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Background: The possible link between psychological factors and length of cancer survival has generated a literature of contradictory findings. Associations usually have not been found when general psychological symptoms are assessed. Associations usually have been found for predictors related to expressive versus repressive emotional coping (e.g., depression, 'fighting spirit,' hostility, and type C personality); however, even these associations have been relatively small, when compared with those for medical factors. Yet few studies have adequately controlled for medical and treatment-related factors. Purpose: Within a Cancer and Leukemia Group B (CALGB) national clinical trial of four adjuvant therapy regimens for stage 11 breast cancer (CALGB 8082), this study prospectively examined the contribution of potential psychological predictors to length of disease-free and overall survival over a 15-year period. Methods: Subjects were 280 women with stage 11 breast cancer, out of a total of 899, who were randomly assigned to receive CMFVP (cyclophosphamide-methotrexate-fluorouracil-vincristine-prednisone) for two 6-week cycles or six 4-week cycles, then subsequently randomly assigned to receive or not to receive VATH (vinblastine-doxorubicin-thiotepa-fluoxymesterone). Subjects were recruited during the period between October 1980 and August 1984, inclusive, and followed until January 1996. Prior to chemotherapy, psychological symptoms were assessed using the Symptom Check List-90-Revised (SCL-90-R). SCL-90-R scores were trichotomized into categories representing high, medium, and low distress. Basic base-line sociodemographic data (including age, ethnicity, education, and marital status) and medical data (including lymph node status, estrogen receptor status, menopausal status, and performance status) were collected. Subjects with psychosocial data differed from those without psychosocial data solely in their higher percentage of classification in the mild limitation category of the Zubrod (Eastern Cooperative Oncology Group) performance status rating (subjects with psychosocial data: 14%; subjects without psychosocial data: 8%). Results: In stepwise Cox regression analyses that controlled for sociodemographic and medical variables, there was no significant predictive effect of the level of distress (as measured by the SCL-90-R trichotomized scores) on length of disease-free and overall survival of the study subjects. Risk ratios for low versus high distress were 1.01 (95% confidence interval [CI] = .62-1.66) for disease-free survival and 1.03 (95% CI = 0.58-1.82) for overall survival. Conclusions: This study failed to provide evidence that psychological factors contributed to length of disease-free or overall survival of women who received adjuvant chemotherapy (either CMFVP alone or CMFVP followed by VATH) for treatment of stage 11 breast cancer. Implications: In the context of far more potent medical factors, the contribution of psychological factors to disease-free and overall survival is likely to be relatively small. Future research should focus on specific theory-driven predictors rather than on general psychological symptoms. Moreover, it should be based on clinical studies using a controlled, prospective design, in which the effects of medical factors may be distinguished and psychological predictors are clear antecedents of survival outcomes.

Ovarian cancer patients undergoing chemotherapy may benefit from a protein treatment that corrects chemotherapy-induced low white cell and platelet counts. Researchers injected the fusion protein PIXY321 into 34 ovarian cancer patients after the second cycle of chemotherapy with cyclophosphamide and carboplatin. The main side effects were redness and hardness at the injection site, and fatigue, fever and loss of appetite. PIXY321 treatments were not effective in increasing white blood cell and platelet counts after multiple cycles of chemotherapy. PIXY321 treatments may be safe and well tolerated by ovarian cancer patients who are also receiving cyclophosphamide and carboplatin. But they may not be able to support larger doses of chemotherapy.

The effectiveness of adding the anticancer agents bleomycin or methotrexate to standard therapy for non-Hodgkin's lymphoma, a cancer of the lymphatic system, was assessed in afflicted patients recruited between 1978 and 1985. The study included 177 patients with diffuse large cell lymphoma (DLCL) and 97 patients with intermediate-grade non-Hodgkin's lymphoma. The patients received three courses of therapy with cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) every three weeks, with or without bleomycin. Patients who responded to initial treatment were given methotrexate in a high dose of three grams (gm) per square meter of body area per week or standard dose of 30 milligrams (mg) per square meter per week, for three weeks. This was followed by three additional courses of CHOP. Bleomycin or high dose methotrexate did not improve responses of patients with DLCL, who had complete response rates ranging from 47 to 51 percent. The average duration of survival was 12 months, and the survival rate at five years was 27 percent. The addition of bleomycin or methotrexate to standard treatment with CHOP did not improve survival of patients with non-Hodgkin's lymphoma. The five-year survival rate was 47 percent in patients with follicular large cell lymphoma. Survival rates were poorest among patients with other subtypes of diffuse or widespread lymphomas. (Consumer Summary produced by Reliance Medical Information, Inc.)

Malignant mesothelioma was once a relatively rare cancer, but is now increasing due, at least in part, to environmental exposure to asbestos. Research is uncovering other etiologic agents as well, including radiation and zeolites, a class of silicate minerals sometimes used in water softeners and other ion-exchange applications. The majority of patients with malignant mesothelioma are over 40 years of age. Of 181 patients seen with malignant mesothelioma, 11 were under the age of 40. Of these, 10 were available for study and follow-up. Seven patients had histories of asbestos exposure. The median age at initial exposure was 10 years, and the median duration of exposure was 10 years. The median latency, or the time between initial exposure and diagnosis, was 19 years. When compared to mesothelioma patients as a whole, the younger patients were slower to be diagnosed with the disease. The decreased incidence of cancer in this age group, and the rarity of mesothelioma, no doubt delay the consideration of this possibility when symptoms are seen in younger patients. Among these patients, the male to female ratio was 0.7 to 1.0, in marked contrast to other studies which have shown a preponderance of male cases. It is believed that these sex differences represent a difference in exposure to environmental asbestos rather than an increased susceptibility among men. The difficulty with diagnosis suggests that mesothelioma might be more common in patients under 40 than has been suspected, and that this diagnosis should be considered in cases of unidentified pleural or peritoneal disease. (Consumer Summary produced by Reliance Medical Information, Inc.)

Cardiac toxicity is a major limitation in the use of doxorubicin (and related anthracyclins). ON 1910.Na (Estybon, Rogersitib, or 1910), a substituted benzyl styryl sulfone, is equally active as doxorubicin against MCF-7 human mammary carcinoma xenografted into nude mice. 1910 augments the antitumor activity of doxorubicin when given simultaneously. Furthermore, when given in combination, 1910 protects against cardiac weight loss and against morphological damage to cardiac tissues. Doxorubicin induces inactivation of glucose response protein 78 (GRP78), a principal chaperone that serves as the master regulator of the unfolded protein response (UPR). Inactivated GRP78 leads to an increase in misfolded proteins, endoplasmic reticulum (ER) stress, activation of UPR sensors, and increased CHOP expression. 1910 prevents the inactivation of GRP78 by doxorubicin, and the combination, while more active against the tumor, protects against cardiac weight loss.

Sodium (E)-{N-[2-methyloxy-5-(2′,4′,6′-trimethoxy-styrylsulfonyl) methylenephenyl]amino}acetate (C21H24NNaO8S, ON 01910.Na) is a novel, synthetic benzyl styryl sulfone, currently in phase I clinical trials in cancer patients. Our objective was to use electrospray mass spectrometry to determine, in intact complexes, the number of drug molecules bound to albumin and selected enzymes. Native and recombinant albumin incubated with the drug, at various molar ratios, revealed simultaneous and discontinuous progression of drug binding, yielding intact albumin-drug complexes containing up to 22 drug molecules. Comparable complex protein-drug patterns were obtained for several enzymes, e.g., carbonic anhydrase. Intact albumin-ON 01910 complexes were also found in all patient samples. The drug-binding profiles were comparable, but not identical, for increasing sampling times and different doses (400–1700 mg/m2). We concluded that the techniques developed are capable of detecting the simultaneous formation of intact protein-drug complexes and of determining the number of drug molecules bound to proteins. The results enhance our hypothesis that drug binding may lead to conformational changes in proteins that, in turn, account for the exclusion of specific binding complexes and may influence protein behavior and activity. Application of these techniques reveals new insights about the nature of the antineoplastic drug ON 01910 in patient plasma, and the information obtained may have significance in understanding drug delivery to tumors.

Hypoxia-induced up-regulation of vascular endothelial growth factor (VEGF) expression is a critical event leading to tumor neovascularization. Hypoxia stimulates hypoxia-inducible factor-1α (HIF-1α), a transcriptional activator of VEGF. Cyclooxygenase (COX)-2, an inducible enzyme that catalyzes the formation of prostaglandins (PGs) from arachidonic acid, is also induced by hypoxia. We reported previously that COX-2 inhibition prevents hypoxic up-regulation of VEGF in human prostate cancer cells and that prostaglandin E2(PGE2) restores hypoxic effects on VEGF. We hypothesized that PGE2mediates hypoxic effects on VEGF by modulating HIF-1α expression. Addition of PGE2to PC-3ML human prostate cancer cells had no effect on HIF-1α mRNA levels. However, PGE2significantly increased HIF-1α protein levels, particularly in the nucleus. This effect of PGE2largely results from the promotion of HIF-1α translocation from the cytosol to the nucleus. PGE2addition to PC-3 ML cells transfected with a GFP-HIF-1α vector induced a time-dependent nuclear accumulation of the HIF-1α protein. Two selective COX-2 inhibitors, meloxicam and NS398, decreased HIF-1α levels and nuclear localization, under both normoxic and hypoxic conditions. Of several prostaglandins tested, only PGE2reversed the effects of a COX-2 inhibitor in hypoxic cells. Finally, PGE2effects on HIF-1α were specifically inhibited by PD98059 (a MAPK inhibitor). These data demonstrate that PGE2production via COX-2-catalyzed pathway plays a critical role in HIF-1α regulation by hypoxia and imply that COX-2 inhibitors can prevent hypoxic induction of HIF-mediated gene transcription in cancer cells.

Arsenic trioxide (As2O3) has been found to induce apoptosis in leukemia cell lines and clinical remissions in patients with acute promyelocytic leukemia. In this study, we investigated the cytotoxic effect and mechanisms of action of As2O3in human tumor cell lines. As2O3caused inhibition of cell growth (IC50range, 3–14 μM) in a variety of human solid tumor cell lines, including four human non–small-cell lung cancer cell lines (H460, H322, H520, H661), two ovarian cancer cell lines (SK-OV-03, A2780), cervical cancer HeLa, and breast carcinoma MCF-7, as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometry analysis showed that As2O3treatment resulted in a time-dependent accumulation of cells in the G2/M phase. We observed, using Wright-Giemsa and 4′,6-diamidine-2-phenylindole-dihydrochloride staining, that As2O3blocked the cell cycle in mitosis. In vitro examination revealed that As2O3markedly promoted tubulin polymerization without affecting GTP binding to β-tubulin. Immunocytochemical and EM studies of treated MCF-7 cells showed that As2O3treatment caused changes in the cellular microtubule network and formation of polymerized microtubules. Similar to most anti-tubulin agents, As2O3treatment induced up-regulation of the cyclin B1 levels and activation of p34cdc2/cyclinB1 kinase, as well as Bcl-2 phosphorylation. Furthermore, activation of caspase-3 and -7 and cleavage of poly(ADP-ribose) polymerase and β-catenin occurred only in As2O3-induced mitotic cells, not in interphase cells, suggesting that As2O3-induced mitotic arrest may be a requirement for the activation of apoptotic pathways. In addition, As2O3exhibited similar inhibitory effects against parental MCF-7, P-glycoprotein–overexpressing MCF-7/doxorubicin cells, and multidrug resistance protein (MRP)-expressing MCF-7/etoposide cells (resistance indices, 2.3 and 1.9, respectively). Similarly, As2O3had similar inhibitory effect against parental ovarian carcinoma A2780 cells and tubulin mutation paclitaxel-resistant cell lines PTx10 and PTx22 (resistance indices, 0.86 and 0.93, respectively), suggesting that its effect on tubulin polymerization and G2/M phase arrest is distinct from that of paclitaxel. Taken together, our data demonstrate that As2O3has a paclitaxel-like effect, markedly promotes tubulin polymerization, arrests cell cycle at mitosis, and induces apoptosis. In addition, As2O3is a poor substrate for transport by P-glycoprotein and MRP, and non–cross-resistant with paclitaxel resistant cell lines due to tubulin mutation, suggesting that As2O3may be useful for treatment of human solid tumors, particularly in patients with paclitaxel resistance.

Development of multidrug resistance (MDR) is the major obstacle to successful cancer chemotherapy. We have developed Daudi human lymphoma cells that are 20-fold more resistant than the parent cell line to vincristine (VCR) by infecting cells with pHaMDR1/A retroviral vector (Daudi/MDR20). Three DNA sequences of anti-MDR1 hammerhead ribozymes (Rzs), one cleaving codon 196 of MDR1 mRNA (196MDR1-Rz), the second a stem II base-modified (U9 G9, U13 A13, G14 A14, A18 C18) Rz against codon 196 (196 MDR 1- sRz), and the third a stem II base-modified Rz directed against the -6~ -4 GUC sequence of the translation initiation site of the MDR1 mRNA (iMDR1-sRz), were synthesized and cloned into the retroviral vector N2A+tRNAiMet downstream of the RNA polymerase III promoter and adjacent to a tRNA gene sequence, forming the constructs N2A+tRNAiMet-196MDR1-Rz, N2A+tRNAMet-196 MDR1-sRz, and N2A+tRNAiMet-iMDR1-sRz. The three constructs were transfected into GP+envAM 12 cells for packaging the retroviral vectors. The supernatants containing the packaged retrovirus in high titers (1.1-2.5 x 10 5 CFU/ml as determined by infection of NIH 3T3 cells) were used to infect Daudi/ MDR20 cells. The iMDR1-sRz and 196 MDR1-sRz-transduced Daudi/MDR20 cells completely restored chemosensitivity to VCR and doxorubicin, and were accompanied by blocked expression of MDR1 mRNA and P-glycoprotein as well as overexpression of anti-MDR1 Rz. In a cell-free system, the chimeric tRNA-sRz molecules were more stable and had more efficient catalytic activities than the corresponding naked Rz molecules. The stem II base-modified Rz were also more stable and efficient in catalytic activities than the unmodified Rz molecules. The base modification in the Rz stem II structure and the development of chimeric tRNA-Rz molecules were identified to enhance the cleavage efficacy. The combination of these two factors, together with the use of a retroviral vector, appear to have contributed to the complete reversal of MDR.

The efficacy of the addition of intensive therapy with daunorubicin (45 mg/m2IV on days 1, 2, 3) to an otherwise identical induction program consisting of vincristine, prednisone, and L-asparaginase was assessed in 177 previously untreated adults (≥20 years of age) with acute lymphocytic leukemia (ALL). In the prospectively randomized phase of the investigation, 46 patients received daunorubicin in induction, whereas 53 did not. The two groups were otherwise comparable for pretreatment variables. A complete response was observed in 38/46 patients (83%) treated with daunorubicin, compared to 25/53 (47%) induced with vincristine, prednisone, and L-asparaginase alone (P= .003). The high response rate attributable to the use of the anthracycline was confirmed by the nonrandomized treatment of 78 subsequent patients, in whom a complete response rate of 76% was attained. A common program for central nervous system therapy and for maintenance therapy was employed in 103 patients achieving complete response. Maintenance consisted of cycles of 6-mercaptopurine (6-MP) and methotrexate with periodic reinforcement with vincristine and prednisone. Maintenance therapy proved to be minimally toxic. The average duration of complete response was 15 months and was not affected by the induction program employed. Approximately 25% of responders are projected to remain in continuing complete response for 36 months. The failure of the daunorubicin-containing programs to produce a higher percentage of long-term survivors, despite the higher complete response rates achieved, was thought to be due to the use of a maintenance program that was weak in intensity and dependent on reinforcement with vincristine and prednisone. These data clearly establish the increased effectiveness of vincristine, prednisone, L-asparaginase, and daunorubicin, as compared to this combination without daunorubicin, in the induction of complete response in adults with ALL. The results support the concept of an intensive, rather than a conservative, chemotherapeutic approach as the most appropriate strategy for the treatment of adult ALL.

Between 1974 and 1982, 273 patients with epithelial cancer of the ovary (International Federation of Gynaecology and Obstetrics Stages III and IV) were randomized in four therapeutic trials. In Trial I Adriamycin plus cisplatin versus cisplatin alone versus thiotepa plus methotrexate was tested. The superiority of Adriamycin plus cisplatin in producing the best response rate led to its use as the reference arm in subsequent trials. All investigational arms included cisplatin plus other drugs (cyclophosphamide, Adriamycin, hexamethylmelamine, and thiotepa) in various combinations. Eligibility for second look required complete clinical remission and completion of at least 10 cycles of chemotherapy. To date, 73 second-look operations have been performed on randomized patients. An additional 43 nonrandomized patients underwent second-look procedures and are analyzed separately. Between 40% and 46% of patients treated with cisplatin regimens had no disease at second look. Cell differentiation and volume of postoperative disease did not influence response.

Suramin, an organic polyanion with six sulphonic groups, is under clinical trials as an agent against hormone‐refractory prostate cancer. The drug binds strongly to serum albumin. The objectives were to use electrospray to measure the molecular masses of the intact complexes of albumin and suramin to determine the number of suramin molecules bound under different molar ratios, and to investigate the binding of suramin in human serum. With albumin in excess (2:1 to 25:1 ratio), only 1 and 2 bound suramins were found; with suramin excess (2:1 to 1000:1) up to 20 bound suramin molecules/albumin were found. Up to 5 bound suramins were found in human serum with 4:1 suramin:albumin ratio, which corresponds to recommended therapeutic doses (200–300 μg/mL). At 8:1 ratio, which would be toxic, complexes with up to ten bound suramin molecules were found, and unreacted albumin diminished. © 1998 John Wiley & Sons, Ltd.

Women treated by mastectomy for node-positive breast carcinoma were randomly assigned to receive an induction course and 2 years of maintenance chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) or CMF plus vincristine and prednisone (CMFVP). Five-hundred twenty-five evaluable patients were entered between 1975 and 1980. CMVFP was superior to CMF for patients with more than 3 positive nodes (p=0.01) with disease-free survival of 50% at 5 years with CMFVP compared with 36% with CMF. The advantage of CMFVP was not seen in patients with 1–3 positive nodes and was most marked in patients with 10 or more nodes. This suggests benefit from increased treatment with increasing disease burden. The superiority of CMFVP was more marked in postmenopausal patients (p=0.04) than in premenopausal (p=0.12). The advantage of CMFVP in disease-free survival is not yet apparent in overall survival.

Effects of human natural interferon a (nIFN) alone, human natural tumor necrosis factor a (nTNF) alone and their combination (OH-1) were tested on three human mesothelioma lines implanted in nude mice. Tumors were transplanted subcutaneously by trocar on treatment day -12. nIFN was given intraperitoneally (i.p.) at a dose of 2 × 107 or 2 × 108 IU kg-1 day-1, 5 days a week for 3 weeks. nTNF was given i.p. at a dose of 2 × 107 or 2 × 108 U kg-1 day-1 in the same schedule as that of nIFN. Tumor diameters were serially measured and tumor volumes were calculated. Antitumor effects were assessed by two methods: comparison of final tumor volumes in treated and control groups (T/C), and changes in median average total tumor volume. The treatment produced no clinically discernible toxicities. nIFN had strong inhibitory activity against all three human mesothelioma lines. nTNF alone had modest activity only at the high dose used. The combination of the two produced activity essentially similar to that produced by nIFN alone. High-dose nIFN may have a role as an active agent in the treatment of patients with mesothelioma.

Summary In order to gain a better understanding of the interaction between immunotoxins and tumor cells at the level of three-dimensional tumor mass, we evaluated the cell kill effects of monoclonal antimelanoma-antibody/ricin-A-chain immunotoxin (ITN) on melanoma cells in multicellular tumor spheroids (MTS) as well as the penetration of ITN into MTS. For Minor melanoma cells in monolayer the ITN exerted cytotoxic effects after as little as 1 h of exposure. Increasing exposure time resulted in progressive increases in cytotoxic activity. In contrast, the cell kill effects of ITN were markedly delayed and reduced when Minor cells were in MTS. The ITN cytotoxic effects on the melanoma MTS were more than 100 fold less than those in monolayer. Patterns of ITN-induced cytotoxicities for Minor and for another melanoma cell line, DND-1A, were comparable. The native ricin A was more active against PC-10 squamous lung cancer cells than Minor cells, whereas the ITN was more cytotoxic against Minor cells than PC-10 cells, thus exhibiting selectivity. An autoradiographic study revealed time-dependent penetration of radiolabeled ITN from the surface of Minor MTS into the core. Incubation for 1 h resulted in the penetration of ITN into only the two or three outer layers of the Minor MTS, and low grain counts. Prolonged exposure resulted in inhomogeneous penetration of ITN into almost the entire melanoma MTS. Penetration of ITN into PC-10 MTS was extremely poor. The reduced cytotoxicity of ITN on melanoma cells in MTS as compared to cells grown in monolayer appears to correlate with its inhomogeneous distribution in the MTS. The delayed cytotoxicity of ITN is also consistent with its slow penetration into the core of the MTS.

Homoharringtonine and harringtonine are esters of cephalotaxine and are naturally occurring alkaloids in certain coniferous trees in China. These compounds have been shown to have activity against certain types of leukemia in cell cultures, experimental animals, and initial clinical trials in China, and will undergo Phase I trials in several institutions. A gas chromatographic mass spectrometric technique was developed for the quantification of both drugs in serum. One drug serves as internal standard for the other. The drugs are extracted from serum with dichloromethane and are quantified by monitoring the protonated molecular ions of the trimethylsilyl derivatives obtained by chemical ionization (methane). Masses monitored are: m/z= 690 for homoharringtonine and m/z= 676 for harringtonine. Detection limit: 10 ng ml-1(20 nmol); reproducibility: 1.6–15.0% in the 0–200 ng ml-1range. Serum levels of harringtonine reached 145 ng mg-1upon intraperitoneal injection of 3mg kg-1in BDF-3 mice.

The maturation of malignant cells in response to differentiating agents is interesting as a model of normal differentiation. The response of a freshly explanted neoplastic population of phenotypically well-characterized lymphosarcoma cell leukemia blasts was studied after incubation with the differentiating agent TPA (12-0-tetradecanoyl-phorbol-13-acetate). Terminal differentiation was assessed by measuring the immunoglobulin secreted in culture supernatants and the production of intracytoplasmic immunoglobulins. Activation of the cells was studied using fluorescein-labeled monoclonal antibodies to various antigens in a flow cytometer (fluorescence-activated cell sorter) and sH-thymidine (SH-Tdr) incorporation was evaluated to measure DNA synthesis in cells grown in complete medium and TPA-supplemented medium. The events induced by TPA were characteristic of B cell maturation and included morphological changes to plasmacytoid cells, reduction in surface immunoglobulins (slgM, slgD, and K), enhancement of cytoplasmic immunoglobulin, and amplification of immunoglobulin secretion. Surface antigen changes were accompanied by increased SH-Tdr incorporation. Cell proliferation and differentiation appeared to be coupled and both were amplified by TPA treatment. These observations indicate that TPA can promote maturation of malignant secretory B cells to a terminal differentiation stage. The significance of these findings to normal B cell differentiation and their potential clinical utility is discussed. © 1985 by Grune & Stratton, Inc.

In a randomized study of acute myelocytic leukemia (AML), 352 patients of all ages were treated for remission induction by one of the four regimens: 7 days of cytosine arabinoside (ara-C) by continuous intravenous (i.v.) infusion or bolus injection every 12 hr, together with daunorubicin (DNR) by rapid i.v. injection on days 1, 2, 3; or 5 days of ara-C by infusion or bolus injection and DNR for 2 days only. The regimen of 7 and 3 infusion was significantly superior to the other 3 regimens, resulting in 56% complete remission (CR). For remission maintenance, ara-C was given for 5 days every month and each month one of the following four drugs added on a cyclic rotational basis: thioguanine, cyclophosphamide, CCNU, or DNR. Although ara-C dosage each month was the same, the route of ara-C administration by random allocation was either rapid i.v. bolus or subcutaneous (s.c.) injection. The median duration of CR was significantly longer for s.c. ara-C group: 14 mo for patients less than 60 yr old (versus 8 mo for i.v.) and 31 mo for 60 or older age group (versus 9 mo for i.v.). Patients who received a combination of the best of the four induction regimens (7 and 3 infusion) and the better of the two maintenance schedules (s.c. ara-C) had a median remission duration of 22 mo and a median survival of 35 mo (the longest reported in a prospective randomized trial of therapy for AML). These results establish the validity of an intensive chemotherapy to produce rapid marrow aplasia followed by a sequential maintenance therapy for achieving prolonged disease-free survival in AML.

Adjuvant chemotherapy has improved the prospects of disease-free survival for patients with breast cancer. Women at highest risk have had the most dramatic benefits. Combined cyclophosphamide (C), methotrexate (M), fluorouracil (F), vincristine (V), and prednisone (P) is superior to CMP and to L-phenylalanine mustard (L-PAM) in women with four or more nodes at all ages. L-PAM, F, and tamoxifen is better than L-PAM and F in postmenopausal women. The combination of 5-fluorouracil, Adriamycin, and cyclophosphamide appears to be equal to that of CMFVP, but with an unknown risk of later cardiac damage.

The choice of a chemotherapeutic agent or agents for adjuvant therapy in osteosarcoma is not clear; the value of prophylactic lung irradiation and immunotherapy is also not clear. Resection of pulmonary metastases is unequivocally a major advance in thoracic surgery.

Spiking blood with14C-labeled 2,2', 4,4',5,5'-hexabromobiphenyl (14C-HxBB) or a mixture of 2,2',4,5,5'-pentabromobiphenyl, 2,2',4,5',6-pentabromobiphenyl and14C-HxBB has been found, in comparative measurements, to be a representative model of polybrominated biphenyl (PBB) contaminated blood from Michigan residents. Blood components were obtained by Ficoll-Hypaque techniques, apolipoprotein B and A fractions by immunoprecipitation with specific antisera; congeners were quantified by negative chemical ionization mass spectrometry or scintillation counting. The distribution of PBB among plasma, erythrocytes, mononucleocytes and polymorphonucleocytes was 89:9:?1:?1. In serum, 20% of the PBB was not bound to protein. The remaining 80% was bound to apolipoproteins B and A in a 4:1 ratio, which is close to the ratio (by weight) of the lipid content of these apolipoproteins. No preferential absorption of PBB congeners occurred in the examined blood compartments.

The cure rate of childhood acute lymphoblastic leukemia (ALL) has improved dramatically. Still there is a paucity of long-term data. With the improving cure rate, the quality of life and avoidance of second cancers have become important concerns. We evaluated 596 children and adolescents with ALL on Cancer and Leukemia Group B 7611 (CALGB 7611) who were randomized between 1976 and 1979 to receive intermediate-dose methotrexate (IDM) plus intrathecal methotrexate (IT MTX) or cranial radiation (CRT) plus IT MTX. After 10 additional years of follow-up, the pattern and significance of the results reported in 1983 are confirmed. IDM offered better hematologic protection (P < 0.0006), better testicular protection (P = 0.002), but CRT offered better central nervous system (CNS) protection (P < 0.0001). The retrieval rate for the 231 patients who relapsed while on therapy or within 6 months of elective cessation of therapy is 20 ± 5%. For the 33 patients who relapsed more than 6 months after cessation of therapy, the retrieval rate is 49 ± 10%. For all patients, the 12-year event-free survival was 37 ± 3.6% and the overall survival was 49 ± 3.5%. There were two cases of second malignancies reported in 3,502 person-years of survival. Both occurred following salvage therapy. There was no evidence of an excessive number of second primaries over the general population of children. There were no reported instances of clinical cardiopathy. After a median follow-up of 11 years, there have been no reports of cardiopathy and no evidence of an increased risk of second cancers in children treated on CALGB 7611. While the overall outcome is not what would be expected with modern therapy, one can conclude that CRT offered better CNS protection, but IDM offered better systemic and testicular protection. A small risk of second cancers or cardiac dysfunction may be acceptable with therapies which produce long-term documented survival benefits. Med. Pediatr. Oncol. 28:98–107 © 1997 Wiley-Liss, Inc.

Purpose.Recombinant human interleukin-6 (rhuIL-6) is a glycosylated cytokine with hematopoietic stimulatory effects. In particular, preclinical studies suggest the agent can stimulate thrombopoiesis, even in conjunction with chemotherapy. We attempted to determine whether higher dose chemotherapy for ovarian cancer was possible given the pharmacologic use of this important growth factor.Methods.We conducted a randomized, double-blind phase II study of IL-6 plus granulocyte colony-stimulating factor (G-CSF) versus placebo plus G-CSF in combination with a standard chemotherapy regimen. Patients with epithelial ovarian cancer, stages Ic to IV, were eligible. All patients were previously untreated with chemotherapy and had Karnofsky performance status ≥60. rhuIL-6 (Escherichia coli,SDZ ILS 969) 1.0 μg/kg or placebo was given subcutaneously on days 2–8 every cycle together with G-CSF 5.0 μg/kg subcutaneously days 2–15, following administration of paclitaxel 175 mg/m2as a 3-h infusion and carboplatin given to a desired AUC of 7.5 on day 1 every 21 days.Results.Fifty patients were entered in this study, although the study was temporarily suspended by the FDA in midstudy over manufacturing concerns. Therefore, 37 patients were evaluable for efficacy of growth factor; 19 patients received placebo plus G-CSF and 18 rhIL-6 plus G-CSF. There was no difference in prognostic variables between these two groups. Platelet nadirs were lower in the first cycle for the placebo group (P= 0.004, Wilcoxon sum-rank test) but not in other cycles. There was no statistically significant difference in cycle treatment delays, carboplatin dose delivered, number of patients with grade 4 thrombocytopenia, or platelet transfusion. Nonetheless, the trend of the data favored IL-6 in all cases.Conclusions.This study demonstrated a minimal effect (statistically significant in the first cycle only) on thrombopoiesis in women undergoing paclitaxel and carboplatin therapy of ovarian cancer. No clinically significant effect on actual chemotherapy delivery was demonstrated, however. Future studies, if warranted, to ameliorate thrombocytopenia should be carried out with regimens producing even greater thrombocytopenia than the current regimen in the control arm.

Abstract: Purpose: Multidrug resistance (MDR) is a major obstacle in cancer chemotherapy. We examined whether cationic liposome-mediated transfer of a ribozyme could reverse MDR. Methods: A ribozyme which cleaved codon 196 of MDR1 mRNA was constructed from synthetic oligonucleotides. The MDR1 ribozyme was mixed with N-(1-(2,3-dileoyloxy)propyl)-N,N,N-trimethylammonium methyl sulfate (DOTAP) to form a liposomal complex. The complex was used to treat two P-glycoprotein-producing MDR cell lines: MCF-7/R human breast cancer cells resistant to doxorubicin and MOLT-3/TMQ800 human ALL cells resistant to trimetrexate (TMQ). In order to investigate the differential sensitivity of these two cell lines to the liposome-ribozyme complex, cellular pharmacological studies including phase-contrast and confocal microscopic studies were performed. Results: Treatment with the liposome-ribozyme complex resulted in reversal of vincristine (VCR) resistance in MCF-7/R cells, but not in MOLT-3/TMQ800 cells. In MCF-7/R cells the treatment resulted in decreases in MDR1 mRNA expression and P-glycoprotein production, whereas no changes in these parameters were seen in MOLT-3/TMQ800 cells. Phase-contrast microscopy revealed that in MCF-7/R cells treatment with DOTAP led to the formation of cytoplasmic vacuoles, and treatment with latex beads resulted in the development of a shiny material in the cytoplasm. In contrast, in MOLT-3/TMQ800 cells hardly any morphological changes occurred. Confocal microscopic imaging showed cytoplasmic fluorescence in MCF-7/R cells after treatment with DOTAP/FITC-dextran or FITC-conjugated latex beads. In MOLT-3/TMQ800 cells no fluorescence was detected. Treatment with cytochalasin B abolished fluorescence in MCF-7/R cells after treatment with DOTAP/FITC-dextran or FITC-conjugated latex beads. These studies show that MCF-7/R cells have high endocytotic activity whereas MOLT-3/TMQ800 cells have little activity. Conclusions: Endocytotic activity was correlated with the success of cationic liposome-mediated transfer of MDR1 ribozyme. Determination of endocytotic activity of target tumor cells may be predictive of efficacy of liposome-mediated gene transfer.

The cancericidal efficacy of a new synthetic tripeptide was demonstrated using both in vitro cultures and in vivo tumorigenic assays. The antitumor agent PTT.119 (p-F-Phe-m-bis-(2-chloroethyl) amino-Phe-Met ethoxy HCl) was highly effective against three virulent murine tumor models; the L1210 leukemia, MJY-alpha mammary tumor and B16 melanoma. Treatment of tumor cells for periods as short as 15 min to 4 h with concentrations of 1–50 µg PTT.119/ml irreversibly reduced tumor cell viability, as evidenced by vital dye exclusion and abrogation of tumor formation and prolongation of host survival. Examination of the sensitivity of mice to PTT.119 revealed that the in vitro antitumor activity of the synthetic tripeptide was exerted at concentrations easily attainable and well tolerated in vivo.

Protein kinase C (PKC) plays a critical role in signal transduction for a variety of cell activation processes. Enhanced PKC activity is often found in cancer cells that show marked invasive and/or metastatic potential. Thus, a specific PKC inhibitor may serve as a tool to reduce invasive or metastatic potential of cancer cells. We show here that phorbol 12-myristate 13-acetate (PMA), a PKC activator, also reduces invasiveness of EJ invasive transitional carcinoma cells. PMA-induced reduction in invasiveness was parallel with inhibition of cell motility. PMA neither induced E-cadherin expression nor augmented cell-matrix adhesion of EJ cells. PMA caused retraction of microspikes from the rim of the cells and consequently rounding of the cellular rim, and the disappearance of microfilaments from the cytoplasm. PMA at 10⁻⁷ M, at which concentration the motility of EJ cells was completely inhibited, down-regulated PKC activity over 5 hr after transient translocation of PKC activity to the membrane fraction. At the same time, PMA induced hyperphosphorylation of MARCKS and talin. During the process of cell movement, actin-binding proteins are in a cycle of phosphorylation and dephosphorylation. Once this cycle is interrupted, cells can no longer maintain the dynamics of cytoskeletal structure. We suggest that retention of the hyperphosphorylated state of MARCKS and talin is responsible for the mechanism(s) by which PMA produces inhibitory activity against invasiveness of EJ cells. Int. J. Cancer 75:774–779, 1998.© 1998 Wiley-Liss, Inc.

• We compared the efficacy of cisplatin plus fluorouracil vs cisplatin plus cytarabine against HEp-2 head and neck carcinoma cells in monolayer and multicellular tumor spheroid (MTS) systems. Increases in exposure time to cisplatin and fluorouracil from one to 24 hours resulted in approximately tenfold and 1000-fold increases, respectively, in cell lethality for both monolayer and MTS cells. Dose-response curves for cisplatin or fluorouracil on MTS cells closely followed those from monolayer cells, indicating good drug penetration into the MTS core. In contrast, dose-response curves on MTS cells after 24-hour exposure to cisplatin and cytarabine showed progressively lesser efficacy at higher drug concentrations. For monolayer cells, cisplatin plus fluorouracil and cisplatin plus cytarabine were both synergistic, the latter combination more synergistic than the former. For MTS cells, both combinations again showed synergistic interaction at moderate to high effect levels. Heightened synergistic interaction was demonstrated especially with the cisplatin plus cytarabine combination. Thus, the cisplatin plus cytarabine combination was always more synergistic than cisplatin plus fluorouracil. These data may serve as a basis for additional clinical trials of cisplatin plus cytarabine in the treatment of patients with head and neck carcinoma.(Arch Otolaryngol Head Neck Surg 1988;114:157-161)

A combination chemotherapy (MACC) consisting of methotrexate, doxorubicin hydrochloride (Adriamycin), cyclophosphamide, and lomustine (CCNU) was given to 41 patients with stage III bronchogenic carcinoma, 34 of whom had disseminated disease. The objective response rate was 46% for all patients with a median actuarial survival of nine months. Response was seen in all cell types, including four of ten patients with squamous cell carcinoma, six of 17 with adenocarcinoma, and six of seven with small-cell anaplastic carcinoma. Prolongation of survival was apparent for patients of all cell types. Toxic reactions were moderate and allowed for easy outpatient use.(JAMA 237:2392-2396, 1977)

The disorganization of multicellular architecture and function that constitutes a cancer is, although abnormal, not wholly chaotic. Specific genes determine the cancerous behavior of affected cells. In cancer-associated retroviruses the specific genes are called "viral oncogenes," and they seem, because of similar deoxynucleotide sequences that are demonstrable in the chromosomal complement of normal cells, to have been acquired from progenitor cellular oncogenes (c-oncogenes). C-oncogenes have been preserved throughout evolution, since near-identical sequences are found in vertebrates from fish to man, and some are even found in fruit flies and worms. This suggests that c-oncogenes likely determine important unidentified functions in normal cells.C-oncogenes in tumors may be activated from the protooncogene state by insertion of viral genes nearby, in the absence of a viral oncogene, or by a chemical carcinogen. The gene product in the cancer cell may be a normal molecule in excess or, because of substitution of a

A randomized comparison of the relative efficacy and toxicity of daunorubicin (DNR) at 30 or 45 mg/sq m or adriamycin (ADM) at 30 mg/sq m, given on the first 3 days of a 7-day continuous infusion of cytosine arabinoside (ara-C) at 100 mg/sq m/day. shows the outcome to be dependent on anthracycline, dose, and patient age. DNR 45 is significantly better than DNR 30 or ADM 30 for inducing complete remissions (CR) in patients younger than 60 yr, (72%. 59%. 58% CRs. respectively). DNR 30 is better than DNR 45 or ADM 30 for inducing CR in patients older than 60 yr (47%, 31 %, 35%. respectively). There was a corresponding shift in the induction mortality for the age. dose, and anthracycline groups. Adriamycin was significantly more toxic to the gastrointestinal tract than daunorubicin. The duration of complete remission, with cyclic courses of maintenance therapy, was independent of the patient's age. the dose, or choice of anthracycline used in induction, and of whether the maintenance courses were given every 4 wk or every 8 wk.

We designed a hammerhead ribozyme which site-specifically cleaved the GUC sequence in codon 179 of MDR1 mRNA. The cleavage site was 6 amino acids upstream from the drug binding site and was considered sufficiently close to the essential locus for P-glycoprotein function. The ribozyme cleaved the MDR1 mRNA under physiological conditions in vitro. The cleavage was dependent on ribozyme concentration and on incubation time. Mg 2+ion was essential for the cleavage. These results show that a potentially useful tool is at hand which may inactivate MDR1 mRNA and revert the multidrug resistance phenotype.

We studied the folate requirements of a human acute lymphoblastic leukemia cell line, MOLT-3, and methotrexate (MTX)-resistant sublines established in vitro. The requirement of pteroylglutamate (PGA) for optimal cell growth was different for each cell line. With increasing MTX resistance, there was progressive increase in PGA requirements, moving the PGA concentration-cell growth curve (dose-response curve) 1 log order of magnitude to the right. The increases in the requirement of 5-methyltetrahydrofolate (5-methyl-THF) by the resistant sublines were more pronounced than PGA requirement, moving the dose-response curve nearly 3 log orders in magnitude to the right. The concentrations in vitro of 5-methyl-THF required for optimal growth of the MTX-resistant sublines far exceeded the normal serum 5-methyl-THF concentrations known in humans. These observations show that MTX-resistant cells established in vitro in culture media containing PGA instead of 5-methyl-THF, a physiological folate, cannot be expected to grow in vivo. The collateral sensitivity of transport-impaired MTX-resistant sublines to 2,4-diamino-5-methyl-6-[(3',4',5'-trimethoxyanilino) methyl] quinazoline (trime-trexate, TMQ) was negated in the absence of PGA. With the addition of 5-methyl-THF, the parent cells became more resistant than the transport-impaired sublines to TMQ. These data indicate that the collateral sensitivity of MTX-resistant cells to the substituted 2,4-diaminoquinazoline is due to functional folate deficiency by virtue of the impaired transport of folate.

A 69-year-old woman was admitted to the hospital because of recurrent cervical nodules, a large anterior mediastinal mass, and malignant left pleural effusion. Light and electron microscopy of the resected cervical nodules and cytology of the pleural fluid showed findings consistent with parathyroid carcinoma. There was no evidence of hyperparathyroidism on clinical evaluation, multiple serum calcium and phosphorus determinations, skeletal survey, intravenous pyelogram, or radioimmunoassay of intact and carboxyl-terminal parathyroid hormones in the serum. Electron microscopy revealed secretory granules in the cytoplasm of malignant cells. A dramatic and complete resolution of the mediastinal mass and pleural effusion occurred after 18 months of chemotherapy with "MACC" (methotrexate, adriamycin, cyclophosphamide and CCNU).

The difference between the chemotherapeutic response in patients with acute myelocytic leukemia (AML) and in those with acute lymphocytic leukemia (ALL) would appear to be more a problem of lack of regeneration of normal myeloid tissues than a lack of susceptibility of the neoplastic cell to chemotherapy. The lymphoblasts of ALL are more readily damaged by treatments used in induction than are the leukemic cells in AML. It is easily possible, however, to produce marrow aplasia in patients with AML with the multitude of myelosuppressive drugs available. The therapeutic dilemma is that treatments that are active in this regard also damage the normal myeloid tissue. This damage is often not repaired during the period available prior to death from infection or bleeding. The fact that differentiation between neoplastic and normal cells can be accomplished at all on chemotherapeutic grounds in such a critical organ as the marrow is remarkable. That

Suramin, an organic polyanion with six sulphonic groups, is under clinical trials as an agent against hormone-refractory prostate cancer. The drug binds strongly to serum albumin. The objectives were to use electrospray to measure the molecular masses of the intact complexes of albumin and suramin to determine the number of suramin molecules bound under different molar ratios, and to investigate the binding of suramin in human serum. With albumin in excess (2:1 to 25:1 ratio), only 1 and 2 bound suramins were found; with suramin excess (2:1 to 1000:1) up to 20 bound suramin molecules/albumin were found. Up to 5 bound suramins were found in human serum with 4:1 suramin:albumin ratio, which corresponds to recommended therapeutic doses (200–300 μg/mL). At 8:1 ratio, which would be toxic, complexes with up to ten bound suramin molecules were found, and unreacted albumin diminished. © 1998 John Wiley & Sons, Ltd.

Patients with advanced ovarian carcinoma, Stage III or IV (International Federation of Gynaecology and Obstetrics), were randomized to primary chemotherapy with doxorubicin (Adriamycin) and cisplatin plus or minus hexamethylmelamine, and cyclophosphamide (CHAP). The four-drug CHAP regimen produced a 57% complete clinical response rate and a 26% partial response rate for clinically evaluable patients. The median survival of CHAP patients is 25 months. The two-drug Adriamycin-cisplatin (AP) regimen produced a 43% complete response rate and a 35% partial response rate. The median survival is 18 months. The four-drug regimen produced a significantly longer median survival (28 versus 18 months) for patients with poorly differentiated tumors than for patients with well-differentiated tumors on either treatment. Examination of treatment failure or death by treatment, histology, and size of largest residual tumor and comparison to similar patients treated with AP in this and two preceding controlled trials also suggest that CHAP is superior to AP for patients with poorly differentiated tumors.

Harringtonine (HT) is a new antitumor agent reported to be active in patients with leukemia and lymphoma. The interaction of HT with various antitumor agents was studied in vitro using a human acute myelogenous leukemia cell line KG-1. For the analysis of the drug-drug interaction at the cellular level, Steel proposed the concept of an envelope of additivity. Using this concept, the effect of a two drug combination can be classified as supraadditive (enhancement of the effect), non-interactive (additive), subadditive, and protective (antagonistic). Combination of HT and cytosine arabinoside or HT and dexamethasone produced only additive effects. Combination of HT and methotrexate was subadditive. For HT plus adriamycin or HT plus 5-fluorouracil, data points indicated both subadditive and protective interaction. HT plus acivicin or HT plus L-asparaginase combinations were found to be protective of each other. None of the seven agents produced supraadditive interaction. These results may provide the basis for selecting sequential rather than concurrent combinations which include HT for the treatment of leukemia in man.

An attempt to prevent the blast crisis in chronic myeloid leukemia by the use of pulsed doses of (cytarabine cytosine arabinoside) and lomustine was attempted as a cooperative group study by Cancer and Leukemia Group B. The basis for this study was to delay the development of blast crisis by pulsing dose of drugs known to be effective against emerging ““blast”” cells. The experimental arm which consisted of cytarabine and lomustine did not produce overall results superior to conventional treatment with busulfan. This was related to the non-hematologic effects of the combination which produced significant gastrointestinal toxicity leading to relatively early discontinuation of the combination. Nevertheless, the trial design allowed relatively prompt discontinuation of experimental arm and cross-over to conventional treatment with either hydrea or busulfan. No evidence existed that the use of new drug combinations in CML prejudiced the patient's chance to response to conventional chemotherapy. Thus, a role model for future trials in this disease was developed. With the development of the interferons and other experimental forms of therapy this conceptual development may be of significance.