304 Abstracts /Lung Cancer 12 (I 995) 265-329

0.006). The median survival of patients treated with the PAV-CyMOC combination was significantly longer than that of patients receiving we&y CBDCAiVM (260 days vs. 147 days; p = 0.0035). The l-year survival rate was 30% in the PAV-CyMOC a~rm compared to 4% in the CBDCANM-treated paticnts. As expected, side effects including myelo-suppression, alopecia and mucositis wcrc significantly more pronounced in patients trcatcd with the PAV- CyMOC regimen. No significant difference WBS found in patient-rated tumor symptoms and general quality-of-life categories. Conclusion: Contrary to cur initial expectation that we would achieve similar therapeutic results with less subjective toxicity, in this randomiscd prospective trial the results achieved by wzckly carboplatin and tmiposidc wcrc significantly inferior in terms of remission rate and survival to those of our ‘standard regimen’ of cisplatin, adriamycin and etoposidc alternating with cyclophosphamidc, methotrcxatc, vincristinc and lomustinc. The weekly regimen was less toxic than the standard chemotherapy. Whether patients are willing to accept a signiticant trade-off between quantity and quality of life remains to be evaluated.

Eff~d~Q,,mdeelrstioonpmtoetingrndistionpoeumonitis with hmg cancer Imanaka K, humiyama K, Sakaguchi T. Kushime T. Okamota Y. Kono M. et al. Deparbnenf ofRadioloa Kobe Uniwrsily School ofMedicine, Kobe. J Jpn Sot Cancer Thcr 1994;29:2010-5.

A rctmspcctive analysis was pcrformcd to investigate the effect of Cocnzyme Q,, and azclastin on protecting radiation pncumonitis in patients with lung cancer. Twenty patients were administered Cocnzymc Q,, and azclastin cvety day during and s&r radiotherapy for 6 months. Historical controls of 20 patients were irradiated without administration of drugs. According to the findings of chest X-ray taken at the completion of radiotherapy, 1, 3 and 6 months after radiotherapy, the severity of radiation pncumonitis was evaluated. As a result, scvcrc pncumonitis was observed mmx frcqucntly in the group without drugs. Severe cescs with drugs were all irradiated with doses more than 60 Gy, with field sizes more than 100 cm’. On the other hand, 7 of 9 scvere cases without drugs were irradiated with doses less than 60 Gy, with field sizes less than 100 cm’. These results strongly suggested that Coenzyme Q,, and azelestin was effective in reducing severe radiation pncumonitis.

Cyclocreatiae in cancer chemotherapy T&her BA, Menon K, Northey D, Liu J, Kufe DW. Kaddurah-Daouk &no- Farber Cancer Inrrirute, Joinf Center for Radiation Therapy. 44 Binnty Sr?ee~, Bosfon, u4 02115. Cancer Chcmothcr Pharmacol 1995;35:41 I-6.

Cyclcaestinc, an analog of creatinc, is an cffricient substrate for creatine kinase, but its phosphorylated form is a poor phosphate donor in cornprison with crcatinc phosphate. Cyclocrcatine was not very cytotoxic upon 24 h of exposure of human SW2 small-cell lung cancer cells to concentrations of up to 5 mM. However, combinations of cyclocreatine (0.5 mM, 24 h) with each of four antitumor alkylating agents, cis-diamminedichloroplatinum(II), melphslan, 4- hydropcmxycyclophosphamide, and carmustine, rcsultcd in additive to greater- than-additive oytotoxicity toward exponentially growing SW2 cells. The grcatcst levels of synergy were scat at higher concentrations of rl-hydroperoxy- cyclophosphamidc and carmustine as determined by is&&gram analysis. In viva cy&crcatinc (0.5 or I gikg) was more effective if given i.v. rather than i.p. The longest tumor-growth delays, up to 10 days, were produced by cxtcndcd regimens of cyolocreatinc. Cyclocrcatinc was an cffcctive addition to therapy with standard anticancer agents including cisdiamminedichloropIetinum(II), cyclophosphamidc, Ad&my&, or 5-tiuorouracil. No additional toxicity was observed when IO days of cycloxcatine trcahnent was given with full standard- dose rcgimms of each drug. The rcsultmt increases in tumor-growth delay were I .7- to 2.4-fold as compared with those obtained for each of the drugs alone. These results indicate that cycIocreatine may Lx an effective single agent and an effective addition to combination chemotherapy regimens.

Poteatiatian dgmw4h inhibition due to vincristine by ascorbii acid in a resistant human non-small cell lung cancer cell line Song E-J, Yang VC, Chiang CD, Chao CC-K. Tumor Bio/ogv. Deparbnenl of Biochemistiy, Chong Gung Medical College, Taoyuan. 333. Eur J Phernuxol Environ Toxicol Phannacol Sect 1995;292:119-25).

A human cell sublinc (PC-9NCR) resistant to vincristine was established from non-small cell lung cancer PC-9 cells by incremental exposure of the cells to

vincristinc. The resistant cells showed phenotypic resistance to vincristine (IO- fold), colchicine (6.9-fold) and cisplatin (1.6fold) but they showed sensitivity to other chemotherapeutic agents including merphalan and ctoposide VP-16. The characteristics of the vincristinc resistance was partially inhibited (S-7- fold) by co-treatmmt of PC-WVCR cells with a nontoxic concentration of L- ascorbic acid (25 &/ml). Co-tratmcnt or 96 h pre-treatment with ascorbic acid rcsultcd in potent&ion of the vincristinc effect on the resistant, but not on the sensitive, cell line. The growth inhibition due to vincristine treatment after 24 or 96 h growth in ascorbic acid-fret medium was decreased in the rcsistmt as well as in the sensitive cell line. In both cell lines, enhanced growth rate has been shown aficr ascorbic acid trcatmcnt. Similarly, cross-resistance of PC-9NCR cells to colchicinc could also be blocked by ascorbic acid. In addition, a nontoxic concentration of vempamil, a known multidrug resistance inhibitor, did not affect the resistant phenotype of FC8NCR cells. These findings suggest that an ascorbic acid-sensitive mcchmism may be involved in drug resistance per sc in the human lung cancer cells, which differs from the classical phosphoglyeoprotcin-mediated or previously rcportcd non-phosphoglycoprotcin-mediated multidrug resistant.

Therapy for small cell lung cancer using carboplatin, ifosfamide, etoposide (without dose reduction), mid-cycle vincritine with thoracic and cranial irradiation Pnndiville J, Lorigan P, Hicks F, Leahy B, Stout R, Burt P et al. CRC Deperment of Medical Oncolo~, Christie HospiIal, Manehate,: Eur J cancer Part A Gen Top. 1994;30:2085-90.

The aim of this study was to assess the efficacy and toxicity of intensive chemotherapy, administered without dose reduction, with cranial and thoracic radiotherapy given when possible as a single fraction in small cell lung cancer. 87 patients were eligible on the basis of good perfornw~cc status, normal or near normal biochemistry and clinical staging, 73 limited and I4 extensive stage, computed tomography scanning was not mandatory. Six cycles of carboplatin, ifosfamidc and etoposide with vincristine on day 15 at 4 weekly intervals were planned. Dosages were not reduced in response to myelosuppression. Prophylactic cranial irradiation (PCI) as B single fraction after the first cycle and thoracic irradiation (when possible as a single fraction) following the third cycle were delivered. Seventy-two per cent of patients completed the protocol. Complete response rate was 55% and 26% of patimta had a partial response. The median nadirs of ncutropcnia were 0.5 x lop/l and thrombocytopenia I4 x 109/1, with 6% probable treatment-related deaths. Performance status and dyspnoca improved markedly to normal or near normal levels following the second course. Brain metastascs occurred in 13% ofpatients. The median survival was 16.2 months with a 2-year survival of 31% (95% confidence interval, 24- 41%) for a minimum follow-up of 26 months. These results cotnparc favourabty with other combined modality studies, using multiple radiotherapy fractions with cisplatin-based combinations and dosage reduction for patients steged in more anatomical detail. The toxicity spectrum and ctlicacy data could lead to the USC of this chemotherapy regimen with hacmatapoietic growth factors and, in the future, peripheral blood progenitor cell rcscuc.

The role of methoxymorpholiao anthracyclioe and cyanomorpholimo anthracycline in a sensitive small-cell lung-cancer cell line and its m~drug~tbutP-glyeoploteia-aegativePndcisplatin-resi~t counterparts Van dcr Graaf WTA, Muldcr NH, Mcijcr C, De Vries EGE. Departmenf of Internol Medicine. Division of Medical Oncologv. UniversiQ Hospilel, Oosrersingel 59, 9713 EZ G~oningen. Cancer Chcmothcr Pharmacol 1995;35:345-8.

The cytotoxic action of two morpholino anthracyclines. mcthoxymorpholino anthracyclinc (W-MT, FCE 23762) and cyanomorpholino anthracyclinc (MRA-CN), was compared with the cytotoxicity of doxorubicin (DOX), the topoisomcr~sc II inhibitor etoposidc (VP-16). the topoisomcrase I inhibitor camptothccin, mcthotrcxate, and cisplatin in GLC4, a human small-cell lung- cancer cell line, in GLC4-Adr, its P-glycoprotcin (Pgp)-negative, multidrug- resistant (MDR; loo-fold DOX-resistant) sublinc with ovcrcxprcssion of the MDR-associated protein (MRP) and a lowered topoisomcrasc II activity, and in GLG&CDDP, its cisplatin-resistant subline. GLC4-Adr was about I-fold cross- resistant for the morpholino anthmcyclines and GIC4CDDP was, relative to GLC4, more rcsistmt for the morph&o snthracyclincs than for DOX. GvcraII, MRACN wes about 2.5-fold more cyiotoxic than MRA-MT. The cytotoxicity profile of the morpholino anthncyclincs in these cell lines mimicked that of camptothccin.