Taxol is an antitumor agent in clinical trial that has been shown to have activity against advanced ovarian carcinoma and melanoma. Hypersensitivity reactions (HSRs) have been one of the toxicities observed with administration of this drug. Of 301 patients treated, 32 patients have had definite (27 patients) or possible (five patients) hypersensitivity reactions to taxol. All but one patient had the reaction from the first or second exposure to this agent. Reactions occurred at a variety of doses and were characterized most frequently by dyspnea, hypotension, bronchospasm, urticaria, and erythematous rashes. Thirteen (41%) patients had received premedication designed to prevent such toxicity; nevertheless, they sustained HSRs. Prolonging the drug infusion appears to have somewhat reduced, but not obviated, the risk of HSRs. The cause (taxol itself or its excipient Cremophor EL; Badische Anilin und Soda-Fabrik AG [BASF], Ludwigshafen, Federal Republic of Germany) and the mechanism of these reactions to taxol are unknown. We provide guidelines to prevent or minimize such toxicity and treat reactions if they still occur.

By means of the multiple marker analysis, a total of 55 human leukemia-lymphoma cell lines which included 15 T-cell, 30 B-cell, four myelomonocytic-cell, and six non-T, non-B cell lines was characterized for their marker profiles. The multiple markers used included a number of cell surface markers as detected by either rosette or immunofluorescence tests, enzyme assays, cytogenetic analysis, and certain functional assay. Based on the criteria previously defined it was found that all the cell lines were proved to represent original leukemia-lymphoma of ALL, AML, CLL, CML in blastic phase or variety of lymphomas. The monoclonality, a "frozen" state at a specific state of differentiation-maturation, and cytogenetic marker in each leukemia-lymphoma cell line were remarkable common properties and were stable for years of cultivation. Similar, if not identical, general characteristics were observed in the study on 344 cases of uncultured fresh leukemia-lymphomas by the multiple marker analysis. While no single marker specific to any type of tumor was found, the study offers not only a basis for better understanding of the biology of leukemia-lymphoma but also an insight into normal hematopoietic cell differentiation in man.

Blood, urine, and tissue distributions of Bleomycin in animals and man were studied by microbiological assay using Bacillus subtilis ATCC 6633. Bleomycin was inactivated in vitro by a variety of tissues. Contact of Bleomycin with mouse intestinal or liver homogenates resulted in almost complete inactivation, whereas mouse plasma, kidney, lung, skin, and muscle produced lesser inactivation grossly in that order. Similar trends of inactivation were demonstrated by available human tissues. The present data do not establish whether the inactivation is enzymatic or non‐enzymatic. After single injection of a large dose of Bleomycin into mice, the decrease of plasma level did not follow first order kinetics, indicating that multiple factors are participating in the clearance of the antibiotic. Following the injection of Bleomycin into mice, activity was detected in the skin, lung, and subcutaneously transplanted Ehrlich tumor. Concentrations in liver, intestine, and muscle tissues were too small to detect. Inability to detect activity in the liver and intestine appears to result from inactivation rather than poor distribution of the drug. In general, the concentration of measurable antibiotic was high in tissues where toxicity was described, whereas there was no good correlation between the degree of inactivation of the antibiotic by a tumor tissue in vitro and therapeutic effect in vivo. In man, plasma clearance curves resembled those of mouse plasma. About 50% of injected antibiotic was excreted into the urine in 24 hours. The sensitivity of the method did not permit detailed measurement of the drug levels in various tissues after injection of therapeutic doses of Bleomycin in man.

Treatment with adriamycin (ADM) and bleomycin (BLEO) alone and in combination has been evaluated in 56 patients with a variety of advanced stage gynecologic cancers. ADM has a high degree of antitumor activity against uterine sarcomas (leiomyosarcoma and stromal sarcoma) and some of the unusual ovarian cancers including ovarian teratoma. ADM was also active and gave clinically worthwhile responses against squamous cell carcinoma of the cervix and vagina. Occasional objective remissions were seen in patients with epithelial ovarian adenocarcinomas. The combination of ADM plus BLEO appeared to show no enhancement of the effect achieved by ADM alone. There were no objective responses in patients with squamous cell carcinoma of the cervix treated with BLEO alone. The usual toxic manifestations of ADM and BLEO were observed, and there appeared to be no potentiation of the toxicity of each agent when used in combination. It is concluded that ADM is a valuable chemotherapeutic agent for certain gynecologic cancers which are usually refractory to other chemotherapeutic agents. Further investigation of its use alone and in combination with other drugs is indicated.

The benzyl styryl sulfone, ON 01910.Na, is a novel anticancer agent that inhibits mitotic progression and induces apoptosis in most cancer cell lines. We examined the effect of ON 01910.Na on DNA damagesignaling molecules upstream of Cdc25C (Chk1, Chk2, and H2AX), as well as on Ran GTPase-activating protein 1 conjugated to small ubiquitin-related modifier 1 (RanGAP1ÁSUMO1), a mitosis coordinator. Prostate cancer, lymphoma, and leukemic cells were incubated with the drug for 4, 16, or 24 hours. Cell lysates were resolved on SDS-PAGE and analyzed by Western blot. Camptothecin and doxorubicin treatment caused activation/phosphorylation of DNA damage-responsive molecules by 4 hours, whereas ON 01910.Na did not do so. ON 01910.Na caused hyperphosphorylation of RanGAP1ÁSUMO1 within 4 hours that was sustained for more than 24 hours. Mild phosphorylation of Chk2 was observed only after 24-hour exposure, indicating that DNA damage response was not an initial effect of ON 01910.Na. MOLT-3 cells, synchronized by double-thymidine block, when released into a medium containing ON 01910.Na, accumulated mitotic cell number with a peak from 10 to 14 hours and remained near plateau for 20 hours, which corresponded with the time of RanGAP phosphorylation. ON 01910.Na had minimal effects on tubulin polymerization. These findings imply that ON 01910.Na neither induces DNA damage directly nor acts as a tubulin toxin. Its biological activity appears to rely on prolonged phosphorylation/hyperphosphorylation of RanGAP1ÁSUMO1. M-phase arrest and the consequent induction of apoptosis that follows could possibly be attributed to it. ON 01910.Na may act as an inhibitor of a RanGAP1ÁSUMO1 phosphatase or a stimulant of a new kinase. RanGAP1ÁSUMO1 appears to be a new target pathway for cancer chemotherapy. Cancer Res; 71(14); 4968-76. Ó2011 AACR.