Microspectrofluorometry of cell coenzymes (NAD(P)H, flavins) in conjunction with sequential microinjections into the same cell of metabolites and modifiers, reveals aspects of the regulatory mechanisms of transient redox changes of mitochondrial and extramitochondrial nicotinamide adenine dinucleotides. The injection of ADP in the course of an NAD(P)H transient produced by glycolytic (e.g. glucose 6-phosphate, G6P) or mitochondrial (e.g. malate) substrate leads to sharp reoxidation (state III, Chance and Williams, 1955), followed by a spontaneous state III to IV transition, and an ultimate return to original redox steady state. The response to ADP alone is biphasic, i.e. a small oxidation-reduction transient followed by a larger reverse transient. Similarities between responses to injected ATP and ADP suggest possible intracellular interconversions. Sequential injections of glycolytic and Krebs cycle substrates into the same cell, produce a two-step NAD(P) response, possibly revealing the intracellular compartmentation of this coenzyme. A two-step NAD(P)H response to sequentially injected fructose 1,6-diphosphate and G6P indicates the dynamic or even structural compartmentation of glycolytic phosphate esters in separate intracellular pools. The intracellular regulation and compartmentation of bioenergetic pathways and cell-to-cell metabolic inhomogeneities provide the basis on which the quantitative biochemistry of the intact living cell may be reconciled with these in situ findings.

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Twenty-one patients with unresectable non-small cell lung cancer (NSCLC), 11 with stage III M0, five with malignant pleural effusion, and five with a single resectable metastasis were treated with multimodality therapy. All received two to three cycles of preoperative chemotherapy with a new sequential combination of cisplatin (50 mg/m2 IV X 1) followed by 5-FU infusion (40 mg/m2/hr X 72) and etoposide (80 mg/m2/day X 3). Thirteen of 21 (62%) had a partial response, and three (14%) had a minor response to chemotherapy. Of the 19 who underwent surgical exploration, 17 were confirmed to have NSCLC. Ten patients with NSCLC and one with choriocarcinoma were rendered disease free by resection of the primary tumor and lymph nodes. Six received intra- and/or perioperative interstitial therapy with 125I and/or 192Ir. Another patient was treated with 32P. Postoperative external radiotherapy was administered in 15 patients, and adjuvant chemotherapy was administered in ten. This multimodality therapy was well tolerated, safe, and highly effective, resulting in excellent palliation even in patients with pleural effusion and metastasis. The most promising results were in unresectable stage III M0 with a partial response rate of 82% following neoadjuvant chemotherapy and a complete response rate of 73% after surgery. In this group, median survival has not yet been reached and will exceed 12 months.

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