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In many freshwater habitats, green algae form intracellular symbioses with a variety of heterotrophic host taxa including several species of freshwater sponge. These sponges perform important ecological roles in their habitats, and the poriferan:green algae partnerships offers unique opportunities to study the evolutionary origins and ecological persistence of endosymbioses. We examined the association between Ephydatia muelleri and its chlorophyte partner to identify features of host cellular and genetic responses to the presence of intracellular algal partners. Chlorella-like green algal symbionts were isolated from field-collected adult E. muelleri tissue harboring algae. The sponge-derived algae were successfully cultured and subsequently used to reinfect aposymbiotic E. muelleri tissue. We used confocal microscopy to follow the fate of the sponge-derived algae after inoculating algae-free E. muelleri grown from gemmules to show temporal patterns of symbiont location within host tissue. We also infected aposymbiotic E. muelleri with sponge-derived algae, and performed RNASeq to study differential expression patterns in the host relative to symbiotic states. We compare and contrast our findings with work in other systems (e.g., endosymbiotic Hydra) to explore possible conserved evolutionary pathways that may lead to stable mutualistic endosymbioses. Our work demonstrates that freshwater sponges offer many tractable qualities to study features of intracellular occupancy and thus meet criteria desired for a model system.

Gender disparity exists in leadership roles within healthcare. While the majority of the healthcare workforce is comprised of women, significantly fewer women occupy leadership positions, particularly at executive and board levels. As the field of oncology pharmacy continues to rapidly expand and evolve, an assessment of the current state of women in oncology pharmacy leadership roles is vital to the growth and development of the profession. In the fall of 2017, the Hematology/Oncology Pharmacy Association (HOPA) hosted a summit to explore leadership issues facing women in oncology pharmacy which have the potential to affect our membership and our profession. This meeting included invited participants from across the fields of oncology and pharmacy and was part of HOPA's strategic leadership initiative developed through the work of the HOPA Leadership Development Committee in 2016. This promotes a primary goal of HOPA, which is to support oncology pharmacists as they assume leadership roles within their practices and within healthcare to assure oncology pharmacy is integrated into cancer care. The purpose of this white paper is to (1) summarize key issues that were identified through a membership survey; (2) review ongoing efforts to address the needs of female oncology pharmacists in leadership development; (3) serve as a call to action for individuals and professional organizations to assist with and disseminate these efforts and highlight available resources, and (4) to provide practical steps to meet the needs of individuals, training programs, and institutions/employers.

Introduction: Due to enhanced T-cell activity, immune checkpoint inhibitors cause immune-related adverse effects. Corticosteroids are the mainstay of immune-related adverse effect management but the optimal strategy has not been determined, putting patients at risk for steroid-related adverse effects and potentially decreased efficacy of immunotherapy. This study aims to characterize the use of corticosteroids for the management of immune-related adverse effect., Methods and Materials: A retrospective, single-center evaluation of patients receiving checkpoint inhibitors was conducted. The primary objective was to evaluate corticosteroid use for immune-related adverse effects, including starting dose, taper strategy, total duration, and resumption of immunotherapy. Secondary objective was to describe the incidence and significance of hyperglycemia., Results: One hundred and three patients met inclusion criteria and experienced 123 immune-related adverse effects. Prednisone was used most commonly (67%) at an average starting dose of 0.88 mg/kg (range 0.07-17.0). On average, steroid tapers began 9.2 days after initiation (range 0-89) and were continued for a total of 84.2 days (range 3-693). In 21.1% of cases, checkpoint inhibitor therapy was not delayed and 68.6% resumed checkpoint inhibitors, while the patient was taking steroids (30.4 mg prednisone on average, range 5-80). On average, checkpoint inhibitor therapy was resumed 18.6 days after detection of immune-related adverse effect (range 0-150). Clinically relevant hyperglycemia occurred in 8.9%., Conclusion: Utilization of steroids for immune-related adverse effect at our institution is highly variable. The majority of patients received prolonged courses of steroids and resumed checkpoint inhibitor therapy with concomitant steroids above recommended doses. Additional monitoring for hyperglycemia and other steroid associated adverse effects should be considered.

Background: The aims of this study were to determine the feasibility of the combination of low dose, anti-angiogenic chemotherapy with standard therapy for patients with metastatic Ewing sarcoma (ES), and to obtain preliminary outcome data., Procedures: Patients with metastatic ES were eligible. Therapy consisted of alternating cycles of ifosfamide-etoposide, and vincristine, doxorubicin, cyclophosphamide. Vinblastine and celecoxib were concomitantly administered. Surgical, radiotherapeutic, or combination local control therapy was given per institutional preference., Results: Thirty-five eligible patients were enrolled. Ninety percent received at least 75% of planned vinblastine/celecoxib doses. There was no excess of neurologic, infectious, hemorrhagic, or cardiovascular toxicities. However, 7 of 21 patients who received pulmonary irradiation prior to experiencing pulmonary toxicity did develop grade 2 or greater pulmonary toxicity, including two deaths of apparent radiation pneumonitis. Fourteen of 16 patients with pelvic disease received local irradiation. Hemorrhagic cystitis developed in six patients, five of whom had received pelvic irradiation. The overall 24-month event free survival was 35% (19-51%); 71% (26-92%) for the seven with isolated pulmonary metastases, 26% (10-45%) for all others., Conclusion: The combination of vinblastine/celecoxib metronomic therapy with standard ES treatment was feasible according to the protocol definitions. However, excess toxicity in irradiated areas was noted and limits the usefulness of this protocol. The 24-month EFS for those with isolated pulmonary metastases is better than historical controls, although the number of patient number is small, follow up short and we are lacking contemporaneous controls., (Copyright © 2012 Wiley Periodicals, Inc.)

Study Objectives: To assess the effectiveness of prophylactic albumin for the prevention of ifosfamide-induced encephalopathy (IIE), and to describe risk factors for IIE and investigate the predictive potential of a novel risk-stratification model for IIE., Design: Retrospective analysis., Setting: Single academic medical center., Patients: Forty-one adults who received 93 chemotherapy cycles of regimens that included ifosfamide for the treatment of hematologic or solid tumor malignancy between November 2007 and November 2008. Patients were divided into two groups based on the use of albumin for IIE prophylaxis: albumin group (32 cycles) and no albumin group (61 cycles)., Measurements and Main Results: Overall occurrence of neurotoxicity during therapy served as the primary outcome measure. Proposed risk factors for IIE were assessed by conducting a subgroup analysis of patients who did and those who did not experience IIE. A novel risk-stratification model was developed in an attempt to predict patients at risk for IIE. The validity of the scheme was assessed by comparing the occurrence of IIE among high- and low-risk patients as identified by the model. Overall, among the 93 cycles, six cases of IIE (6.5%) were identified. The occurrence of IIE was more common in the albumin group compared with the no albumin group (15.6% [5/32] vs 1.6% [1/61], p=0.01). Baseline albumin level was significantly lower, and serum creatinine and aspartate and alanine aminotransferase concentrations were significantly higher among patients experiencing IIE. All cases of IIE occurred among patients identified as high risk according to the risk-stratification model (p=0.01)., Conclusion: Prophylactic therapy with exogenous albumin is not an effective strategy for the prevention of IIE. The novel risk-stratification model appears to be an effective method for predicting patients with the greatest potential for developing this adverse effect.

The development of three novel chemotherapeutic agents - thalidomide, lenalidomide, and bortezomib - has resulted in a fundamental shift in the management of multiple myeloma. Despite this tremendous advancement, the selection of initial treatment must still be made with a degree of uncertainty as a true standard therapy has yet to be established. Although challenging, the relative abundance of therapeutic options, when taken into consideration with unique patient characteristics, creates the potential for individualization of care.For patients eligible for autologous stem cell transplantation, various combinations of novel agents with dexamethasone or traditional chemotherapy have supplanted the previous standard regimen consisting of vincristine, doxorubicin, and dexamethasone. In elderly patients or others that are deemed ineligible for the transplant procedure, the addition of a novel agent to melphalan-prednisone has demonstrated significant improvements in response rates. Due to the immaturity of the available data, it is perhaps best to regard the era of novel agents with a degree of rational enthusiasm, as the ultimate impact on patient care remains undetermined. Although further research is clearly implicated, recent advancements have resulted in significant progress toward obtaining optimum outcomes in a historically challenging disease.

Today's obesity pandemic began in the United States, spread to Western Europe and other developed regions, and is emerging in developing countries. Its influences on outcomes of childhood cancer are unknown. A recent Children's Oncology Group symposium considered epidemiology of obesity, pharmacology of chemotherapy and outcomes in obese adults with cancer, excess mortality in obese pediatric patients with acute myeloid leukemia (AML), and complications in obese survivors. The salient points are summarized herein. Body mass index (BMI) is the accepted index of weight for height and age. In the US, obesity prevalence (BMI > 95th centile) is increasing in all pediatric age groups and accelerating fastest among black and Hispanic adolescents. Pharmacologic investigations are few and limited: half-life, volume of distribution, and clearance in obese patients vary between drugs. Obese adults with solid tumors generally experience less toxicity, suggesting underdosing. For patients undergoing bone marrow transplantation, obese adults generally experience greater toxicity. In pediatric acute myeloblastic leukemia, obese patients have greater treatment-related mortality (TRM), similar toxicity and relapse rates, and inferior survival compared with patients who are not obese. An excess of female survivors of childhood leukemia who received cranial irradiation are obese. Ongoing treatment effects of childhood cancer may predispose to a sedentary lifestyle. These findings call for measures to prevent obesity, retrospective and prospective studies of chemotherapy pharmacology of analyzed according to BMI and outcomes, additional studies of the obesity impact on outcomes in pediatric cancer, and promotion of a healthy lifestyle among survivors., (2005 Wiley-Liss, Inc.)

Objective: Trifluoromethane and CO are produced simultaneously during the breakdown of isoflurane and desflurane by dry CO2 absorbents. Trifluoromethane interferes with anesthetic agent monitoring, and the interference can be used as a marker to indicate anesthetic breakdown with CO production. This study tests representative types of gas monitors to determine their ability to provide a clinically useful warning of CO production in circle breathing systems., Methods: Isoflurane and desflurane were reacted with dry Baralyme at 45 degrees C. Standardized samples of breakdown products were created from mixtures of reacted and unreacted gases to simulate the partial degrees of reaction which might result during clinical episodes of anesthetic breakdown using 1% or 2% isoflurane and 6% or 12% desflurane. These mixtures were measured by the monitors tested, and the indication of the wrong agent or a mixture of agents due to the presence of trifluoromethane was recorded and related to the CO concentration in the gas mixtures., Results: When presented with trifluoromethane from anesthetic breakdown, monochromatic infrared monitors displayed inappropriately large amounts of isoflurane or desflurane. Agent identifying infrared and Raman scattering monitors varied in their sensitivity to trifluoromethane. Mass spectrometers measuring enflurane at mass to charge = 69 were most sensitive to trifluoromethane., Conclusion: Monochromatic infrared monitors were unable to indicate anesthetic breakdown via interference by trifluoromethane, but did indicate falsely elevated anesthetic concentrations. Agent identifying infrared and Raman monitors provided warning of desflurane breakdown via the interference of trifluoromethane by displaying the wrong agent or mixed agents, but may not be sensitive enough to warn of isoflurane breakdown Some mass spectrometers provided the most sensitive warnings to anesthetic breakdown via trifluoromethane, but additional data processing by some patients monitor units reduced their overall effectiveness.

Background: The chemical breakdown of isoflurane, enflurane, or desflurane in dried carbon dioxide absorbents may produce carbon monoxide. Some mass spectrometers can give false indications of enflurane during anesthetic breakdown., Methods: During clinical anesthesia with isoflurane or desflurane, the presence of carbon monoxide in respiratory gas was confirmed when enflurane was inappropriately indicated by a clinical mass spectrometer that identified enflurane at mass to charge ratio = 69. In vitro, isoflurane, enflurane, or desflurane in oxygen was passed through dried carbon dioxide absorbents at 35, 45, and 55 degrees C. Gases were analyzed by gas chromatography and by mass spectrometry., Results: Mass spectrometry identified several clinical incidents in which 30-410 ppm carbon monoxide was measured in respiratory gas. Trifluoromethane was produced during in vitro breakdown of isoflurane or desflurane. Although these inappropriately indicated quantities of "enflurane" correlated (r2 > 0.95) to carbon monoxide concentrations under a variety of conditions, this ratio varied with temperature, anesthetic agent, absorbent type, and water content., Conclusions: Trifluoromethane causes the inappropriate indication of enflurane by mass spectrometry, and indicates isoflurane and desflurane breakdown. Because the ratio of carbon monoxide to trifluoromethane varies with conditions, this technique cannot be used to quantitatively determine the amount of carbon monoxide to which a patient is exposed. If any warning of anesthetic breakdown results from this technique then remedial steps should be taken immediately to stop patient exposure to carbon monoxide. No warning can be provided for the breakdown of enflurane by this technique.

The extent to which the procainamide-dextrose complex reverts to free procainamide hydrochloride in plasma was studied in vitro. The procainamide-dextrose species was formed, isolated using preparative liquid chromatography, and then added to six different lots of pooled plasma that were maintained at physiological temperature (37 +/- 0.1 degrees C). At zero, four, and eight hours after preparation of the samples, 1-mL portions were removed from each sample, extracted, and assayed for procainamide hydrochloride using high-performance liquid chromatography. The mean procainamide hydrochloride concentrations at zero, four, and eight hours after preparation were 2.67, 4.81, and 1.38 g/mL, respectively. Each lot of pooled plasma was statistically analyzed to determine if a significant amount of procainamide hydrochloride reappeared. Analysis of variance showed significant difference between the concentrations of free procainamide hydrochloride in the samples at zero, four, and eight hours (p less than 0.02). Follow-up with Duncan's multiple comparisons test determined that the mean procainamide hydrochloride concentrations immediately after preparation were not significantly different from those at eight hours, but the mean procainamide hydrochloride concentrations at four hours were significantly different from those at eight hours (p less than 0.01). A paired Student's t test comparing the data from zero and eight hours showed a significant reduction in mean procainamide hydrochloride concentrations with time (p less than 0.05). The procainamide-dextrose complex in vitro does not revert to free procainamide hydrochloride in plasma at physiological temperature during the first eight hours.

An open-label, dose-escalation study was conducted to determine doses of lorazepam required to induce anterograde amnesia and sedation in children without producing excessive toxicity. Oncology patients 4 to 17 years of age undergoing lumbar puncture or bone marrow aspiration were eligible; a patient could be entered in the study for a second procedure at a different lorazepam dose. A single oral dose of lorazepam was administered 45-60 minutes before the procedure. Starting with 0.02 mg/kg, the same dose was given to three patients; if no dose-limiting effects occurred, dose was increased by 0.01 mg/kg. Before the procedure the patient was shown a toy that he or she was later asked to identify. Immediately after the procedure (usually 60-75 minutes after the lorazepam dose), sedation was assessed on a scale of 0 (alert) to 4 (coma), and the clinician performing the procedure was asked to subjectively evaluate sedation. Patients were rated for amnesia 24 hours after the procedure; a scale of 0 (recalls procedure and toy without prompting) to 4 (recalls nothing since procedure) was used. Twenty patients received 28 doses of lorazepam. The study was terminated when two patients who received 0.10 mg/kg had excessive ataxia. Sedation was subjectively considered adequate for 24 of the procedures. Sedation and amnesia scores were not well correlated with increased dose. Amnesia occurred in some patients with doses as low as 0.03 mg/kg. In children undergoing lumbar puncture or bone marrow aspiration, premedication with oral lorazepam 0.02-0.09 mg/kg generally produced adequate sedation for the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

A highly deactivated octadecyl-bonded silica column and a mobile phase consisting of an water-methanol mixture in the range of blood pH and ionic strength are used to correlate log kappa' with biological activity for a series of sulfonamides and barbiturates. The results were compared to literature methods by using retention volume (VR) and retention indexes (I). For the nine sulfonamides tested, log VR and log kappa' were used with and without correction for ionization. For each biological end point (protein binding and minimum inhibitor concentration against Eschericia coli from two sources) and each independent variable (log kappa' and log VR) the residual standard derivation for the regression was determined. the standard derivations were compared in an F test for each of 12 relevant regressions. Log kappa' was statistically superior in for cases, while log VR was superior in one case. Overall, the methods were statistically indistinguishable. Log kappa' values and I values for 15 barbiturates were regressed against three biological end points [hypnotic activity (the minimum effective dose in rabbits), inhibition of Arbacia egg cell division, and inhibition of rat brain respiration]. Standard deviations were compared by an F test, and the two methods were indistinguishable as far as the goodness of biological correlations are concerned. Procedures for controlling the column's activity are presented. Choices for an appropriate mobile phase are discussed, and a method of calculating pH and ionic strength in a methanol-aqueous mobile phase is presented.

Structural characteristics of Adriamycin and daunorubicin analogs are discussed in terms of three antitumor activity classifications: compounds with potency and efficacy equivalent to or superior to the parent antibiotics, compounds displaying high efficacy but with decreased potency, and compounds in which a key structural change has destroyed all in vivo antitumor activity. It is first concluded that analogs possessing efficacy and potency comparable to the parent antibiotics are quite similar to the parents in structural terms, ie, their hydrophilic character, functional groups, and stereochemistry. Within this group there is suggestive evidence that altered electronic character of the aglycones may be associated with improved cardiotoxicity characteristics. The second general conclusion is that high efficacy accompanied by decreased potency is compatible with a much wider array of structural variants than is high efficacy accompanied by high potency. Thus, analogs with substantially higher or lower lipophilicity than the parent antibiotics, as well as those with an array of ionic characteristics differing from the parents, retained significant efficacy. These characteristics are compatible with the concept of multiple mechanisms of action for the anthracycline antibiotics. In general, structural changes in the sugar side chain are appreciably more compatible with retention of in vivo antitumor efficacy than are changes in the aglycone, both in terms of functional groups and stereochemistry.

A series of rubidazone analogues (4-14) with varying phenyl group substituents was prepared. The effect of these compounds on inhibition of nucleic acid synthesis in cultured cells, on in vivo antitumor properties, and on cardiotoxicity was examined. Substituent effects on drug-DNA binding as indicated by DNA melting temperature measurements were also investigated. Substituent effects were essentially absent among the rubidazone analogues in in vivo and in vitro test systems which measure cytotoxic characteristics; however, the rubidazone analogues varied substantially in their cardiotoxic effects and this variation was closely correlated with the electronic character of the phenyl substituent.

2-Deaminoactinomycin D has been synthesized and characterized. It binds to DNA by intercalation according to NMR, CD, thermal denaturation, and unwinding studies on the drug-DNA complex. Loss of the 2-amino group does not seriously affect binding parameters relative to actinomycin D; affinity for calf thymus DNA may even be increased, according to deltaTm measurements. The unwinding of circular DNA caused by this compound is at least as large as that effected by actinomycin D and ethidium bromide. Nevertheless, 2-deaminoactinomycin D is less effective than actinomycin D in inhibiting nucleic acid syntheses in L1210 cell culture and in in vivo antitumor activity against P388 leukemia.

3-Aminopyrrolidines bearing acyl substituents on either nitrogen and N-acylated 1,4-diazabicyclo[3.2.1]octanes are potent microfilaricides in the Litomosoides carinii gerbil test system but have no effect on adult worms. The high activity of the pyrrolidine derivatives establishes that diethylcarbamazine (DEC) like antifilarial activity does not require that both pharmacophores be incorporated into one ring. Results with the 1,4-diazabicyclo[3.2.1]octanes establish that an axial conformation of the alkyl substituent corresponding to the equatorial N-methyl group of diethylcarbamazine is fully consistent with high activity. Other conformational consideration pertinent to DEC analogues are discussed.

Reaction of daunorubicin (1) and adriamycin (2) with aldehydes and ketones in the presence of NaCNBH3 afforded N-alkyl- and N,N-dialkylanthracyclines along with their 13-dihydro derivatives. Product ratios depended upon the nature of the carbonyl reagent and the starting drug. The majority of these analogues retained in vivo antitumor activity comparable to 1 and 2. However, unlike the parent compounds, which inhibit DNA and RNA synthesis at comparable concentrations, several of these analogues inhibit RNA synthesis at markedly lower concentrations than required to inhibit DNA synthesis. In addition, in some cases the ability to bind to DNA in vitro was reduced while antitumor activity was retained. N,N-Dibenzyldaunorubicin was especially notable for increased efficacy (T/C 259, qd 1--9) against P388 leukemia in mice, despite reduction of DNA binding in vitro. It showed almost complete loss of mutagenicity vs S. typhimurium (Ames test) and it was tenfold less cardiotoxic by electrocardiographic measurements (Zbinden test) in the rat.

Treatment of daunorubicin with methanolic ammonia affords 5-iminodaunorubicin, the first quinone-modified analogue of either daunorubicin or adriamycin. This product retains antileukemic activity in mice, is less cardiotoxic by electrocardiographic measurements in rats, and is nonmutagenic in Salmonella typhimurium (Ames test).

The stability of a propranolol hydrochloride suspension compounded from commercially available tablets was studied. Propranolol hydrochloride 10-mg tablets were triturated to a powder and incorporated into a commercially available suspension vehicle to yield a suspension with a theoretical propranolol hydrochloride concentration of 1 mg/mL. The suspension was divided into portions and stored in amber glass bottles at either room (25 degrees C) or refrigerated (2 degrees C) temperature for four months. The concentration of propranolol hydrochloride in the samples was determined by a stability-indicating, high-performance liquid chromatographic (HPLC) assay at 0, 30, 60, 90, and 120 days. Also at these times, the pH of the samples was measured, and the samples were inspected visually for evidence of microbial growth and ease of resuspension. The concentration of propranolol hydrochloride in the samples remained within 90% of the initial concentration throughout the study period. No important changes in the pH of the samples and no visible evidence of microbial growth were noted. This extemporaneous suspension of propranolol hydrochloride compounded from commercially available tablets is stable for at least four months when stored at room or refrigerated temperature.

The syntheses of several 13-deoxyanthracyclines are described. Koenigs-Knorr condensation of epsilon-rhodomycinone (12) with the protected daunosaminyl chloride 15 afforded 14 after deprotection. Efforts to decarbomethoxylate 12, as well as attempts to selectively deoxygenate the 13 position of daunomycinone and adriamycinone, were unsuccessful as approaches to 13-deoxyanthracyclines. However, reaction of the readily available tosylhydrazones 4 and 5, of daunorubicin and adriamycin with NaCNBH3 in acidic MeOH, afforded the 13-deoxy analogues 6 and 7 in satisfactory yield. These compounds retained antitumor activity, being comparable to the parent compounds in both efficacy and potency in the P-388 mouse leukemia screen. The epsilon-rhodomycinone glycoside 14 was less active than 6 and 7.

Synthetic approaches to anthracyclines bearing novel 9-acyl substituents were investigated. Reaction of the lithium enolate of N-(trifluoroacetyl)daunorubicin (9) with methyl iodide in tetrahydrofuran afforded only the 9-propionyl derivative 10 in high yield. Reaction of 10 under identical conditions cleanly afforded the 9-isobutyryl derivative 11. Extension of this procedure to other alkylating agents (ethyl iodide, benzyl bromide, and heptyl iodide) required hexamethylphosphoramide as cosolvent and afforded mixtures of mono- and dialkylated products as well as recovered 9. The amino group was deblocked with NaOH in aqueous tetrahydrofuran, except in the case of the dibenzyl derivative 13 which was inert under these conditions. The 9-formyl analogue 23 was prepared via NaIO4 cleavage of 13-dihydroadriamycin (21). Antitumor evaluation against P388 leukemia in mice showed 23 to have activity comparable to the parent compounds, while the C-alkylated analogues were less active.

The 3-(hydroxymethyl) branched homologue of 2-deoxyribofuranose was synthesized from the corresponding branched ribofuranose 2-O-(S-methyl dithiocarbonate) with tributyltin hydride in the first direct, one-step deoxygenation at C-2 of a ribofuranose. Nucleoside coupling afforded the corresponding 3'-branched 2'-deoxyribonucleosides of thioguanine. The alpha- and beta-nucleosides were equally inhibitory to growth of WI-L2 human lymphoblastoid cells, were phosphorylated and incorporated into the DNA of Mecca lymphosarcoma in mice to the same degree, and were more effective in these tests than the parent analogue alpha-2'-deoxythioguanosine. These results indicate that the hydroxy functions at the 3' and 5' positions of 2'-deoxynucleosides are interchangeable and that acceptance by the that the furanose ring oxygen and 2'-methylene are corresponding interchangeable, and that acceptance by the enzymes is improved if primary hydroxyls are provided at both the 3' and 5' positions.

A series of ten S-substituted derivatives of the alpha and beta anomers (1a and 1b) of 2'-deoxy-6-thioguanosine has been prepared by S-alkylation of the parent nucleosides and/or by mercaptide displacement reactions on 6-chloro intermediates. Against L1210 murine leukemia all beta anomers were active but potency was reduced relative to 1b. Most S-alkyl alpha anomers were inactive in this test. Limited testing against P388 murine leukemia showed all alpha-anomer derivatives to be inactive but the beta anomers were more effective than the parent. S-Substitution sharply reduced acute toxicity in both series. In vitro DNA and RNA synthesis inhibition data are also reported. The antitumor activity of these derivatives and of the 2',5'-di-O-acetyl derivatives of 1a and 1b against lymphoid leukemia L1210 is reported. Some results with the lymphocytic leukemia P388 and an in vitro assay of the inhibition of nucleic acid synthesis are also given.

Adriamycin is selectively cleaved in high yield at the C13-C14 bond by 1 equiv of sodium metaperiodate to yield carboxylic acid 3. The corresponding methyl ester 4 is obtained by Fischer esterification. Spectral studies indicate that 3 and 4 bind to calf thymus DNA in a manner similar to adriamycin and daunomycin but Tm measurements suggest that less stable complexes are formed. Ester 4 inhibits DNA and RNA synthesis in cultured L1210 cells at levels comparable to adriamycin but acid 3 is much less effective. Both new compounds are moderately effective as antitumor agents against P388 lymphocytic leukemia in the mouse.

One-step treatment of daunomycinone with excess 2-aminoethanethiol and 2-aminoethanol in trifluoroacetic acid afforded at C-7 the thioether (77% yield) and ether (30% after recycling), respectively. Stereoselectivity for the natural 7S over the 7R configuration was greater for the ether (97:3) than for the thioether (2.5:1). Esterification of daunomycin at C-7 with beta-alanine was accomplished through the mixed anhydride of Z(OMe)-beta-alanine. Preliminary biological tests suggests that the antitumor and DNA interactive properties of the anthracyclines can be retained in such structures.

The activity of a number of substituted alkylaminoanthraquinones was compared in transplanted murine tumor systems including P388 and L1210 leukemias, B16 melanoma, and colon carcinoma 26. The structure-activity relationships among this class of compounds are discussed. Several derivatives had very high antitumor activity in several tumor systems. Two of the most active derivatives, namely, 1,4-bis(2-[(2-hydroxyethyl)amino]ethylamino)-9,10-anthracenedione (bisalkylAAD) and 1,4-dihydroxy-5,8-bis(2-[(2-hydroxyethyl)amino]ethylamino)-9,10-anthracenedione (dihydroxybisalkylAAD), which had curative activity in the above-mentioned tumors, were compared in considerable detail. DihydroxybisalkylAAD showed distinct advantages over bisalkylAAD in several tumor systems and is tenfold more potent with respect to effective dose range. This last difference is important for two reasons. First, these aminoanthraquinones are strong and persistent blue dyes and the administration of lower doses would minimize a potential cosmetic drawback of these compounds. Second and most important, iv administration of dose levels of bisalkylAAD which are within the therapeutic dose range on intermittent dose schedules produced convulsions and immediate death. IV administration of dihydroxybisalkylAAD also caused acute toxicity, but, because of its increased potency relative to antitumor activity and delayed toxicity, this acute toxicity was apparent only at doses well above the therapeutic dose range. All of the aminoanthraquinones evaluated, regardless of their activity as antitumor agents in vivo, proved to be potent inhibitors of DNA and RNA synthesis in vitro and bound strongly to DNA as evidenced by deltaTm values (deltaTm = upward shift in DNA melting temperature). Thus, the strong antitumor activity of aminoanthraquinones would appear to be due to some mechanism other than, or in addition to, DNA binding and inhibition of nucleic acid synthesis.