Effect of camptothecin and adriamycin on bleomycin-induced tritiated thymidine triphosphate incorporation in a rat nuclear system.

We investigated the effect of camptothecin and adriamycin on [3H]TTP incorporation and bleomycin-stimulated [3H]TTP incorporation in host liver and hepatoma nuclei of rats. Camptothecin neither stimulated nor inhibited incorporation in the regular nuclear incorporating system. Bleomycin stimulated incorporation to a much greater extent in host liver nuclei and slow-growing hepatomas than it did in the fast-growing hepatoma 7777. Addition of camptothecin to bleomycin stimulated incorporation of [3H]TTP even further. This camptothecin stimulation was slightly greater in hepatoma nuclei than it was in host liver nuclei. Adriamycin inhibited [3H]TTP incorporation in the regular system as well as the bleomycin-induced incorporation. Hepatoma nuclei were more sensitive to this inhibition than were host liver nuclei. Sucrose density gradients indicated that camptothecin caused DNA strand scissions in addition to those produced by bleomycin. Camptothecin alone produced some single-strand but no double-strand scissions. The action of bleomycin was dependent on sulfhydryl-reducing agents. Camptothecin could partially substitute for this requirement. Adriamycin did not produce DNA breaks as determined by neutral or alkaline sucrose density gradients. Despite complete inhibition of bleomycin-induced [3H]TTP incorporation, adriamycin did not prevent bleomycin-induced DNA breaks. The inhibitory effect of adriamycin might have been on the repair system.

Effect of bleomycin on [3H]Thymidine 5'-Triphosphate incorporation into host liver and hepatoma nuclei.

The effect of bleomycin on [3H]thymidine 5'-triphosphate ([3H]TTP) incorporation into isolated sucrose nuclei from host liver and Morris hepatomas has been compared. Bleomycin stimulates [3H]TTP incorporation 13-fold in host liver and hepatoma 16 nuclei, 8-fold in hepatoma 7800 nuclei, and 3-fold in hepatoma 7777 nuclei. Differences in the nuclear membranes are not responsible for the different response of the nuclei. Nuclei, denuded of their membranes by Triton X-100 treatment, give similar results to sucrose nuclei. Analysis of DNA extracted from liver or hepatoma nuclei incubated with bleomycin indicates that bleomycin produces scissions in the nuclear DNA and that some repair synthesis takes place. Incubation of nuclei with 111indium-labeled bleomycin shows an equal binding capacity of liver and hepatoma nuclei for bleomycin. Bleomycin also stimulates incorporation of [3H]TTP in a system using chromatin or calf thymus DNA as primer. Host liver or hepatoma chromatin incubated with a DNA polymerase extracted from normal rat liver nuclei is stimulated approximately to the same extent by bleomycin. When DNA polymerase extracts from host liver and hepatoma nuclei are assayed with calf thymus DNA as primer, bleomycin has a greater stimulatory effect on [3H]TTP incorporation with host liver DNA polymerase than with hepatoma DNA polymerase in the system. We suggest that a defect in the repair system in hepatoma nuclei is responsible for the relatively lower response to bleomycin.

GR 38032F (GR-C507/75): a novel compound effective in the prevention of acute cisplatin-induced emesis.

We evaluated, in a multi-center trial, the safety and efficacy of GR 38032F (GR-C507/75), a novel and selective serotonin antagonist, in preventing acute emesis in chemotherapy-naive patients receiving treatment with regimens containing high-dose cisplatin (greater than or equal to 100 mg/m2). Eighty-five patients were randomized to receive GR 38032F, 0.18 mg/kg, either every six or every eight hours for three doses, beginning 30 minutes before cisplatin. Patients were evaluated for emetic episodes (vomiting or retching) over a 24-hour period following cisplatin. All patients were evaluable for toxicity and 83 were evaluable for efficacy. The overall antiemetic response rate was 75% (55% complete response [CR], 20% major response). No difference in antiemetic control between the two administration schedules was noted. Patients with histories of heavy ethanol use had significantly better antiemetic control (74% CR) than modest or non-drinkers (33% CR). Toxicity of GR 38032F was modest and independent of administration schedule. The most common adverse events included mild hepatic transaminase elevations, self-limited diarrhea, dry mouth, headache, and mild sedation. Our data indicate that GR 38032F is a safe and effective agent in the control of acute cisplatin-induced nausea and vomiting. Additional trials exploring dosing, schedule, and comparison to standard antiemetic agents are indicated.

A multicenter phase II trial of losoxantrone (DuP-941) in hormone-refractory metastatic prostate cancer.

Our purpose in this study was to determine the efficacy and toxicity of losoxantrone (DuP-941), an anthrapyrazole, in patients with metastatic hormone-refractory prostate cancer. Patients with metastatic prostate cancer progressing on androgen ablation therapy without demonstrable antiandrogen withdrawal response were treated with losoxantrone 50 mg/m2 i.v. bolus every 21 days. All of the patients had elevated serum prostate-specific antigen (PSA) before study entry and had no prior chemotherapy. Forty-three assessable patients were entered. The median age was 70.6 years (range, 53.9-85.9), median Karnofsky performance scale (KPS), 70% (50-90%), and the median serum PSA, 173 microg/liter (12.5-11,140). The median number of courses was 4 (1-9). Five patients (25%) had a partial response as defined by >50% decline in the serum PSA. Two of nine patients with measurable disease had partial responses and three had minor responses. Thirty percent of patients had improvement in KPS and 37% had an improvement in symptoms with decrease in pain and/or decrease in analgesic requirement. Nonhematological grade 3 and 4 toxicities were one each of grade 3 headache, grade 4 hypocalcemia, grade 3 hyperbilirubinemia, and grade 3 dyspnea. Twenty-six patients (60%) had grade 3 or 4 absolute neutropenia. In conclusion, losoxantrone demonstrated a partial biochemical response rate of 25%, response in measurable disease sites in 22%, and improvement in clinical symptoms in one-third of patients. In this study, PSA increase was not necessarily associated with lack of palliative response.

Influence of dimercaprol on the early hepatic uptake of 111In-bleomycin in the BALB/c mouse.

Dimercaprol (BAL) administered 1 hr before 111In-bleomycin in the normal BALB/c mouse produced an early preferential hepatic loading of 111In-bleomycin without a loading of the spleen, skin, bone, or muscle. Liver-to-muscle ratios were increased about threefold under the influence of BAL. Liver (c BAL)/liver (s BAL) ratios also increased threefold at 3 hr whereas relative muscle uptake remained at about unity. Indium-111 chloride (colloid, pH 6.5) used as a control did not show a similar increase. The findings suggest that the kinetics and distribution of 111In-bleomycin in the normal BALB/c mouse can be influenced by pretreatment with BAL.

Simultaneous ectopic production of parathyroid hormone and calcitonin.

Two patients with cancer were evaluated in whom there was evidence for the simultaneous ectopic production of parathyroid hormone (PTH) and calcitonin (CT). One patient had a gastric carcinoid and the other had a pancreatic islet cell carcinoma. Abnormal concentrations of parathyroid hormone and calcitonin were demonstrated by radioimmunoassay in the peripheral blood of each patient and in the gastric tumor. In the pancreatic tumor, immunohistologic studies also demonstrated the presence of CT and PTH and suggested that each hormone was produced by different cells of the tumor. Plasma concentrations of the hormones responded to functional tests of secretion and to tumor chemotherapy. These studies demonstrate the simultaneous ectopic production of the two physiologically antagonistic hormones, PTH and CT, and confirm their value as diagnostic markers for several types of malignancies.

Inhibition of bleomycin-induced [3H] thymidine 5'-triphosphate incorporation into liver and hepatoma nuclei by N-ethyl maleimide and daunomycin.

The addition of bleomycin to a nuclear incorporating system results in an increased incorporation of 3H-thymidine 5'-triphosphate (3H-TTP) into the DNA of liver and hepatoma nuclei. Bleomycin added to the nuclear incorporating system also produces scissions of DNA as determined by sucrose density gradient centrifugation of the extracted DNA. The action of bleomycin is dependent on the presence of sulfhydryl agents in the incubation mixture. Two compounds, N-ethyl maleimide and daunomycin, inhibit the bleomycin-induced incorporation of 3H-TTP preferentially. N-Ethyl maleimide inhibits bleomycin-induced activity in liver and hepatoma 7777 nuclei equally. Lower levels of daunomycin inhibit the bleomycin-induced activity in the hepatoma 7777 nuclei than are required to inhibit the activity in liver nuclei. The two compounds inhibit the bleomycin effect by different mechanisms. The addition of N-ethyl maleimide to bleomycin in the incubation system prevents bleomycin from causing breaks in the DNA. The addition of daunomycin, despite inhibition of bleomycin-induced 3H-TTP incorporation, does not affect the bleomycin-produced breaks in the DNA. N-Ethyl maleimide acts by binding to the DNA and by competing with a sulfhydryl agent for bleomycin-sensitive sites on the DNA. Daunomycin apparently inhibits a repair enzyme that is responsible for the increased incorporation following bleomycin treatment.

Profound ambulatory hypoglycemia: a rare entity.

A 49-year-old man with a history of hepatocellular carcinoma, alcohol abuse, and insulin-dependent diabetes mellitus was noted to be completely asymptomatic despite a plasma glucose level of 4 mg/dL. The possible pathophysiology of this unusual occurrence of "hypoglycemia unawareness" is discussed.

Hypotonic exchange-loading of erythrocytes. II. introduction of hemoglobins S and C into normal red cells.

A rapid, simple technique whereby erythrocytes transiently exposed to hypotonic hemoglobin preparations undergo exchange of endogenous for exogenous hemoglobin has now been applied to normal, hemoglobin A-containing erythrocytes into which hemoglobin S or hemoglobin C have been introduced. Erythrocytes containing an average of 12 to 61 percent of hemoglobin S undergo sickling when incubated in isotonic dithionite solution and are morphologically indistinguishable from natural sickle cells. Ultrastructural studies of thin sections of these artificial sickle cells show microfialments and fascicles which appear typical of microtubular tactoids of hemoglobin S seen in natural sickle cells. Erthrocytes containing 43 percent introduced hemoglobin C developed all of the morphologic alterations associated with intra-erythrocytic hemoglobin C, including hemoglobin aggregation, targetting, and intracellular crystallization, after inclbation for 24 hours in isotonic saline: dithionite. The results support the concept that the sickling process, and morphologic erythrocyte alterations occurring in hemoglobin C disorders are primary to the respective hemoglobins rather than the membrane. They also suggest that any role played by the inner surface of the erythrocyte membrane in the development of these alterations is probably secondary and not specific to the inner membrane surface of the natural sickle cell or hemoglobin C-containing cell.

Nephrotoxic and cytoproliferative effects of streptozotocin: report of a patient with multiple hormone-secreting islet cell carcinoma.

The nephrotoxic and cytoproliferative side effects observed in a patient with Streptozotocin-treated, multiple hormone-secreting, pancreatic islet cell carcinoma are described. Streptozotocin induced prolonged partial remission of the patient's multiendocrine syndrome but resulted in progressive azotemia, which was controlled by temporary hemodialysis. A renal biopsy, the first to be reported in detail in such a condition, demonstrated a tubulo-interstitial nephritis and a glomerular alteration consisting of cellular nodules. At autopsy there were numerous bilateral renal cortical spindle cell "tumors" and cellular aggregates in glomeruli. These findings suggest that the tumorigenic effects of Streptozotocin demonstrated in animals may also occur in man.

Erythrocytes as carriers of chemotherapeutic agents for targeting the reticuloendothelial system.

The object of this work was to define a model using hypotonically loaded erythrocytes as a vehicle to target drugs to the reticuloendothelial system (RES). The optimum hemolytic event was found to occur at 100 mOsm/kg using a 0.5-min exposure at 0 degrees C. Approximately one third of the total volume of the cells could be replaced with hypotonic drug solutions under these conditions. Although cytosine-beta-D-arabinofuranoside, ara C, is membrane permeable and could not be entrapped in the erythrocytes, phosphorylation of this nucleoside antimetabolite enabled it to be loaded efficiently. Actinomycin D could be loaded and retained within the cells at 0 degrees C, but 90% of this loaded drug leaked out of the erythrocytes in 1 min at 37 degrees C. Actinomycin D-DNA complexes, however, could be loaded and retained for longer periods. In this case, 50% of the DNA-bound drug was retained in the cells for one hour at 37 degrees C. It was found that the glycopeptide antitumor antibiotic, bleomycin, could be entrapped and retained in the cells without appreciable leakage. It was possible to load a human therapeutic dose of this drug in 1-2 ml of packed cells. Furthermore, it was demonstrated that bleomycin entrapped in erythrocytes was significantly more effective than the same dose of free drug in suppressing the phagocytic function of the RES in Balb/C and C3H mice. The rationale is discussed for the possible use of these drugs, entrapped in erythrocytes, for the production of RES blockade in the treatment of disorders in man.

Influence of dimercaprol (2,3-dimercapto-1-propanol) on the pharmacokinetics of 111In-bleomycin in the P-1798 lymphoma-bearing BALB/c mouse.

The pharmacokinetics of 111 indium-labeled bleomycin were altered in the P-1798 tumor-bearing BALB/c mouse when pretreated with the dithiol 2,3-dimercapto-1-propanol (Bal). 1 mg of BAL administered 1 h prior to 20 microCi of 111In-bleomycin resulted in 2:1 tumor loading and 3:1 liver loading of 111In-bleomycin over controls (p less than or equal to 0.05 at the 2- to 3-hour interval). Muscle uptake during this interval remained at unity.

Vincristine (NSC-67574), cytosine arabinoside (NSC-63878), 6 thioguanine (NSC-752) and daunorubicin (NSC-82151) (VAT-D): a pilot study of combination chemotherapy for remission induction in acute myeloid leukemia in adults.

Fifteen newly diagnosed unselected adult patients with acute nonlymphocytic leukemia were treated in a pilot study of the combination of vincristine, cytosine arabinoside, 6-thioguanine, and daunorubicin (VAT-D) for remission induction therapy. Eleven of fifteen (75%) achieved a remission bone marrow. Median duration of remission was seven months in all responders (11 patients). The 11 patients achieving initial remission reached a median survival of 14 months. Twelve of seventeen attempts at reinduction of remission with VAT-D were successful. The total amount of daunorubicin required for induction was less than that required in the majority of reported acute leukemia treatment regimens utilizing daunorubicin.

Carcinocythemia (carcinoma cell leukemia) due to metastatic carcinoma of the breast: report of a case.

A patient with a 17-year course of metastatic lobular carcinoma of the breast is described who developed large numbers of circulating carcinoma cells which were easily detectable in several routine peripheral blood smears shortly before death. This rare complication of carcinoma has been called "carcinocythemia." Carcinocythemia is probably due to widespread infiltration of many bone marrow sites and may also be related to splenectomy, which may impair reticuloendothelial clearance of circulating tumor cells. The differential diagnosis of carcinocythemia from superimposed acute myelogenous leukemia, which can complicate radiotherapy and chemotherapy for the primary tumor, is discussed. Cytomorphology, histochemistry, and electron microscopy of abnormal circulating cells should aid in the distinction of these two processes.

Ameloblastoma of the mandible with pulmonary metastasis.

A patient with ameloblastoma of the mandible with histologically confirmed pulmonary metastases 9 years after onset of tumor is described. The effectiveness of three chemotherapeutic agents (cyclophosphamide, methotrexate, Adriamycin), each given alone intravenously, were evaluated. Marked symptomatic improvement was noted with Adriamycin therapy. Ten previous cases of metastatic ameloblastoma are reviewed. The incidence of metastases cannot be predicted on the basis of histology. Three commonly discussed modes of metastasis are via hematogenous and lymphatic routes and the unusual mechanism of aspiration of tumor cells.

Continuous intravenous infusion combination chemotherapy for head and neck squamous cell carcinoma.

42 consecutive patients with head and neck squamous cell carcinoma were entered into a multi-agent chemotherapy protocol including: bleomycin and Cis-platinum (in continuous infusion), sequenced with methotrexate and Vinblastine (by bolus infusion). Hydroxyurea was substituted for bleomycin when the accumulative dose of bleomycin reached 400 units. 9 of 11 patients with untreated disease responded to chemotherapy, with 36.4% showing complete response following the second cycle. After completion of all therapy, complete response had occurred in 10 patients and partial response in 1. At a median follow-up of 1 year, 9 patients are disease-free, and the median duration of response has not yet been reached. For recurrent disease, the overall regression rate is 45.1% (14/31). The median duration of response is 6.5 months, with responding patients showing a median survival of 8.7 months and non-responders, 5.4 months. The data for response and survival are comparable to previous studies and suggest that toxic manifestations may be mitigated by careful attention to nutrition and production of an anabolic state prior to therapy.