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5-Azacytidine and several of its analogues are known to inhibit DNA methylation, alter gene expression, and inhibit cell growth. We report a Phase II study in which we investigated the antineoplastic activity of 5,6-dihydro-5-azacytidine and its induction of fetal hemoglobin synthesis when given by a 5-day continuous i.v. infusion of 1650 mg/m2/day that was repeated every 21 days. Fetal hemoglobin was measured in all patients; increased synthesis was found in 13 of the 17, in the absence of clinically significant anemia. Of the four patients who did not develop increased fetal hemoglobin, three had only one cycle of therapy. Fourteen patients with bronchogenic carcinoma were treated, and ten were evaluable for disease response. Five patients had disease stability of 2 or more mo, and five progressed on treatment. Three additional patients with mesothelioma were treated, and the two who were evaluable for disease response had stabilization of their disease. Fifteen of the 17 patients who received 5,6-dihydro-5-azacytidine developed a pleuritic-type chest pain, 12 had abnormal electrocardiograms, and four developed positive anti-nuclear antibodies. No significant hemopoietic, hepatic, or renal toxicities were observed. This study demonstrates that 5,6-dihydro-5-azacytidine in the dose and schedule used has no significant therapeutic activity in the treatment of lung cancer but does possess an unusual spectrum of clinical toxicities as well as the property of inducing fetal hemoglobin synthesis.

Seventeen patients with small-cell lung cancer refractory to combination chemotherapy were entered in a study of VP-16 and infusional Ara-C. All patients were evaluable for response and 14 were evaluable for toxicity (three deaths that occurred after the first cycle of therapy were due to progressive tumor, and toxicity could not be evaluated in these three patients). Ara-C was given as a continuous intravenous infusion of 45 mg/m2/day for 72 h; VP-16 was given as three daily intravenous bolus doses of 50 mg/m2 at hours 12, 36, and 50 of the 72-h Ara-C infusion. Because of excessive myelotoxicity in the first six patients, the last 11 patients began treatment at a lower dose of Ara-C, 25 mg/m2/day. Six of 17 patients had previously been exposed to VP-16 as part of their initial chemotherapy regimen. The 17 patients received 32 cycles of therapy. Myelotoxicity was severe, with nadir granulocyte counts less than 500/microliters or platelet counts less than 30,000/microliters in four treatment cycles (including two at the lower Ara-C dose). No patient experienced an objective response to this therapy. We conclude that the combination of VP-16 and infusional Ara-C at these doses is excessively toxic and does not warrant further investigation in refractory small-cell lung cancer.

The pharmacokinetics of the active and inactive diastereoisomers of leucovorin and its active metabolite, 5-methyltetrahydrofolate (5-CH3-THF) were studied after iv injection of leucovorin in normal human subjects at a dose of 28 mg/m2, and in patients given 500 mg/m2 daily by constant iv infusion for a 5.5 day period. In both studies the plasma half-life (t1/2) of the active isomer, L-formyltetrahydrofolate (CHO-THF), was only 32 to 35 minutes, whereas the inactive isomer, D-CHO-THF had a plasma t 1/2 of 352 to 485 minutes. During constant infusion, the plasma levels reached plateaus of 2.33 and 37.5 microM for L-CHO-THF and D-CHO-THF, respectively. The inactive isomer was cleared from plasma only by urinary excretion of the unchanged drug. The active isomer was also excreted unchanged in the urine but in addition was extensively metabolized to the active metabolite L-5-CH3-THF. The active metabolite achieved a plasma level of 4.85 microM during constant infusion and appeared to have a longer t 1/2 after constant infusion than was observed after iv injection. Furthermore a larger apparent volume of distribution (Vd) of 5-CH3-THF was obtained in the constant infusion study. These findings suggest that constant iv infusion of large doses of leucovorin can considerably expand the intracellular pools of active folate. The consequence of the extensive accumulation of the inactive isomer, D-CHO-THF, is not known. However, the small Vd of D-CHO-THF suggests that it does not extensively accumulate in tissues.

The water-soluble derivative of vitamin K, menadiol sodium bisulfite (K3), and the related anticoagulant dicumarol, inhibited growth of murine leukemia L1210 in liquid suspension culture. K3, but not dicumarol, cytotoxicity was abrogated by 1 mM cysteine. Isobolographic analysis of the effect of K3-dicumarol combinations, in the concentration ranges between 5 and 75 microM, on L1210 growth, indicated synergy between the two drugs. K3 (10 microM) caused a 3-fold stimulation of KCN-resistant O2 consumption by L1210 cells; addition of 50 microM dicumarol did not enhance KCN-resistant O2 consumption further, suggesting that K3-dicumarol synergy in L1210 was not due to dicumarol-mediated augmentation of K3-semiquinone-free radical formation. We examined the effect of dicumarol addition on L1210 cellular metabolites known to be affected by K3, i.e., glutathione, NADPH and ATP. Dicumarol prevented the elevation of the glutathione pool caused by less than or equal to 18 microM K3. K3-dicumarol combinations depleted the NADPH pool significantly, at concentrations of each which did not affect the NADPH pool. No synergistic effect on the ATP pool was observed. Thus, although the mechanism of K3-dicumarol synergy vs. leukemia remained unclear, it was possible that effects on the glutathione and/or NADPH pools contributed. We also investigated the effect of K3 and dicumarol on 45Ca++ transport by L1210 cells because of their effects on glutathione. Neither drug affected 45Ca++ influx or efflux rate constants. However, equilibrium 45Ca++ uptake was suppressed by K3 at concentrations lower than those which depleted glutathione.

The intrinsic fluorescence properties of the anthracycline antitumor antibiotics were studied in an effort to understand how 14-valerate side chain substitution modulates drug associations with small unilamellar phospholipid vesicles (SUVs) under near physiological conditions. Drug location and dynamics in fluid-phase dimyristoylphosphatidylcholine (DMPC) bilayers were evaluated for several analogs; accessibilities of bound fluorophores to membrane-impermeable iodide were evaluated in quenching experiments, while the diffusive motions of these agents were studied using lifetime-resolved anisotropy plots. The bulky and hydrophobic valerate substituent was found to further hinder the rotations experienced by a bound drug molecule, with apparent limiting anisotropy (a infinity) values showing increases of 13-82% upon valerate group substitution. In addition, the bimolecular quenching rate constants (unit, 10(9) M-1.s-1) for membrane-bound adriamycin (1.4), N-trifluoroacetyladriamycin (0.4), and their corresponding valerate-substituted analogs (kq values of 1.1 and 0.5, respectively) reveal that the side chain is a weak modulator of fluorophore penetration into the bilayer, with stronger modulation being achieved through amino group substitution. Similar results were obtained for drugs bound to negatively-charged dimyristoylphosphatidylglycerol (DMPG) bilayers. Finally, comparison of the equilibrium binding affinities of the various congeners for electroneutral DMPC versus negatively-charged DMPG bilayers demonstrate that positively-charged parent anthracyclines display high levels of selective binding to negatively-charged phospholipids, unlike valerate-substituted analogs which display no such selectivity. The modulation of anthracycline-membrane interactions achieved through valerate substitution offers potential explanations, at least in part, for some of the novel biological properties of valerate-containing anthracyclines.

As of August 1984, 115 women with advanced breast cancer have been randomized to receive a combination of either cyclophosphamide, Novantrone (mitoxantrone) and 5-fluorouracil (CNF) or cyclophosphamide, Adriamycin (doxorubicin) and 5-fluorouracil (CAF). Seventy-one percent of all patients were post-menopausal and 44% of CNF patients and 57% of CAF patients were estrogen receptor (ER) negative. Slightly over 30% of all patients had received hormonal therapy or chemotherapy in an adjuvant setting. Hematologic toxicity was similar in regard to platelet counts but slightly lower nadirs were experienced with CNF therapy than with CAF. However, there were fewer dosage decreases with CNF. Significantly less nausea and vomiting were observed with the CNF regimen compared to CAF. Moreover, alopecia was reduced appreciably in patients who received CNF. The response rate to CNF for the first 38 eligible and evaluable patients was 42%, and for 53 eligible and evaluable patients who received CAF the response rate was 45%, a non-significant difference. Median response durations were similar also, 140 days for CNF and 168 days for the CAF regimen. Time to treatment failure was similar for both regimens. CNF is an effective regimen for patients with advanced breast cancer, with less toxicity than CAF.

In the accompanying paper (Davies, K. J. A., and Doroshow, J. A. (1986) J. Biol. Chem. 261, 3060-3067), we have demonstrated that anthracycline antibiotics are reduced to the semiquinone form at Complex I of the mitochondrial electron transport chain. In the experiments presented in this study we examined the effects of doxorubicin (Adriamycin), daunorubicin, and related quinonoid anticancer agents on superoxide, hydrogen peroxide, and hydroxyl radical production by preparations of beef heart submitochondrial particles. Superoxide anion formation was stimulated from (mean +/- S.E.) 1.6 +/- 0.2 to 69.6 +/- 2.7 or 32.1 +/- 1.5 nmol X min-1 X mg-1 by the addition of 90 microM doxorubicin or daunorubicin, respectively. However, the anthracycline 5-iminodaunorubicin, in which an imine group has been substituted in the C ring quinone moiety, did not increase superoxide production over control levels. In the presence of rotenone, initial rates of oxygen consumption and superoxide formation were identical under comparable experimental conditions. Furthermore, H2O2 production increased from undetectable control levels to 2.2 +/- 0.3 nmol X min-1 X mg-1 after treatment of submitochondrial particles with doxorubicin (200 microM). The hydroxyl radical, or a related chemical oxidant, was also detected after the addition of an anthracycline to this system by both ESR spectroscopy using the spin trap 5,5-dimethylpyrroline-N-oxide and by gas chromatographic quantitation of CH4 produced from dimethyl sulfoxide. Hydroxyl radical production, which was iron-dependent in this system, occurred in a nonlinear fashion with an initial lag phase due to a requirement for H2O2 accumulation. We also found that two quinonoid anti-cancer agents which produce less cardiotoxicity than the anthracyclines, mitomycin C, and mitoxantrone, stimulated significantly less or no hydroxyl radical production by submitochondrial particles. These experiments suggest that injury to cardiac mitochondria which is produced by anthracycline antibiotics may result from the generation of the hydroxyl radical during anthracycline metabolism by NADH dehydrogenase.

We have established a variant of the human breast cancer cell line MCF7, designated MCF7/H2O2, which is 5-fold resistant to H2O2 by clonogenic assay. The specific activity of the H2O2 disposal enzyme catalase was elevated 3-fold in MCF7/H2O2; activities of other antioxidant enzymes, including glutathione peroxidase and superoxide dismutase, were not increased. The steady-state level of catalase mRNA was only slightly elevated (approx. 1.6-fold) in MCF7/H2O2 cells; however, degradation of catalase mRNA was markedly retarded in MCF-7/H2O2 compared to MCF-7 (82% of catalase mRNA remained 24 h after inhibition of RNA synthesis by actinomycin D in MCF-7/H2O2 vs. 32% in MCF7). The degradation rates of superoxide dismutase mRNA and 28 S ribosomal RNA were not reduced in MCF-7/H2O2; however, the rate of degradation of another mRNA species, beta-actin, was also significantly decreased. These data suggest that resistance to H2O2 in MCF7/H2O2 cells is mediated by elevated catalase activity which can be explained by stabilization of certain mRNA species, including catalase mRNA.

The cytotoxicity of the clinically important antineoplastic quinones doxorubicin, mitomycin C, and diaziridinylbenzoquinone for the Ehrlich ascites carcinoma was significantly reduced or abolished by the antioxidant enzymes catalase and superoxide dismutase, the hydroxyl radical scavengers dimethyl sulfoxide, diethylurea, and thiourea, and the iron chelators deferoxamine, 2,2-bipyridine, and diethylenetriaminepentaacetic acid. However, tumor cell killing by 5-iminodaunorubicin, a doxorubicin analog with a modified quinone function that prohibits oxidation-reduction cycling, was not ameliorated by any of the free radical scavengers tested. Furthermore, treatment of intact tumor cells with doxorubicin, mitomycin C, and diaziridinylbenzoquinone but not 5-iminodaunorubicin generated the hydroxyl radical, or a related chemical oxidant, in vitro in a process that required hydrogen peroxide, iron, and intact tumor cells. These results suggest that drug-induced hydrogen peroxide and hydroxyl radical production may play a role in the antineoplastic action of redox active anticancer quinones.

In this study, 50 patients were randomly assigned to treatment with 5-fluorouracil (FUra) or FUra plus high-dose continuous-infusion folinic acid. Five of 27 evaluable patients in the FUra group versus 10 of 21 patients in the FUra plus folinic acid arm of the study had objective partial remissions, P = 0.02. Time to progression was 3.9 months for FUra and 8.0 months for FUra and folinic acid, P = 0.006; however, median survivals (11.9 versus 14.5 months) were not different in this crossover study. Toxicity in both treatment arms was mild, although patients receiving FUra plus folinic acid experienced significantly more stomatitis than patients treated with FUra alone. This study suggests that high-dose, continuous-infusion folinic acid, which produces a steady-state level of biologically active folates of 10 microM, significantly increases the therapeutic activity of FUra.

The endogenous defenses of the mouse heart against reactive oxygen metabolites were investigated. The activities of three enzymes capable of detoxifying activated oxygen were determined in both the heart and liver; cardiac muscle contains 150 times less catalase and nearly four times less superoxide dismutase than liver. Glutathione peroxidase activities were, however, similar to the two tissues. Assay of glutathione peroxidase in the heart after 6 wk of selenium depletion with both hydrogen peroxide and cumene hydroperoxide as substrates revealed a >80% drop in enzyme activity and gave no indication that murine cardiac tissue contains nonselenium-dependent glutathione peroxidase. The selenium-deficient state, which was characterized by markedly decreased cardiac glutathione peroxidase levels, led to significantly enhanced doxorubicin toxicity at a dose of 15 mg/kg i.p. Doxorubicin administration in selenium-sufficient animals resulted in a dose-dependent decrease in cardiac glutathione peroxidase activity; the decrease in enzyme activity lasted 72 h after 15 mg/kg i.p. In contrast, cardiac superoxide dismutase and hepatic superoxide dismutase and glutathione peroxidase were unaffected by this dose of doxorubicin. These results suggest that the major pathway in cardiac tissue for detoxification of reactive oxygen metabolites is via the concerted action of superoxide dismutase and selenium-dependent glutathione peroxidase. The latter enzyme may be depleted by a selenium-deficient diet or doxorubicin treatment, leaving the heart with limited mechanisms for disposing of hydrogen peroxide or lipid peroxides.

The metastatic spread of a trnasplantable murine ovarian cancer is similar to the spread of ovarian cancer in patients with advanced disease, making it a useful model to investigate novel experimental therapies. The ip inoculation of 10(6) tumor cells into C3HeB/FeJ mice leads to the formation of ascites, sub-diaphragmatic tumor deposits, intra-abdominal tumors, and death within 25 days. Adriamycin (ADR) was found to be an active agent against this murine ovarian cancer. The effects of ADR were dependent upon the route of administration. A single ip LD10 dose of ADR (5 mg/kg) administered 2 days after inoculation with 10(6) tumor cells produced long-term survival (greater than 60 days) in 70% of the mice. An iv LD10 dose had no effect on survival. The survival advantage of ip ADR (compared to the iv route) was found to be related to: (a) a greater suppression of DNA synthesis in the tumor; (b) a rapid penetration of ADR into the nuclei of ascites tumor cells and into sub-diaphragmatic tumor deposits; and (c) significantly higher levels of ADR in tumor cells following ip administration. The ip route may also be less cardiotoxic since the peak levels after an iv dose were three times greater than after an equal ip dose. If local toxicity does not prove to be a major problem, then ip ADR may be a useful mode of therapy in patients with intra-abdominal tumors.

Eleven patients treated with a 5.5-day continuous i.v. infusion of 500 mg/m2/day of (6R,S)-folinic acid in combination with daily bolus 5-fluorouracil had a median steady-state plasma concentration of 3.25 microM (6S)-folinic acid (the bioactive diastereoisomer). The bioactive metabolite (6S)-5-methyltetrahydrofolic acid, analyzed in six patients, reached a median steady-state plasma concentration of 5.7 microM. The lowest plasma concentrations at steady-state were 1.86 microM (6S)-folinic acid and 3.12 microM (6S)-5-methyltetrahydrofolic acid. These concentrations are above the minimum concentrations shown by other investigators to produce synergism between (6R,S)-folinic acid and 5-fluorouracil in vitro. The median steady-state plasma concentration of (6R)-folinic acid was 38.2 microM, more than 10 times the concentration of (6S)-folinic acid. Along with other plasma pharmacokinetic parameters, terminal half-lives were estimated for (6S)-folinic acid (median, 45.4 min), (6R)-folinic acid (median, 388 min), and (6S)-5-methyltetrahydrofolic acid (median, 446 min). Investigation of the renal pharmacokinetics confirmed the marked difference in the renal clearance of the two diastereoisomers of folinic acid which had been observed after low doses of (6R,S)-folinic acid (J. A. Straw, D. Szapary, and W. T. Wynn, Cancer Res., 44: 3114-3119, 1984). However, the low renal clearance of (6R)-folinic acid (median, 8.2 ml/min/m2) was attributable to the extensive binding of (6R)-folinic acid to plasma proteins (median, 8.7% free), not to reabsorption in the kidney.

Changes in blood pressure, renal function, and fluid balance were studied in 12 patients receiving intravenous recombinant interleukin-2 (IL-2) (100,000 units/kg every eight hours) over five days for treatment of metastatic melanoma and renal and colorectal cancers. The IL-2 regimen produced progressive hypotension, azotemia, and sodium avidity (fractional excretion of sodium = 0.20 +/- 0.07 percent) despite massive fluid administration (mean: 18.4 liter per five days) and weight gain (mean: 4.0 kg). Plasma renin activity rose. Hypoalbuminemia developed rapidly (3.6 +/- 0.1 g/dl to 2.2 +/- 0.1 g/dl, p less than 0.01) with widespread edema formation despite normal central venous pressures. Hematocrit did not change during the IL-2 period, consistent with a "capillary-leak." Hemodynamic and renal functional changes reversed after the IL-2 regimen was discontinued, but hypoalbuminemia and elevated urinary n-acetyl-glucosaminidase levels persisted after six days. These studies demonstrate widespread hemodynamic and vascular effects of IL-2 administration that limit its safe use and suggest a possible role for the lymphokine in mediating cardiovascular instability under other circumstances, such as endotoxic shock.

In this study, the authors examined the effect of the anti-tumor agent Adriamycin, a known cardiotoxin, on mouse heart, diaphragm, and gastrocnemius muscle. Using an established model of Adriamycin cardiac toxicity, they found that 4 days after the intraperitoneal injection of 20 mg/kg of Adriamycin, characteristic heart lesions, including vacuolation of the sarcoplasmic reticulum, interstitial edema, and mitochondrial degeneration, were demonstrated in all treated animals. Furthermore, similar, but much more severe, myocyte damage was demonstrated in the diaphragm; muscle toxicity followed a decreasing gradient of injury from the peritoneal to the thoracic surface of the tissue. On the other hand, treatment with Adriamycin resulted in an increase in the size and number of lipid droplets in the red fibers of the gastrocnemius muscle without any other ultrastructural evidence of drug-induced damage to myocytes. An examination of the pharmacokinetics and metabolism of Adriamycin after intraperitoneal treatment revealed that relative drug levels in muscle (diaphragm much greater than heart much greater than gastrocnemius) paralleled the degree of ultrastructural damage observed. This study indicates that treatment with Adriamycin can produce significant injury to non-cardiac muscle in a fashion that strongly resembles the characteristic pattern of Adriamycin-related damage to the heart, and that the degree of myocyte damage is apparently dependent upon the Adriamycin concentration in the tissue.

This study investigated the effect of the anthracycline antibiotics on oxygen radical metabolism by cardiac mitochondrial reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase [NADH:(acceptor) oxidoreductase, EC 1.6.99.3]. Superoxide formation by NADH dehydrogenase after anthracycline treatment appeared to follow saturation kinetics with an apparent Km of 167.3, 73.3, 64.0, or 47.6 microM for doxorubicin, daunorubicin, rubidazone, or aclacinomycin A, respectively. Superoxide formation by NADH dehydrogenase after doxorubicin treatment occurred with a pH optimum of 7.6 and was accompanied by the production of hydrogen peroxide. Furthermore, drug-related hydroxyl radical generation was detected in this enzyme system by the evolution of methane gas from dimethyl sulfoxide. Hydroxyl radical production proceeded only in the presence of superoxide anion, hydrogen peroxide, and trace amounts of iron or a chelate of iron and ethylenediaminetetraacetate and thus was probably the by-product of a transition metal-catalyzed Haber-Weiss reaction. The antitumor agents mitoxantrone and actinomycin D did not significantly enhance reactive oxygen metabolism by NADH dehydrogenase. These results suggest that the specific activation of the anthracycline antibiotics to free radicals by NADH dehydrogenase leads to the formation of a variety of reactive oxygen species that may contribute to the mitochondrial toxicity of these drugs.

This study investigated the antiemetic properties of four different doses of prochlorperazine (10 mg, 20 mg, 30 mg, 40 mg) when given randomly to patients receiving four cycles of the same dose of cisplatin-based chemotherapy. Prochlorperazine was given to 71 patients by slow intravenous infusion 30 minutes before and 3 and 6 hours after the start of cisplatin chemotherapy. The higher doses of prochlorperazine proved to be effective in the control of cisplatin-induced emesis. For the 20 patients who completed all 4 study cycles of treatment, a relationship was discerned between the dose of prochlorperazine administered and the antiemetic effect. When all 71 patients were analyzed in terms of the results of the first cycle of chemotherapy, a significant dose-response effect was also found. Overall toxic reactions in 82 treatment cycles using either 30 mg or 40 mg of prochlorperazine were dystonia (1 patient), restlessness (2), hypotension (3), and drowsiness (12). This study demonstrates that higher-than-conventional doses of prochlorperazine have an impressive antinauseant effect with only moderate toxicity.

Study Objective: To confirm the antitumor efficacy of treatment with interleukin-2 and lymphokine-activated killer cells in patients with metastatic renal cancer., Design: Nonrandomized, phase II clinical trial., Setting: Tertiary care units in university medical centers., Patients: Consecutive trial of 35 patients with metastatic or unresectable renal cell cancer who have bidimensionally measurable disease, performance status 0 or 1, and normal function of all vital organs. Thirty-two patients completed interleukin-2 priming and received at least one lymphokine-activated killer cell infusion. Three patients were removed from the study and did not receive infusion of cells secondary to rapid tumor progression or toxicity., Interventions: Patients initially received recombinant interleukin-2, 100,000 units/kg body weight every 8 hours, on days 1 to 5 in a priming phase to stimulate lymphokine-activated killer cell precursors and effector activity in vivo. Leukapheresis was done on days 8 to 12 and lymphocytes were cultured in vitro with interleukin-2 for 3 to 4 days to amplify lymphokine-activated killer cell activity. Finally, interleukin-2, 100,000 units/kg every 8 hours, was infused with cultured cells on days 12 to 16. All doses of interleukin-2 and lymphokine-activated killer cells were administered in intensive care units., Measurements and Main Results: The mean number of doses of interleukin-2 administered during the priming phase was 12.9 +/- 0.4; the mean number of lymphokine-activated killer cells reinfused was 7.0 +/- 0.6 X 10(10); and the mean number of interleukin-2 doses administered during the last phase was 10.2 +/- 0.6. The overall objective response rate was 16%; two patients had complete responses and three patients had partial responses with greater than 50% reduction of all measurable tumor. The complete responders remain disease-free at 12 and 9 months. Two partial responders have not had tumor regrowth at 16 and 15 months. The third partial responder relapsed at 4 months. Toxicity was severe but generally of short duration and manageable. There were no treatment-related deaths. Hypotension, weight gain, anemia, and elevations of serum creatinine levels and liver enzymes were common. Two patients required intubation; one patient had a myocardial infarction., Conclusions: This phase II study confirms the antitumor activity of interleukin-2 and lymphokine-activated killer cell therapy in patients with metastatic or unresectable renal cell cancer. Response rates, especially complete remission rates, are comparable or better than rates achieved with other forms of therapy.

This study investigated the effect of doxorubicin-related oxygen radical formation on Ca2+ uptake by rat heart sarcoplasmic reticulum vesicles. Enzymatic activation of doxorubicin by cardiac NADH dehydrogenase produced a dose-related inhibition of Ca2+ uptake that was enzyme- and cofactor-dependent and that was inhibited by catalase, various hydroxyl radical scavengers, and the iron chelator deferoxamine. Furthermore, inhibition of Ca2+ uptake paralleled the production of the hydroxyl radical by NADH dehydrogenase after doxorubicin treatment. These results suggest that doxorubicin-stimulated reactive oxygen metabolism can alter Ca2+ transport by cardiac sarcoplasmic reticulum and may represent one pathway involved in the cardiac toxicity of this potent antineoplastic agent.

Hepatic metastases occur rarely in epithelial ovarian carcinoma and also appear to be unusual in malignant stromal tumors of the ovary (granulosa cell tumors). Recently two patients with extensive hepatic metastasis from this primary tumor, were treated. Review of the experience at the City of Hope National Medical Center provided three additional patients with a confirmed diagnosis of granulosa cell tumor of the ovary, one of whom is alive and disease-free. A review of clinical and pathologic data revealed that both of the other patients died of their disease and had hepatic metastases proven at autopsy. Hemorrhagic events complicating the clinical course of these patients were frequent. It is believed that the frequency of hepatic metastasis in granulosa cell tumor of the ovary may be higher than has been appreciated in the past, and that the cystic-hemorrhagic nature of these lesions contributes to the morbidity and mortality associated with granulosa cell tumors of the ovary.

Based on the demonstration of in vitro and in vivo synergy between cytosine arabinoside (Ara-C) and cis-diamminedichloroplatinum (CDDP), we designed a Phase II trial of Ara-C plus CDDP for patients with advanced squamous cancers of the head and neck and esophagus. Sixteen patients were treated on a unique schedule of continuous-infusion Ara-C, 30 mg/m2/day over 72 h, plus CDDP, 30 mg/m2/day at hours 12, 36, and 60 of the Ara-C infusion. The objective response rate was 38% (95% confidence limits 14-62%), with two patients achieving complete clinical and radiographic response (9 and 27+ months duration) and four partial responses (median duration 4 months, range 1-7 months). There was no CDDP-related nephro- or neurotoxicities, but a flu-like syndrome of anorexia and asthenia was common. Myelosuppression was the dose-limiting toxicity, necessitating Ara-C dose adjustments in 11 cycles of therapy and leading to fatal sepsis in one patient. We conclude that the activity of this combination, though comparable to that of other CDDP-containing regimens, offers no significant therapeutic advantage, and given the excessive hematologic toxicity, should not be investigated further.

Since patients exhibit both acute and chronic cardiac toxic effects from Adriamycin, the salient characteristics of the reported animal models for both acute and chronic cardiotoxicity are reviewed. This review reveals that while the pathology of these models is often well-characterized, the physiologic, biochemical, and nutritional variables are, in general, poorly defined.

Eighty-nine patients with advanced measurable metastatic renal cell carcinoma were entered into a prospective randomized trial comparing alpha-interferon to gamma-interferon and to the combination. The trial was performed in order to confirm the activity of gamma-interferon and assess the potential clinical synergism. Response rates were 5, 10, and 5%, respectively. The low response rate may have been due to the inability to raise the doses of the interferons to higher levels. Clinical synergy at this dose, route, and schedule of administration in renal cell carcinoma does not exist.

The effect of the antitumor antibiotic doxorubicin on glutathione and glutathione disulfide levels in mouse heart and liver has been evaluated. The glutathione content of hepatic and cardiac tissue from saline-treated controls exhibited a statistically significant diurnal variation. Doxorubicin administration produced a dose-related decrease in hepatic glutathione which was not blocked by pretreatment with the free radical scavenger alpha-tocopherol; a lesser drop in cardiac glutathione was also documented. These changes may play an important role in the metabolism and toxicity of doxorubicin.

One hundred patients were entered on a randomized prospective protocol to evaluate the effectiveness of hepatic resection of single as well as multiple hepatic metastases from colorectal primaries in combination with continuous hepatic artery infusion (CHAI) of fluorodeoxyuridine (FUDR) via the implantable pump (Infusaid, Intermedics Infusaid Inc., Norwood, MA). The eight patients with single metastases were randomized to hepatic resection alone (three patients) or hepatic resection plus CHAI (five patients). The 22 patients with resectable multiple metastases were randomized between receiving CHAI only (12) or CHAI after resection of all metastases (10). Patients who had positive portal lymph nodes (14) were all treated with CHAI. Patients with unresectable metastases (31) were randomized between intravenous 5-fluorouracil or CHAI of FUDR. FUDR was alternately infused every 2 weeks at a dose of 0.1 mg/kg/24 hour escalated to .3 mg/kg/24 hour with heparinized saline as the alternative infusate. The median follow-up of all patients was 20 months. All patients with multiple resectable metastases had at least a partial response (PR) to the CHAI (PR defined as greater than or equal to 50% decrease of the sum of the products of the diameters of the lesions measured on computerized axial tomography scans), and four patients given CHAI only had no metastases in the liver on relaparotomy. Patients with resection and CHAI had a better survival than patients with CHAI only; however, the difference was not significant. Patients with positive portal nodes and CHAI had a lower PR (36%) than patients with unresectable disease treated with CHAI (52%). Patients with positive portal nodes or metastatic disease outside of the liver did significantly worse than patients with unresectable disease treated with CHAI.