398 Abstracts/Lung Cancer 14 (19%) 377-408

carcinoma; the other five had squamous cell carcinoma. Results. Five patients, including two patients with squamous cell carcinoma and three with adenocarcinoma, obtained a partial response (response rate 50 W). The time needed to achieve a sustained response ranged from 5 to 13 weeks with a median of 8 weeks. The response duration ranged from 14 to 37 weeks with a median of 20 weeks. The overall survival time for the ten patients ranged from 2 to 20 months with a median of 8 months. All 10 patients needed dose modifications of IFN-alpha and/or cisplatin because of myelosuppression and/or impaired renal function. Other frequently encountered side effects included gastrointestinal disturbances and a flu-like syndrome, but these were well tolerated. Conclusions. These preliminary results indicate that chemoimmunotherapy with IFN- alpha and cisplatin can be an effective alternative therapy for patients with advanced NSCLC, but there are significant side effects.

Effect of human recombinant interferon-a on the activity of cis-diamminedichloroplatinum(II) in human non-small cell lung cancer xenografts French RC, Bowman A, MacLeod KG, Ritchie AA, Cummings J, Smyth JF. Imperial Cancer Research Fund, Medical Oncology Unit, Western General Hospital, Crewe Road, Edinbugh EH4 2XU. Scotland. Cancer Invest 1995;13:595-603.

Interferons (IFNs) augment the effect of some antitumor agents, including cis-diamminedichloroplatinum(II) (cDDP), in experimental systems. Theeffectofhumanrecombinant interferon+dpha(2b)(rIFNa) on the cDDP-dependent growth delay in a human non-small cell lung cancer established as a xenograft in nude mice (NXO02) has been investigated. IFN (lo5 IU/mouse, s.c.) as a single agent had no effect on thegrowthofthexenograft. cDDP (4.2 mgnig, i.p.)caused aspecific growth delay of 0.42, and this delay was significantly enhanced (to 1.08) by concomitant dosing with the otherwise inactive IFN. Possible mechanisms for this supra-additive relationship between IFN and cDDP havebeen investigated: increased intratumoral accumulationofplatinum wasseenatlatetimepoints(maximallyat36hr)duringthepharmacokinetic B-phase of cDDP elimination from the plasma of the nude mice. Tumor:plasma platinum concentration ratios at 36-48 hr indicated significantly increased accumulation of platinum in tumors from IFN- treated mice compared to controls (p < 0.05). Scheduling experiments suggest that this IFN-mediated effect can persist for 4 hr. These differences may account for the enhanced antitumor activity of cDDP when coadministered with IFN.

Mitomycin C and menadione for the treatment of lung cancer: A phase II trial TetefM,MargolinK,AhnC,AkmanS,ChowW,LeongLetal.Dept. Med. Oncol. therapeutics Res., City of Hope National Medical Center, 1500 East Duane Road, Duarte. CA 91010. Invest New Drugs 1995;13:157-62.

A phase11 trial of menadione [2.5 gmlm’as acontinuous intravenous (iv) infusion over 48 hours] followed by mitomycin C (lo-20 mglm’ iv bolus) administered every 4 to 6 weeks was performed in 23 patients with advanced lung cancer. Menadione, a vitamin K analog which lowers intracellular pools of reduced glutathione (GSH), was combined with mitomycin C in an attempt to overcome thiol-mediated resistance to alkylating agent chemotherapy. The median age of patients entered on this trial was 62 years; performance status ranged from 60-90 46. Two of the 23 patients (9%; 95 I confidence interval, 1% to 28%) had objective responses lasting 3.5 months and 13 months respectively, while 4 additional patients developed short unconfirmed responses (lacking follow-up responsedata to estimate responseduration). Median survival for all patients was 5.5 months. Treatment with mitomycin C and menadione was well tolerated except for hematologic toxicity and

cardiac events of unclear relationship to the study drugs. Thirty-one percent of treatment courses were complicated by grade3 or 4hematologic toxicity including one episode of hemolytic anemia. One patient developed interstitial pneumonitis. Two patients developed a decrease m left ventricularejection fraction: one patient remainedasymptomatic, but the other patient developed congestive heart failure. Although only 9 % of patients had confirmed objective responses, 28 96 (5 of 18) of the patients with non-small cell lung cancer demonstrated biological activity (tumor regressions fulfilling the criteria for objective response on a single occasion but 3 patients lacking a follow-up measurement to document response duration) to this combination of mitomycin C and menadione. We conclude that further studies of chemomodulation in non-small cell lung cancer are appropriate.

Modulation of sensitivity to mitomycin C and a dithiol analogue by tempo1 in non-small-cell lung cancer cell lines under hypoxia Bando T, Kasahara K, Shibata K, Numata Y, Heki U, Shims& H et al. L%ird Depanment Internal Medicine, Kanazawa University, School of Medicine, 13-1 Takara-machi, Kanazawa 920. J Cancer Res Clin Oncol 1996;122:21-6.

We examined the mechanisms involved in the bioactivation of mitomycin C (MMC) and a newly developed MMC analogue: 7-N-(2- {[2-(gamma-L-glutamylamino)ethyl]dithio}ethyl)mitomycin C, KW- 2149, in non-small-cell lung cancer (NSCLC) cell lines under aerobic and hypoxic conditions. To investigate these mechanisms, we used MMC-resistant non-small cell lung cancer cell lines (PC-9/MC4) that had been established in our laboratory from the parent PC-9 cell line by continuous exposure to MMC. We previously reported that the MMC- resistant cell line (PC-9/MC4) was poor in NAD(P)H dehydrogenase (quinone) activity and approximately 6-fold more resistant than the parent cells (PC-9) to MMC on 2-h exposure under aerobic conditions. In this study, the subline PC-9/MC4 was 6.7-fold more resistant to MMC than PC-9, the parent cell line, under aerobic conditions, and 5.2- fold more resistant under hypoxic conditions after 2 h exposure to MMC. However, on co-incubation with tempol, an inhibitor oftheone- electron reduction pathway, the sensitivity of PC-9/MC4 to MMC was impaired under hypoxic conditions, but the impairment was not evident under aerobic conditions. KW-2149, the newly developed MMC analogue, was cytotoxic for both PC-9/MC4 and PC-9 cells, and the sensitivity of both cell lines to KW-2149 was not changed by exposure to hypoxic conditions or by coincubation with tempol. There were no significant differences in the intracellular uptake of MMC and the activities of cytosolic detoxification enzymes between the PC-9 and PC- 9/MC4 cell lines. These results support the hypothesis that the one- electron reduction pathway plays a partial role in the bioactivation of MMC, but not of KW-2149, and that KW-2149 is excellent at circumventing resistance to MMC in NSCLC.

Increased expression of Bcl-2 in drug-resistant squamous cell lung carcinomas Volm M, Mattem J. German Cancer Research Center, Dept. 0511, Im Neuenheimer Feld 280. 69120 Heidelberg. Int I Oncol 1995;7: 1333-8.

The aim of this investigation was to prove whether or not an association exists between Bcl-2 expression and in vitro resistance to doxorubicin in biopsies of 85 human squamous cell lung carcinomas. Additionally, the relationship of Bcl-2 expression with resistance related proteins (P-glycoprotein, glutathione S-transferase-b. cat&se) wasanalyzed. Ofthe carcinomas, 17 (20%)revealedBcl-2expression by immunohistochemistry. Seventeen of the tumors were classified as sensitive and 68 as resistant by an in vitro predictive test. All 17 Bcl-2- positive carcinomas were resistant to doxorubicin (p = 0.018; chi’-