306 Abstracts/Lung Cancer 12 (1995) 265-329

COU~SCS WC~C mpeatcd every 28 days for a total of three courses. Toxicity: 15 patients (68%) had received previous chemotherapy. Myclosuppression was the main problem with one grade IV and tive grade III hcmatologic toxicities. WC obscwcd one mild ncurologic toxicity. Results: 19 patients were evaluable for msponsc. WC obsewcd one complete rcsponsc (5%), five disease stabilizations (26%) and 13 disease pmgrcssions. Median survival was 5 months. These msults led to discontinuing this study.

Eflkacyofaanbinathmultidrugckmotbcrapy(mitomy~ifosfamide ~~ldin)~r~yfort~t~b~~~~n small cell lung cancer Cumin I, Law&x H. Mahe M, Dutin JP, Dab&s G. Unite d’Onco/ogieMedicole, HopihdLamnec, CHRU 44035 Nan&s Cedex 01. Bull Cancer 1995;82:57-62.

WC initiated prospective study testing efficacy of multidrug chemotherapy (cisplatin, ifosfamide, mitomycin) with irradiation in brain metsstases of non small cell lung cancer at first diagnosis. Among 22 patients we obtained ten objective Iceal mspcmscs (45%). Median survival was 7 months. Toxicity wss mild (>2 - OMS): hcmatologic = five patients, gastmintcstinal = one pticnt. Among 11 patients who rcceivcd chemotherapy before radiotherapy we had seven objective responses (patients cvaluatcd a&r three ccwses of chemotherapy and bcforc radiothcmpy). This result indicates the interest of this protocol of chemotherapy in brain me&stases. The association of this protocol of chemotherapy and radiotherapy appears effective, well tolerated end few toxic.

Mitomycin-ifosfamide-cisplatinum (ME’) vs MIP-interferon vs cisplatinum-crrboplatin in metastatic non-small-cell lung cancer: A FONICAP randoudacd pbasc llstudy Ardizzoni A, Addamo GF, Baldini E, Botghini U, Portalone L, De Marinis F et al. Deparbnmt of Medical Oncology I, Istitito Narionole Ricerca Cancro, r IeBenedeUoXVIO, 16133 Genoa. Br J Cancer 1995;71:115-9.

The FONICAP group is screening, with mndomised phase II studies, the activity of new chcmothaapy progmmmcs for advanced non-small-cell lung cancer (NSCLC) looking for regimens with > 30% activity In the present study, three regimens wcrc tested: MIP (mitomycin 6 mg m”, ifosfamidc 3 g m-l, cisplatinum 80 mg m” on day I every 28 days); MIP-IFN (MIF end intcrfcron alpha-2b 3 MU s.c. three times a week); and PC (cisplatinum 60 mg m-I end carboplatin 400 mg rn.I on day I every 28 days). Overall 93 chcmotherspy- naive patients were cm&cd: 23 reeeivcd MIF’, 27 received MIP-IFN and 43 received PC. Eighty per cent of the patients had stage IV and 20% stage IIIb disease (positive pleural effusion or supmclavicular nodes). Response rates wcrc as follows: MU - 9% (95% CI l-28%), MIP-IFN = 7% (95% CI l-24%) and PC = 14% (95% CI S-28%). The overall median survival was I83 days. Grade L&IV lcucopcnia was observed in 36% of patients be&d with MIP-IFN vs 10% in the other two arms, and thrombocytopenia grade III-IV was rcpartcd in nearly 10% of patients overall. In conclusion, (1) all three regimens investigated have poor activity (< 30%); (2) when tested in multiccntre randomiwl phase II trials, MlF’ displays lower activity than in phase II trials; (3) PC has similar activity to other platinum-containing rcgimcns; (4) randomiscd phase II studin am a reliable and quick method of dctcrmining the anti-hrmour activity of novel chemotherapeutic regimens in NSCLC.

Reduced topoismnerasc II activity in multidrug-rcaistaat human nou- small cell lung cancer cell lines Eijdems EWHM, De Hans M, Timmemwm AJ, Van Lkr Schans GP, ffimst E, De Nmij J ct al. Divisiaz oJWoIecu&r Biolom The Nerherlandr Cower Insfitute, Plesmanban 121.1066CXAmsterdam. Br J Cancer 1995;71:40-7.

Multidrug-resistant (MDR) cell lines often have a compound phenotype, combining reduced drug accumulation with II decrease in topoisomcrase II. We have analyscd alterations in topoisomerase II in MDR derivatives of the human lung cancer cell line SW-1573. Sclcction with doxorubicin frcqucntly rcsultcd in reduced top0 II& mRNA and protein Icvels, whereas clones selected with vincristinc showed normal levels of top0 IIb. No alterations of top0 II8 levels were detected. To determine the contribution of topo II alterations to drug resistance, topo II activity was analyscd by the determination of DNA breaks induced by the topa II-inhibiting drug 4’6-acridinylamino)mcthanc-sulphon- m-anisididc (m-AMSA) in living cells, as m-AMSA is not affected by the drug

CffIux mechanism in the SW-I 573 cells. The number of m-AMSA-induced DNA breaks correlated well (r = 0.96) with in vitro m-AMSA sensitivity. Drug sensitivity, however, did not always col~elate with mduccd top0 II mRNA or pmtcin levels. In one of the five doxombicin-selected clones m-AMSA resistance and B reduction in m-AMSA-induced DNA breaks were found in the abwnce of reduced topo II protein Icvcls. Therefore we assume that post-translational modifications of topc II also contribute to drug resistance in SW-1 573 cells. These rcs~lts suggest that methods that detect quantitative as well as qualitative alterations of topo II should be used to predict the responsiveness of tumours to cytotoxic agents. The assay we used, which measures DNA breaks BS an end point of topa II activity, could bc a goad candidate.

Cytotoxic effect of herbal medicine Sbo-saikwto on bumao lung cancer cell IineJ in vitro Mizushima Y, Kashli T, Tokimitsu Y, Kobaysshi M. First Dept. of Infernal Medicine, Toyama MedicolF’harmoceutl Unix, Toyama 930-01. On& Rep 1995;2:91-1.

The cytotoxic effect of a herbal medicine She-saiko-to (TJ-9) was examined by the MTT assay on 7 human lung cancer cell lines (4 non-small cell carcinomas, 3 small cell carcinomas) and on 5 hcpatocellularcarcinoma cell lines. TJ-9 showed a dose-dependent cytotoxicily in all cell lines except one (SBC-5). Of the seven herbs in TJ-9, Scutellaria root showed the strongest cytotoxicity followed by the Glycyrrhiza root. Among baicalin, baicalcin and wogonin from the Scutcllaria root, cytotoxicity was observed only with baicalin. The SBCJ cell line which was resistant to TJ-9 showed a lesser sensitivity to both Scutellaria root and baicalin. TJ-9 showed almost equal cyiotoxicity in cisplatin (CDDP)-sensitive PC-10 and CDDP-resistant SBC4 cell lines, and in H69 and H69/CDDP cell lines. TJ-9, Scutellaria root and baicalin were all less cytotoxic for human lymphocytes and bone marrow cells than for a lung canccr cell line of SBC-4. Thcsc results suggest that TJ-9 and its components may be useful antwnncer agents for the treatment of hmg cancer.

Pbasc I/II study of a combination regimen composed of cisplatin, carboplatin and etoposide against small cell lung cancer Ichiki M, Sakumi M, Hayashi I. Jpn J Cancer Chemother 1994;21:2787-91.

Phase I/Ii shidy of combination regimen composed of cisplatin (CDDP), carboplatin (CBDCA) and ctoposide (VP-16) (CPVP) was conducted for small cell lung cancer. The dose level of VP-16 was tixed at IO0 mg/m’, while the dosages of CDDP and CBDCA administcmd at each of the 4 steps were 50/ 200, 601200, 601250 and 701250 mglm’, respectively. Nine patients were allocated to each step dose group. Toxicities were evaluated in the first 2 ccmrses to determine the maximum tolerated dose (MTD). As a result, step 3 dosages proved to be MTD, and the dose limiting factor (DLF) was hematotoxicity, but gastro-intestinal toxicity was tolerated. The response (CR + PR) was found in 21 out of 23 patients with evaluablc lesions (91%). In the 22 patients who had not rcccivcd pretreatment, median survival time (MST) was 16.4 months. These results suggest that the recommended dose is step 2, and that the CPVP regimen is both more tolerable and more cffcctivc than the standard regimen. The CPVP regimen warrants further study in phase III trials.

Acquired resistance and craswesistance ofgemcitabine to cisplatin or vindesiw in human lung cancer xenografted io nude mice Fujita F, Fujita M, Fujita M, Sakamota Y Exp. Cancer Chemotherapy Res. Lab.. Co., Ltd., Osaka Universily. Osaka. Jpn J Cancer Chemother 1994;21:2749-55.

One of the problems in the trcatmcnt of cancer is the development of resistance to anti-tumor agents when used repeatedly. We described the induction of resistance, cross-resistance to cisplatin (CDDP) or vindcsine (VDS) and the side effects of gemcitabinc, a new Am-C derivative. in human lung cancers, Mqnu-1 or H-73 xcnogratled in nude mice. WC investigated the effects of 4-wak treatment with gemcitabinc, CDDP or VDS, followed by repeated or alternate therapy after a 4-week observation period. Gemcitabine was effcctivc and did not show the acquired resistance when given nptatcdly. In contrast, CDDP but not MIS, when given mpcatcdly, showed a dccrcnsc of the anti-hrmor effect in the second cowse. Gcmcitebinc was still effective to the large hlmor grown after CDDP or MS therapy. Thus. gemcitabinc may not develop rcsistancc nor show cmss- resistance to CDDP or VDS. In addition, repeated treatment with gemcitabine was much safer than CDDP or VDS. Thm results suggest that gemcitabinc is a candidate for tbe first choice drug in cancer treatment.