 11,7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecia and 7-ethyl-10-hydroxy-camptothecin, and not to other anticancer drugs, such as vincristine, vinblastine, Adriamycin, etoposide, and teniposide. These results indicate that the difference on the effect of topoisomerase I was considered to be related to a resistance mechanism. The topoisomerase I activities of nuclear extracts eluted from SBC-3/NB#9 cells was only one-tenth of the parent cell activity. A Western blotting study indicated that this lower activity was due to a lower amount of DNA topoisomerase I. Furthermore, we found correlations between topoisomerase I activity and sensitivity to NB-506 in sublines with different degrees of resistance. Accumulation of 3H-labeled NB-506 by SBC-3/NB#9 cells was only one-fifth of that by the parent cells, whereas intracellular accumulation of 3H-labeled camptothecin by both cell lines did not differ. The reduction of accumulation was specific to NB-506, and this result may explain why the resistance ratio for NB-506 was higher than those for 11,7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin and 7-ethyl-10-hydroxy-camptothecin.

Antineoplastic Agents↗
PubMed1995

The scid factor on human chromosome 8 restores V(D)J recombination in addition to double-strand break repair.

The murine severe combined immune deficiency mutation (scid) is characterized by a lack of B- and T-lymphoid cells due to a defect in lymphoid V(D)J recombination. Moreover, defective rejoining of DNA double-strand breaks (dsb) in scid cells also results in a marked increase in sensitivity to ionizing radiation. Recently, the putative human homologue of the murine scid gene locus, HYRC1, was assigned to human chromosome 8q11, based on the radiation sensitivity of scid cells as compared to scid:human cell hybrids carrying portions of human chromosome 8. Given the precedent (e.g., ataxia-telangiectasia) for genes other than the affected one being able to complement radiation defects, we were interested in determining if the V(D)J recombination defect was also corrected by the HYRC1 locus. The V(D)J recombination analysis using extrachromosomal DNA substrates in control scid cells (SC3VA2) versus complemented cells (RD13B2) indicates that the radiation sensitivity-complemented cells (RD13B2) are also fully complemented for the V(D)J recombination reaction, whereas the control (uncomplemented) cells (SC3VA2) fail to carry out V(D)J recombination normally. Slightly over 60% of the radiation-induced dsb are rejoined even in scid cells, and this alternative pathway is temperature sensitive. Only the remaining 30-35% of dsb require the introduction of the HYRC1 locus, and this pathway is not temperature sensitive. This merely partial contribution of the scid factor to the repair process suggests the presence of another pathway of dsb repair. Our results indicate that the HYRC1 locus, assigned to human chromosome 8q11, encodes the scid factor, which is involved in all V(D)J recombination coding joint formation and in 30-35% of dsb repair by the temperature-resistant pathway.

Animals↗
PubMed1995

Immunohistochemical evidence that tumors elicit the synthesis of estrogen receptors in the submandibular gland of female rats.

We have demonstrated the presence of estrogen receptor mRNA and the mature protein in the cytoplasm and nucleus, respectively, of a 9,10-dimethyl-1,2-benzathracene-induced submandibular gland tumor in female rats. We have previously shown that progesterone receptors are also present in human salivary gland tumors. These results suggest that endocrine therapy may be effective in treatment of submandibular gland tumors.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1995

Melittin cardiotoxicity in cultured mouse cardiac myocytes and its correlation with calcium overload.

Venom from the honey bee Apis mellifera induces cardiovascular dysfunction. We studied which constituent(s) of the venom induces cardiotoxicity and how, using cultured cardiac myocytes from mouse fetuses. Among the venom constituents, only melittin caused contractile and morphological effects; other peptides, such as apamin and mastparan; enzymes, such as phospholipase A2; and low-molecular-weight compounds, such as histamine and dopamine, did not. Treatment with 4.5 micrograms/ml melittin, which accounts for about half the dry weight of the venom, induced the same cardiotoxic effects as treatment with 9.0 micrograms/ml whole venom; these effects were a transient increase in the spontaneous beating rate, then a decrease, then cessation of beating, and finally, morphological degeneration. The cardiotoxicity of whole bee venom was completely destroyed by pretreatment of the venom with antimelittin antibody. These results suggest that bee venom cardiotoxicity is attributable to melittin. When spontaneous beating ceased following the addition of melittin or whole venom, an increase in systolic [Ca2+]i, was observed. On further incubation with melittin or bee venom, morphological injury, such as balloon degeneration, occurred concomitant with a further increase in the [Ca2+]i. An extracellular Ca2+ concentration of more than 10(-6) M was necessary for morphological injury. Melittin depolarized the maximum diastolic potentials, inhibited the generation of action potentials, and induced an increase in [Na+]i. Cells were protected against the melittin-induced increase in [Ca2+]i by pretreatment with bepridil, an inhibitor of Na(+)-Ca2+ exchange, but not by Ca2+ channel blockers such as verapamil. These observations suggest that the melittin-induced increase in [Ca2+]i was due to entry of extracellular Ca2+ via the sarcolemmal Na(+)-Ca+ exchange system.

Animals↗
PubMed1995

Characterization of a novel parathyroid hormone (PTH) receptor with specificity for the carboxyl-terminal region of PTH-(1-84)

Carboxyl-terminal fragments of PTH (C-PTH) appear to have biological properties different from those mediated by the amino-terminal portions of PTH and PTH-related peptide (PTHrP). To characterize a C-PTH receptor that may be involved in mediating these functions, we performed RRAs and affinity cross-linking studies with several clonal cell lines. Radiolabeled recombinant [Leu8,18,Tyr34]human PTH-(1-84)[mutPTH-(1-84) and [Tyr34] human PTH-(19-84)[mutPTH-(19-84) showed little or no specific binding to stably expressed recombinant PTH/PTHrP receptors. However, high affinity binding was observed using osteoblast-like and rat parathyroid (PT-r3) cells. The apparent Kd values were 20-30 nM for PTH-(1-84), mutPTH-(1-84), and mutPTH-(19-84), respectively; 400-800 nM for PTH-(39-84); and more than 5000 nM for PTH-(53-84). [Nle8,18,Tyr34]bovine PTH-(1-34)amide [PTH-(1-34)], PTH-(44-68), PTHrP-(37-74), and PTHrP-(109-141) showed no displacement of either radioligand. C-PTH receptor number was increased up to 2-fold by pretreating ROS 17/2.8 cells with increasing doses of PTH-(1-34), PTH-(1-84), or 8-bromo-cAMP, whereas no change was observed in response to dexamethasone or PTH-(39-84). Cross-linking studies using radiolabeled mutPTH-(1-84) or mutPTH-(19-84) revealed specific labeling of two proteins in ROS 17/2.8 cells that were approximately 40 and 90 kilodaltons in size (including the radioligand of approximately 10 kilodaltons). The intensity of affinity labeling of both proteins was dose dependently inhibited by increasing concentrations of unlabeled PTH-(1-84) and several carboxyl-terminal PTH-(1-84) fragments, but not by PTH-(1-34). Similar studies with PT-r3 cells revealed only a single protein band of about 90 kilodaltons. These data indicate that the carboxyl-terminal portion of PTH-(1-84) binds specifically to a unique receptor/binding protein distinct from the previously isolated PTH/PTHrP receptor.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1995

Manipulation of the lighting schedule can modify the pharmacological effects of theophylline in chick embryos.

The effect of the lighting schedule on the pharmacological action of theophylline was studied in chick embryos. Fertile eggs of White Leghorns were incubated and investigated, on two occasions, under constant light conditions or under constant dark conditions. A single injection of theophylline 2.14, 4.29, 8.57 and 17.14 mg/egg into the air sac of fertile eggs was carried out on the 16th day of incubation. Electrocardiograms (ECGs) were recorded 0 to 60 min after drug injection. After drug injection, heart rate increased under constant light conditions, but decreased under dark conditions. In addition, arrhythmia was produced by theophylline, 17.14 mg/egg, under constant dark conditions. These results indicate that the manipulation of the lighting schedule may have a marked influence on the pharmacological effects of theophylline in chick embryos.

Animals↗
PubMed1995

Signalling drug-induced rash with 36 drugs recently marketed in the United Kingdom and studied by Prescription-Event Monitoring.

This study examines skin rash, as a reported event, in the patients who used one of the 36 drugs recently released to the UK market and studied by Prescription-Event Monitoring between 1985 and 1992. The results are also compared to the voluntary reports on rash as a possible adverse drug reaction sent to the Committee on Safety of Medicines (CSM). Specific types of skin rash (e.g. exfoliative dermatitis) are excluded. The rate of rash has been calculated for 2 periods, the first month (T1) and the subsequent 5 months (T2) after the first prescription for the drug. Despite the heterogeneity of the patient groups, the rate for rash between the 2nd and 6th months was consistent in the 36 drugs and probably represented the baseline rate of rash due to a variety of nonspecific causes. This rate (T2) was around 1 per 1,000 patients per month (ranging from 0.5 to 2 per 1,000 patients per month). On the other hand, in the first month after the first prescription for the drug, the rate (T1) varied substantially from 0.9 to 6.4 per 1,000 patients per month. Diltiazem had the highest first monthly rate. These rates are listed for the 36 drugs. The difference of the rates was tested by 2 methods: a standard statistical test assuming a Poisson model and a method based on the ratio of the rates for the 2 periods. When the 2 rates (T1 and T2) were similar to each other, drug induced rash was considered to be rare.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

[Pattern-reversal visual evoked potentials dissociated vertical deviation].

We recorded pattern-reversal visual evoked potentials (P-VEP) from dissociated vertical deviation (DVD) patients to evaluate the sensory system abnormalities in DVD. 91 DVD patients with good visual acuity were studied. Normal subjects and horizontal strabismic patients without DVD were compared for evaluation. Transient and steady state P-VEPs were recorded from three EEG electrodes placed on the posterior scalp. Half-field checker-board reversal stimulation was applied to stimulate monocular temporal retina and responses from right and left hemispheres were also compared for evaluation. Paradoxical lateralization was observed in all normal subjects. Abnormal P-VEPs were observed in 4 of 20 (20%) horizontal strabismic patients without DVD when employing the transient stimulation method and in 2 of 8 (25%) when using steady state stimulation. Abnormal P-VEPs were observed in 31 of 67 (46.3%) DVD patients, with the transient stimulation method and in 20 of 25 (80.0%) DVD patients with the steady state stimulation method. The abnormalities were various and diverse. Our observations indicate that DVD patients frequently have an abnormal sensory system detected by P-VEP, and DVD might be a complex and multi-origin condition involving both sensory and motor systems.

Adolescent↗
PubMed1994

Establishment of a human small-cell lung-cancer subline resistant to okadaic acid.

Okadaic acid (OA), a specific protein phosphatase inhibitor, has various biological functions. To elucidate the mechanism of OA resistance, we have established a small-cell lung-cancer subline (H69/OA100) resistant to the growth-inhibitory effect of OA; this was done by using the parental cell line (H69) and increasing the concentration of OA. H69/OA100 was about 8 times more resistant to OA than H69. Intracellular retention of the fluorescent OA derivative in H69/OA100 was the same as that in H69. The catalytic activity of protein phosphatase from H69/OA100 was significantly reduced compared with that from H69. The protein phosphatase from H69/OA100 was 3.6 times more resistant to OA than that from H69. We examined the effect of OA on the activity of the immunoprecipitated protein phosphatase type I (PPI) and type 2A (PP2A) from the 2 cell lines. The PPI and PP2A from H69/OA100 showed more resistance to OA than those from H69. We next examined the effect of OA on the cell cycle of H69 and H69/OA100. In H69, G2/M block was observed at an OA concentration of 30 ng/ml whereas in H69/OA100, no G2/M block was observed at concentrations up to 100 ng/ml OA. We finally evaluated the amount of p34cdc2 kinase expression and the phosphorylation status of p34cdc2. There was no difference in p34cdc2 expression between H69 and H69/OA100 at several concentrations of OA. However, dephosphorylation of p34cdc2 was observed at 30 ng/ml OA in H69, but not in H69/OA100 up to 100 ng/ml OA. These data suggest that the resistance to OA and the resistance of the cell-cycle block to OA in H69/OA100 might be due to alteration of protein phosphatase activity.

Base Sequence↗
PubMed1994

Ouabain-resistant non-small-cell lung-cancer cell line shows collateral sensitivity to cis-diamminedichloroplatinum(II) (CDDP).

We have reported that the cellular uptake of cis-diamminedichloroplatinum(II) (CDDP) was inhibited by an Na+,K(+)-adenosine triphosphatase (ATPase) inhibitor, ouabain, in a human non-small-cell lung-cancer cell line, PC-14, but not in its CDDP-resistant cell line, PC-14/CDDP. [3H]Ouabain binding of PC-14/CDDP was about 50% lower than that of PC-14. Accordingly, we speculated that a decrease in Na+,K(+)-ATPase activity in PC-14/CDDP might contribute to the decrease in cellular CDDP accumulation. To clarify the relationship between the activity or expression of Na+,K(+)-ATPase and cellular CDDP accumulation, we established an ouabain-resistant non-small-cell lung-cancer cell line (PC-14/OB300), which showed 1.9-fold resistance to the cytotoxicity of ouabain. Interestingly, this cell line was 4.2-fold more sensitive to CDDP than PC-14. The accumulation of CDDP in PC-14/OB300 was increased to 2.7-fold that in PC-14. This elevation of CDDP accumulation was not considered to be caused by increased passive diffusion, because the accumulation of CDDP in PC-14/OB300 was also inhibited by ouabain compared to PC-14. As one of the indices of Na+,K(+)-ATPase activity, we determined cellular 86Rb+ influx rates. The 86Rb+ influx rate was 1.5-fold higher in PC-14/OB300 and fell to 0.7-fold in PC-14/CDDP compared with PC-14. The mRNA expression of Na+,K(+)-ATPase was increased in PC-14/OB300 and decreased in PC-14/CDDP. There was no difference in cellular [3H]ouabain binding between PC-14/OB300 and PC-14. It is possible that Na+,K(+)-ATPase of PC-14/OB300 has a different affinity for ouabain from that of PC-14. Our results suggest that the enzyme activity or the level of expression of Na+,K(+)-ATPase may contribute to the cellular uptake of CDDP and determine the sensitivity to CDDP.

Adenocarcinoma↗
PubMed1994

7-Ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy camptothecin: mechanism of resistance and clinical trials.

The camptothecin derivative 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy camptothecin (CPT-11) has attracted the attention of clinicians because of its high antitumor activity against refractory solid cancers. We established two CPT-11-resistant cell lines, a non-small-cell lung-cancer cell line (PC-7/CPT-11) from the parental PC-7 line and an ovarian cancer cell line (HAC-2/CPT-11) from the parental HAC-2 line. The mechanisms of resistance to CPT-11 in PC-7/CPT-11 cells were reduced conversion of CPT-11 to its active metabolite SN-38 and point mutation topoisomerase I. Those in HAC-2/CPT-11 cells were reduction of topoisomerase I activity and decreased sensitivity of topoisomerase to topoisomerase I inhibitors. No point mutation of the topoisomerase was observed in HAC-2/CPT-11 cells. We conducted two phase I trials using CPT-11 in combination with other anticancer agents. One was a phase I trial of CPT-11 and cisplatin given with a fixed dose of vindesine to patients with advanced non-small-cell lung-cancer and the other was a phase I study on a topoisomerase-targeting combination of CPT-11 and etoposide (VP-16) in patients with various malignant solid tumors. The results of the first trial indicated that the recommended dose of CPT-11 for phase II studies was 80 mg/m2 combined with 3 mg/m2 vindesine on days 1 and 8 and 60 mg/m2 cisplatin on day 1. In the second trial, the recommended dose of CPT-11/VP-16 given with recombinant granulocyte colony-stimulating factor (on days 4-17) was found to be 60/60 mg/m2. In both trials, diarrhea and granulocytopenia were considered to be dose-limiting toxicities.

Amino Acid Sequence↗