Resistance mechanisms in three human small cell lung cancer cell lines established from one patient during clinical follow-up.

Mechanisms for resistance were studied in three classic type, human small cell lung cancer cell lines, GLC14, GLC16, and GLC19, that were established from one patient during clinical follow-up. Clinically the tumor changed from sensitive (GLC14) to completely resistant to (chemo)therapy (GLC19) during this period. The stain with JSB-1 antibody, detecting the Mr 170,000 multidrug resistance associated glycoprotein, was most pronounced in GLC16 and absent in GLC19. Intracellular Adriamycin (Adr) concentrations were decreased in GLC16 and GLC19 versus GLC14. Glutathione levels were 12.9, 15.5, and 16.6 micrograms/mg protein; total sulfhydryl groups were 36.5, 45.7, and 48.8 micrograms/mg protein; and glutathione S-transferase activity was 13, 29, and 43 nmol I-chloro-2,4-dinitrobenzene/min/mg protein for GLC14, GLC16, and GLC19, respectively. Incubation with DL-buthionine-S,R-sulfoximine increased Adr and cisplatin induced cytotoxicity, whereas X-ray induced cytotoxicity remained the same. Catalase activity increased from 0.88 to 1.73 to 3.83 mumol H2O2/min/mg protein in, respectively, GLC14, GLC16, and GLC19. Compared to GLC14 and GLC16, Adr induced a higher amount of DNA strand breaks in GLC19. In none of the three cell lines could Adr induced DNA strand breaks be repaired. X-ray induced a comparable amount of DNA strand breaks in all three cell lines but all cell lines were capable of repairing the X-ray induced DNA strand breaks within 90 min. It is concluded that a number of different mechanisms are operative and that some but not all of the observed changes in mechanisms for drug resistance in these lines correlate with the clinical data.

Characterization of three small cell lung cancer cell lines established from one patient during longitudinal follow-up.

Three classic-type, small cell lung cancer cell lines (GLC-14, GLC-16, and GLC-19) have been established from one patient during longitudinal follow-up. During this period the tumor changed from sensitive to completely resistant to (chemo)therapy. A phenotypical and functional characterization of the different cell lines is given in combination with the matching clinical data. (a) The cell lines have been compared with the biopsies from which they were derived. There was a good match between the morphological, biochemical, and immunohistological findings in the cell lines as compared to those obtained in the biopsies. When the biopsy and cell line (GLC-14) obtained before the start of therapy were compared to the biopsies and cell lines (GLC-16 and GLC-19) acquired after the first and second reinduction therapy, respectively, no major changes could be observed. The only clear alteration was the loss of a neuroendocrine antigen (defined by monoclonal antibody MOC-51) in the posttherapy specimens. (b) The doxorubicin, melphalan, and etoposide sensitivity in vitro reflected the clinically observed development of resistance to treatment. The cell line (GLC-14) established before the start of therapy was more sensitive than the lines (GLC-16 and GLC-19) obtained after treatment. It is concluded that the cell lines described in this paper represent a well-characterized in vitro model in which the development of drug resistance in small cell lung cancer can be studied.

Clinical characterization of non-small-cell lung cancer tumors showing neuroendocrine differentiation features.

In most cases of small-cell lung carcinomas (SCLC) phenotypic features compatible with a neuroendocrine differentiation status can be identified by monoclonal (MOC) antibody-based immunohistological procedures. Similar features can be recognized only in a minority of non-SCLC tumors. During a period of 30 months, all diagnostic non-SCLC biopsies (141 cases) were prospectively analysed for the presence of markers indicative for neuroendocrine differentiation. In 31% of all cases, such a presence could be noticed. Neuroendocrine differentiation (50% to 100% positive-staining tumor cells) was recognized more frequently in adenocarcinoma when compared to large-cell and squamous-cell carcinoma (chi 2 = 9.31, 2 degrees of freedom, P less than 0.01). To investigate whether the clinical behavior of these "neuroendocrine" non-SCLC cases mimics SCLC, a multivariate analysis for prognostic factors was performed. Among other prognostic factors, biopsies containing more than 50% positive-staining tumor cells with the MOC antibody-1 (MOC-1) were recognized as negative prognostic factors.

Interactions between 5-hydroxytryptamine receptor subtypes: is a disturbed receptor balance contributing to the symptomatology of depression in humans?

The purpose of this review is to describe the consequences of antidepressant treatment on the behaviour of rodents after activation of serotonin (5-hydroxytryptamine, 5-HT) receptor subtypes. In a summary table, the involvement of 5-HT receptors in inducing behavioural changes are described. It is emphasized that these effects are not always only exclusively linked to serotonergic functions nor that they are only initiated by central 5-HT receptors. Hereafter, the complex mutual inhibitory effects of 5-HT receptor subtype-mediated processes are discussed by interpreting effects of antagonists and describing the different effects of low and high doses of mixed 5-HT1C/5-HT2 receptor agonists. Mutual influences are seen particularly with 5-HT1A, 5-HT1C and 5-HT2, but not with 5-HT1B, 5-HT1D or 5-HT3 receptor-mediated effects. It is shown that the behavioural consequences of 5-HT1A, 5-HT1C and 5-HT2 receptor stimulation may be changed by brain lesions or chronic treatment with drugs. Among these drugs are the antidepressants. Finally, 5-HT receptor function in depressed patients is discussed, and the hypothesis is proposed that an important function of antidepressants is to restore a disturbed balance between 5-HT1A, 5-HT1C and 5-HT2 receptors in depressed patients.

Second-line carboplatin-based chemotherapy for small cell lung cancer: the Groningen experience.

In this report, the results of two phase II studies and one pilot study of second-line carboplatin-based chemotherapy for small cell lung cancer are described. Carboplatin plus vincristine given with or without ifosfamide resulted in response rates of 36% and 53%, respectively, in so-called chemotherapy-resistant patients. Toxicity of the carboplatin/vincristine regimen was mild (hematologic toxicity grade 4 was seen with 13% of the courses), whereas the combination including ifosfamide resulted in grade 4 thrombocytopenia in 57% of the courses and grade 4 leukocytopenia in 49%. A partial response was seen in one of nine patients with progression of brain metastases after chemotherapy, and in three patients the neurologic function score improved, with minor tumor reduction evident on computed tomography scan of the brain. We conclude that carboplatin is a useful agent for second-line chemotherapy in patients with an early relapse after induction chemotherapy.

Phase I study of oral teniposide (VM-26).

A phase I study of teniposide administered orally for 5 consecutive days was performed. The first dose was 60 mg/m2/d, with increments of 25 mg/m2/d. Nineteen patients entered the study and received a total of 77 courses with a median of two (range, 1 to 12). Dose-limiting toxicity occurred at 160 mg/m2/d and consisted of myelosuppression, mainly leukocytopenia, and gastrointestinal toxicity. Sufficient recovery of blood counts was seen by day 21 to allow for a repeat course. Two patients, treated with teniposide doses of 110 and 160 mg/m2/d, respectively, were considered toxic deaths. Partial alopecia was frequent at doses above 85 mg/m2/d. Retching and vomiting during administration of the drug were encountered in virtually all patients. Oral teniposide 135 mg/m2/d for 5 consecutive days on a 3-week schedule is recommended for evaluation of antitumor efficacy in phase II studies.

Treatment of brain metastases of small cell lung cancer with teniposide.

Over 50% of patients with small cell lung cancer (SCLC) will develop symptomatic brain metastases during the course of their disease. Results of whole brain radiotherapy, the standard treatment, are rather poor and relapses are frequent. Thus, new modes of therapy are urgently needed for these patients. In this study, the efficacy of teniposide was evaluated at a dose of 150 mg/m2 intravenously on days 1, 3, and 5 at 3-week intervals. In 11 of 26 evaluable patients an intracranial response was observed. Median response duration was 23 weeks (range, 9 to 50). Toxicity was acceptable, with grades 3/4 leukocytopenia and thrombocytopenia reported in 37% and 16%, respectively, of 123 courses. Therefore, teniposide is an effective agent against brain metastases of SCLC and is suitable for palliation of these patients.

Single-agent oral etoposide for elderly small cell lung cancer patients.

Among new patients with small cell lung cancer (SCLC), 20% to 25% are over 70 years of age and account for 8,000 cases annually in the United States. For such patients, intensive, aggressive, cytotoxic, combination chemotherapy is not often used because of its association with unacceptable morbidity and mortality rates. However, treatment of these patients is often indicated, if not demanded. Etoposide is among the most active agents for the treatment of SCLC; both oral (PO) and intravenous preparations are available. The bioavailability of etoposide PO ranges from 15% to 75%. We carried out a phase II trial of etoposide PO in elderly patients (greater than or equal to 70 years of age) with a confirmed histologic diagnosis of SCLC. Patients were treated with etoposide capsules 800 mg/m2, with the total dose divided over 5 consecutive days. Cycles were repeated every 3 to 4 weeks for a total of six cycles. All treatment was administered on an outpatient basis. Staging procedures were confined to physical examination, chest x-ray, and laboratory investigations. Further staging procedures were carried out only if clinically indicated. In September 1985, 53 patients (35 male, 18 female) with a median age of 73 years (range, 70 to 95) were treated. After staging, 24 patients (45%) had limited disease (LD); the remaining 29 patients had extensive disease (ED). Overall response was 79% (complete response [CR], 17%; partial response, 62%). CRs were seen in 8 of 24 patients (33%) with LD and in 1 of 29 patients (3%) with ED. Median survival of all patients was 9.5 months (range, 1 to 22+) with 20 patients still alive; the toxicity rate was acceptable. Total alopecia developed in all patients, whereas significant neutropenia (8%) and thrombocytopenia (6%) were rare. There were no treatment-related deaths or hospital admissions. In this study, we showed activity of etoposide PO in patients with SCLC; these results were comparable with those reported for more intensive combination regimens. For elderly patients, etoposide PO provides excellent palliative treatment, with a high response rate and significant prolongation of survival. In addition, therapy is associated with minimal toxicity and can be administered entirely on an outpatient basis.(ABSTRACT TRUNCATED AT 400 WORDS)

Behavioural evidence for functional interactions between 5-HT-receptor subtypes in rats and mice.

1. Different 5-hydroxytryptamine (5-HT) receptor subtypes mediate different behavioural responses. Compounds acting at more than one 5-HT receptor exert behavioural effects which may be the result of response competition or a specific interaction between pathways within the CNS. Therefore the mutual interaction between different 5-HT receptor subtypes was studied. 2. Hypothermia and hypoactivity in mice induced by the 5-HT1A-agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) could be attenuated by the preferential 5-HT1C-agonists MK 212, 1-(meta-chlorophenyl)-piperazine (mCPP) and m-trifluoromethyl phenyl piperazine (TFMPP), and by the mixed 5-HT2/1C-agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). The mixed 5-HT1A/1B-agonist CGS 12066B at 10 mg kg-1 potentiated hypothermia and had no effect on hypoactivity. 3. Forepaw treading in rats induced by the 5-HT1A-agonist 8-OH-DPAT was attenuated by the 5-HT1C-agonists MK 212 and mCPP. The 5-HT1C-agonist TFMPP had a bimodal effect: at low doses (less than 1 mg kg-1) it potentiated, and at higher doses (greater than 2.2 mg kg-1) it attenuated forepaw treading, the mixed 5-HT2/1C-agonist DOI produced 5-HT2-related behaviours and potentiated 8-OH-DPAT-induced forepaw treading. This indicates an attenuating effect of 5-HT1C-receptor activation and a potentiating effect of 5-HT2-receptor activation. CGS 12066B had no effect in this respect. 4. Head shakes in rats induced by DOI could be attenuated by 8-OH-DPAT, TFMPP, mCPP and MK 212. The ID50S were 0.03, 0.7, 0.1 and .2 mg kg-1, respectively. This suggests that a 5-HT2-receptor-mediated effect may be attenuated by activation of 5-HT1A- or 5-HT1c-receptors. CGS 12066B attenuated the head shake response but only at 10mg kg- '. 5. The results suggest that interactions exist between the different 5-HT receptor subtype-mediated events. Therefore, care is needed in drawing conclusions from functional measurements when compounds have more or less equal affinities for more than one 5-HT-receptor subtype.

Attenuation of 5-HT1A and 5-HT2 but not 5-HT1C receptor mediated behaviour in rats following chronic treatment with 5-HT receptor agonists, antagonists or anti-depressants.

The effects of chronic (10 days) treatment with serotonin (5-HT) receptor agonists on 5-HT1A receptor mediated lower lip retraction (LLR), 5-HT1C receptor mediated penile erections (PE) or 5-HT2 receptor mediated head shakes (HS) were studied in rats. It was found that the 5-HT1A and 5-HT2 receptor mediated behaviour could be attenuated after chronic treatment, whereas 5-HT1C receptor mediated behaviour remained unchanged. The ED50 for the 5-HT1A receptor mediated, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT)-induced LLR showed an increase from 0.07 mg/kg in placebo pretreated rats to 0.13 in 8-OH-DPAT (1 mg/kg/day) pretreated rats. The number of 5-HT2 receptor mediated (+/-)-1-2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.46 and 1 mg/kg)-induced HS was significantly reduced (67% and 50%, respectively) after 10 days' pretreatment with DOI (1 mg/kg/day). In the same animals the number of 5-HT1C receptor mediated PE was increased. Ten days' pretreatment with MK 212 (0.46 mg/kg/day) failed to affect MK 212 (0.22 and 0.46 mg/kg)-induced PE. In addition, the effects of chronic treatment with some antidepressants were studied. The monoamine oxidase (MAO) inhibitor tranylcypromine (4 mg/kg/day) given for 10 days caused an increase in the ED50 for 8-OH-DPAT induced LLR (ED50 values were 0.06 and 0.14 mg/kg, respectively, in placebo--and tranylcypromine--pretreated rats) and attenuated MK 212 (0.22 and 0.46 mg/kg)-induced PE. Chronic treatment with mianserin (10 mg/kg/day), a tetracyclic antidepressant with 5-HT1C and 5-HT2 receptor antagonistic properties, did not change PE induced by MK 212, but caused an increase of PE induced by DOI and a decrease of DOI-induced HS. Ten days' pretreatment with the 5-HT re-uptake inhibitor Org 6997 (5 mg/kg/day) had no effect on MK 212-induced PE. The results demonstrate that 5-HT1A and 5-HT2 but not 5-HT1C receptor mediated behaviour can be attenuated by chronic treatment with agonists for these receptors. The 5-HT1C receptor mediated behaviour remains unchanged in response to chronic agonist treatment. Chronic treatment with antidepressants have differential effect on these behaviours. The possible implication for the mechanism of action of antidepressants is discussed.

Indirect in vivo 5-HT1A-agonistic effects of the new antidepressant mirtazapine.

The new antidepressant mirtazapine was tested in two experimental procedures which can reveal direct or indirect 5-HT1A receptor agonistic effects. These procedures were observation for induction of lower lip retraction in rats and comparison of stimulus properties in cross-familiarization experiments with conditioned taste aversion in mice. Mirtazapine induced lower lip retraction in rats, as did the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). However, the response to mirtazapine at doses up to 22 mg/kg remained below the maximum score obtained with 8-OH-DPAT (0.46 mg/kg). Blockade of the 5-HT1A receptors with pindolol (10 mg/kg) caused a strong reduction of the lower lip retraction induced both with mirtazapine and 8-OH-DPAT. In the cross-familiarization conditioned taste aversion experiments it was found that the conditioned taste aversion induced by mirtazapine (0.32 mg/kg) could be prevented if the mice were pre-exposed to injections with mirtazapine (0.22 and 0.46 mg/kg), 8-OH-DPAT (0.22 and 0.46 mg/kg) and after pre-exposure to the 5-HT reuptake inhibitor fluoxetine (22 mg/kg). No familiarization for the mirtazapine stimulus was obtained by pre-exposure to (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI) (0.46-4.6 mg/kg) and MK212 (2.2-22 mg/kg), being agonists for the 5-HT2A and 5-HT2C receptors, respectively. With the reversed sequence, the conditioned taste aversion induced by 8-OH-DPAT (0.22 mg/kg), DOI (1.0 mg/kg) and fluoxetine could be prevented only partially by pre-exposure to mirtazapine in a dose of 1 mg/kg. The conditioned taste aversion induced by MK 212 (4.6 mg/kg) was not affected by pre-exposure to mirtazapine (0.1-1.0 mg/kg). On the basis of these results, it can be concluded that mirtazapine has indirect 5-HT1A receptor agonistic properties which may play an important role in the therapeutic effect of this compound.

Involvement of 5-HT1C-receptors in drug-induced penile erections in rats.

Drug-induced penile erections (PE) were initially suggested to be 5-HT1B receptor mediated. However, since the discovery of the 5-HT1C receptor a number of compounds, considered to be 5-HT1B selective, appear to bind more strongly to the 5-HT1C receptor and this prompted a re-evaluation of the receptor subtype involved in PE induction. PE could be induced by the 5-HT agonists mCPP (0.22-2.2 mg/kg), TFMPP (0.46-1.0 mg/kg) and MK 212 (0.1-1.0 mg/kg). The 5-HT agonist DOI (0.022-0.22 mg/kg) did not induce PE in placebo-pretreated rats but in rats pretreated with various 5-HT2 antagonists it did. These compounds have in common a strong affinity for the 5-HT1C receptor, mCPP (0.46 mg/kg)-induced PE could be antagonized by the 5-HT antagonists metergoline, cyproheptadine, mesulergine, mianserin, ritanserin and ketanserin. Their ED50S were 0.04, 0.4, 0.03, 0.06, 0.4 and 2 mg/kg, respectively. The potency of both the agonists to induce, and the antagonists to inhibit, PE was found to be dependent on their selectivity for the 5-HT1C receptor versus the 5-HT2 receptor. Spiperone (0.1-1.0 mg/kg) and GR 38032F (1-10 mg/kg) did not antagonise mCPP-induced PE. 8-OH-DPAT and 5MeODMT counteracted mCPP (0.46 mg/kg)-induced PE. Their ED50S were 0.03 and 0.4 mg/kg, respectively. DOI counteracted mCPP induced PE only at doses above 1 mg/kg, whereas CGS 12066B (1.0-10 mg/kg) was inactive. The results suggest that PE are induced by activation of the 5-HT1C receptor and are functionally inhibited by activation of 5-HT1A or 5-HT2 receptors.

Differences in presynaptic alpha-blockade, noradrenaline uptake inhibition, and potential antidepressant activity between (+)- and (-)mianserin.

The effect of racemic mianserin on K+-evoked tritium release from rat brain cortex slices previously incubated with 3H-L-noradrenaline was studied. Racemic mianserin (10(-9)--10(-5) M) increased stimulation-induced release dose-dependently. As methysergide, metiamide, and cyproheptadine failed to do so, it was concluded that this effect was probably not caused by the antihistamine or antiserotonin activity of racemic mianserin, but due to its alpha-adrenolytic effect. Evaluation of the effects of the enantiomers (+)(S)mianserin and (-)(R)mianserin showed that the alpha-adrenolytic effect resided in the (+)isomer, whereas the (-)isomer was inactive at a concentration of 10(-6) M. Inhibition of noradrenaline into rat hypothalamic synaptosomes also showed stereospecificity in that (+)mianserin was about 300-times more active than(-)mianserin. Inhibition of rat muricidal behavior, a test for potential antidepressant activity, showed a similar dissociation in the effects of the two enantiomers, in that (+)mianserin was active, whereas (-)mianserin was not.

Mirtazapine enhances the effect of haloperidol on apomorphine-induced climbing behaviour in mice and attenuates haloperidol-induced catalepsy in rats.

Activation of 5-HT1A receptors has been shown to attenuate catalepsy induced by typical antipsychotic compounds. Since mirtazapine (Remeron; Org 3770) has indirect 5-HT1A receptor stimulating properties as well as antagonist properties at alpha2-adrenoceptors and 5-HT2 receptors, it was of interest to investigate how the compound could modulate the effect of haloperidol on apomorphine-induced climbing behaviour in mice and haloperidol-induced catalepsy in rats. In the apomorphine climbing test, it was found that mirtazapine (2.2-22 mg/kg) did not change the climbing behaviour of mice induced by 1 mg/kg of apomorphine. However, when given as a co-treatment with haloperidol, mirtazapine (1 and 10 mg/kg) dose-dependently augmented the inhibiting effect of haloperidol on this climbing behaviour. Co-treatment with the 5-HT1A receptor agonist 8-OH-DPAT (0.1 mg/kg) also augmented the effect of haloperidol. Catalepsy induced by haloperidol (4.6 mg/kg) was attenuated by mirtazapine (2.2-22 mg/kg). The strongest effect was seen at 90 min after haloperidol treatment. The results obtained in these experiments suggest that co-treatment with mirtazapine may enhance the antipsychotic effect of haloperidol and reduce its extrapyramidal side effects, thereby widening its therapeutic window.

Stimulus properties of fluvoxamine in a conditioned taste aversion procedure.

A conditioned taste aversion (CTA) procedure in mice was used to investigate the stimulus effects of the serotonin reuptake inhibitors (SSRIs) fluvoxamine and fluoxetine. Fluvoxamine elicited a reliable CTA (ED50 = 24 mg/kg, SC) and a number of drugs were tested as pre-exposure drugs. Pre-exposure to the serotonin (5-HT)1A receptor agonists flesinoxan and +/- -8-hydroxy-dipropylaminotetralin (8-OH-DPAT) prevented the CTA induced by fluvoxamine (50 mg/kg, SC). Pre-exposure with the 5-HT2C receptor agonist MK 212 [6-chloro-2(1-piperazinyl)pyrazine] partially prevented the fluvoxamine-induced CTA, pre-exposure with the 5-HT2A/2C receptor agonist DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl] did not prevent the CTA induced by fluvoxamine. Flesinoxan pre-exposure also prevented the taste aversion induced by fluoxetine (10 mg/kg, SC) completely. This contrasts previous results obtained with fluoxetine, where was found that its stimulus is primarily mediated by 5-HT2C, and to a lesser degree by 5-HT1A receptors. Therefore, we compared the two SSRIs directly. Pre-exposure to fluvoxamine prevented the fluoxetine-induced CTA, whereas pre-exposure to fluoxetine only partially prevented the fluvoxamine-induced CTA. We conclude that 5-HT1A receptors are involved in the stimulus properties of both fluvoxamine and fluoxetine, that 5-HT2C receptors are involved in fluvoxamine and especially fluoxetine, and, based primarily on the cross-comparison tests, that the two SSRIs have somewhat different stimulus properties.

Detection of small cell lung cancer metastases in bone marrow aspirates using monoclonal antibody directed against neuroendocrine differentiation antigen.

To detect metastases in the bone marrow of patients with small cell lung cancer, immunofluorescence with a monoclonal antibody detecting a membrane antigen (MOC-1) associated with small cell lung cancer was performed on 53 bone marrow aspirates from 30 patients. In 19 (63%) patients MOC-1 reactive cells were detected. Simultaneous histopathological examination of the bone marrow biopsy specimens detected tumour cells in only six (20%). The method is more sensitive than conventional histochemical staining of bone marrow aspirate and may eventually be able to show additional subgroups, such as patients with limited disease who might benefit from adjuvant radiotherapy or surgery.

Premature ejaculation and serotonergic antidepressants-induced delayed ejaculation: the involvement of the serotonergic system.

Premature ejaculation has generally been considered a psychosexual disorder with psychogenic aetiology. Although still mainly treated by behavioural therapy, in recent years double-blind studies have indicated the beneficial effects of some of the serotonergic antidepressants (SSRIs) in delaying ejaculation. We describe here the neurophysiology and the peripheral neuroanatomy of ejaculation and provide a review of the involvement of serotonin in the central nervous system in relation to serotonergic nuclei and their projections. A hypothesis of the role of 5-HT1A and 5-HT2C receptors in premature ejaculation is postulated.

A feasibility study of testing new drugs for small-cell lung cancer in patients with a poor performance status.

Testing of new drugs in small-cell lung cancer is definitely necessary for the development of agents that might be effective against this tumor. However, testing such drugs in previously untreated patients with a good performance status (PS) may give rise to ethical problems. When previously treated patients are used in testing, potentially effective agents could well elude discovery. Patients who are not eligible for "standard" combination chemotherapy, e.g. untreated patients with a poor PS, may be suitable for testing of new drugs. To evaluate the potential usefulness of such patients in the testing of new agents, we evaluated an effective drug (etoposide) at a relatively nontoxic dose in a group of 14 patients with a PS of 4 (WHO). Oral etoposide resulted in a response in only 3 cases, whereas 5 subjects died of therapy-related toxicity. We conclude that previously untreated patients with a poor PS are not suitable candidates for the testing of new drugs.

A phase II study of carboplatin and vincristine in previously treated patients with small-cell lung cancer.

A total of 28 previously treated patients with small-cell lung cancer were treated at relapse with 400 mg/m2 carboplatin and 2 mg vincristine on days 1 and 8, every 4 weeks. Ten partial responses (PRs) (37%) but no complete responses (CRs) were seen. Median survival after the start of second-line treatment was 120 days (range, 39-503 days). Toxicity of this regimen was moderate, including WHO grade 3/4 myelosuppression in 26% of courses (n = 66). Eight PRs were seen in a subgroup of 22 patients who relapsed less than 3 months after first-line treatment. The responses seen in this group of patients may be due to the absence of cross-resistance between the regimens used.

Age dependence of 5-methoxytryptamine-induced hindlimb scratching in rats.

The influence of age on hindlimb scratching induced in rats by the serotonin agonist, 5-methoxytryptamine (5-MeOT), was studied. The 5-MeOT-induced scratching was strongest in 30-day-old rats and least in 90-day-old rats. Sex hormones do not play a role in these differences since treatment of young male rats with testosterone propionate did not change the scratching response. The same age dependence was found for female rats as for males.