Anthracycline Analogues Research Articles

A Novel Anti-CD22 Anthracycline-Based Antibody-Drug Conjugate (ADC) That Overcomes Resistance to Auristatin-Based ADCs.

We are interested in identifying mechanisms of resistance to the current generation of antibody-drug conjugates (ADC) and developing ADCs that can overcome this resistance. Pinatuzumab vedotin (anti-CD22-vc-MMAE) and polatuzumab vedotin (anti-CD79b-vc-MMAE) are ADCs that contain the microtubule inhibitor monomethyl auristatin E (MMAE) attached to the antibody by the protease-cleavable linker maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-vc-PAB). Early clinical trial data suggest that these ADCs have promising efficacy for the treatment of non-Hodgkin lymphoma (NHL); however, some patients do not respond or become resistant to the ADCs. Anthracyclines are very effective in NHL, but ADCs containing the anthracycline doxorubicin were not clinically efficacious probably due to the low drug potency and inadequate linker technology. The anthracycline analogue PNU-159682 is thousands of times more cytotoxic than doxorubicin, so we used it to develop a new class of ADCs. We used the same MC-vc-PAB linker and antibody in pinatuzumab vedotin but replaced the MMAE with a derivative of PNU-159682 to make anti-CD22-NMS249 and tested it for in vivo efficacy in xenograft tumors resistant to MMAE-based ADCs. We derived cell lines from in vivo xenograft tumors that were made resistant to anti-CD22-vc-MMAE and anti-CD79b-vc-MMAE. We identified P-gp (ABCB1/MDR1) as the major driver of resistance to the vc-MMAE-based conjugates. Anti-CD22-NMS249 was at least as effective as anti-CD22-vc-MMAE in xenograft models of the parental cell lines and maintained its efficacy in the resistant cell lines. These studies provide proof of concept for an anthracycline-based ADC that could be used to treat B-cell malignancies that are resistant to vc-MMAE conjugates.

Cytotoxicity and induction of apoptosis by formamidinodoxorubicins in comparison to doxorubicin in human ovarian adenocarcinoma cells

Background/aimIn this study we investigated the effect of DOX and five of its derivatives containing a formamidine group (NCHNRR) at the 3′ position with pyrrolidine (DOX-F PYR), piperidine (DOX-F PIP), morpholine (DOX-F MOR), N-methylpiperazine (DOX-F PAZ) and hexamethyleneimine (DOX-F HEX) ring on SKOV-3 ovarian cancer cells. We have focused on the anti-proliferative activity and the value of apoptosis induced by tested analogues. Materials and methodsThe following methods were used: spectrophotometric assay with MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide); fluorimetric assays – double staining with Hoechst 33258 and propidium iodide (PI), measurement of caspase-3 activity; flow cytometry methods – phosphatidylserine (PS) externalization using Annexin V-FITC and PI fluorochromes, and TUNEL assay. ResultsAll of the investigated derivatives were considerably more cytotoxic to the SKOV-3 cell line than DOX. The predominant type of cell death induced by the anthracycline analogues was apoptosis. Necrotic cells represented only a small percentage (<5%) of all cells. The number of apoptotic cells was dependent on the compound and the incubation time. Moreover, a significant increase in caspase-3 activity, DNA fragmentation, and morphological changes in ovarian cells were observed predominantly in new DOX analogues. ConclusionsAll new formamidine derivatives of DOX were effective against ovarian cancer cells. They induced mainly the apoptotic pathway of cell death mediated by caspase-3. The most promising results were obtained for DOX-F MOR and DOX-F PAZ. The least potent was DOX-F HEX.

Cardiovascular Safety Monitoring During Oncology Drug Development and Therapy

Assessments of cardiac and cardiovascular toxicity are prominent components of drug safety endeavors during drug development and clinical practice. Oncologic drugs bring several challenges to both domains. First, during drug development, it is necessary to adapt the ICH E14 "Thorough QT/QTc Study" because the cytotoxic nature of many oncologics precludes their being administered to healthy individuals. Second, appropriate benefit-risk assessments must be made by regulators: given the benefit these drugs provide in life-threatening illnesses, a greater degree of risk may be acceptable when granting marketing authorization than for drugs for less severe indications. Third, considerable clinical consideration is needed for patients who are receiving and have finished receiving pharmacotherapy. Paradoxically, although such therapy has proved very successful in many cases, with disease states going into remission and patients living for many years after cessation of treatment, cardiotoxicities can manifest themselves relatively soon or up to a decade later. Oncologic drugs have been associated with various off-target cardiovascular responses, including cardiomyopathy leading to heart failure, cardiac dysrhythmias, thromboembolic events, and hypertension. Follow-up attention and care are, therefore, critical. This article reviews the process of benefit-risk estimation, provides an overview of nonclinical and preapproval clinical assessment of cardiovascular safety of oncology drugs, and discusses strategies for monitoring and management of patients receiving drugs with known cardiotoxicity risk. These measures include cardiac function monitoring, limitation of chemotherapy dose, use of anthracycline analogs and cardioprotectants, and early detection of myocardial cell injury using biomarkers.

Successful Salvage Chemotherapy with Amrubicin for Invasive Thymoma Associated with Myasthenia Gravis

Anthracycline-based regimens with cisplatin have been commonly used for inoperable and relapsed thymoma. However, little information is available regarding the usefulness of salvage chemotherapy. Here, we describe a case of invasive thymoma associated with myasthenia gravis that showed a marked response to third-line chemotherapy, with single-agent amrubicin, a synthetic anthracycline analog and potent deoxyribonucleic acid topoisomerase II inhibitor. Amrubicin appears to have significant activity against invasive thymoma.

Significant dose Escalation of Idarubicin in the treatment of aggressive Non- Hodgkin Lymphoma leads to increased hematotoxicity without improvement in efficacy in comparison to standard CHOEP-14: 9-year follow up results of the CIVEP trial of the DSHNHL

BackgroundDose escalation and modification of CHOP has improved the prognosis of patients with aggressive lymphoma; even in the rituximab era, dose escalation for high-risk patients is exploited and frequently limited by drug toxicity. Idarubicin (Id) is a 4-demethoxy anthracycline analogue of daunorubicin with activity against lymphoma and has been reported to cause less cardiotoxicity than other anthracylines. The aim of this study was to replace doxorubicine with idarubicin in the CHOEP regimen and to find the maximum tolerable dose (MTD) of idarubicin based on hematotoxicity.Patients and methodsBetween 11/96 and 09/98, 64 patients (pts) aged 18–75 yrs (pts. 18–60, LDH not elevated, >60 years all risk groups) with newly diagnosed aggressive lymphoma received 6 cycles of CIVEP-14 with an escalating dose of idarubicin, consisting of idarubicin (11–16 mg/m2 d1) and standard doses of cyclophosphamide, vincristine, etoposide, and prednisone with G-CSF support.Results55 pts (median age 56 yrs) were evaluable for a final analysis with a median observation time of 9.3 years. The CR-rate was 77.4% ; the 5 and 8-year-EFS rates were 46.4% (95%CI 32.5-60.3%) and 43.5% (29.4-57.6%), respectively, and the 5- and 8 yr OS rates were 64.6% (51.7-77.5%) and 59.9% (46.4-73.4%). 14/55 patients have died due to lymphoma progression, and 2/55 patients (3.6%) due to treatment related toxicity, 4/55 due to other causes (3 infections, 1 acute heart failure). In a matched pair analysis comparing CHOEP-14 and CIVEP-14, CIVEP-14 had a higher hematotoxicity with no significant differences in the event free and overall survival for the two regimens.ConclusionsThus, idarubicin cannot be used instead doxorubicin even if its dose is escalated to achieve similar hematotoxicity. Doxorubicin remains the standard anthracycline for the treatment of aggressive NHL.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-3-5) contains supplementary material, which is available to authorized users.

Short and efficient synthesis of a daunosamine donor from l-fucal

Anthracyclines, e.g. daunorubicin, doxorubicin, and idarubicin, consist of a tetracycline moiety linked via a glycosidic bond to a sugar residue, usually the aminosugar daunosamine. The anthracyclines are efficient chemotherapeutic agents against cancer, but their use is limited due to cardiotoxicity and induction of multidrug resistance. In the search for new anthracycline analogs, a daunosamine donor that can be used to glycosylate suitable aglycons is of utmost importance. Here, we present a short and efficient synthesis of the versatile donor p-tolyl 4-O-acetyl-3-azido-2,3,6-trideoxy-1-thio-α-L-lyxo-hexopyranoside in 3 steps from commercially available L-fucal with an overall yield of 32%. The same procedure can be used to synthesize the donor p-tolyl 4-O-acetyl-3-azido-2,3,6-trideoxy-1-thio-α-L-arabino-hexopyranoside in 28% overall yield from L-rhamnal, for the synthesis of epirubicin analogs.

Strategies to Prevent and Treat Cardiovascular Risk in Cancer Patients

Cardiotoxicity due to cancer treatment is of rising concern, for both cardiologists and oncologists, because it may have a significant impact on cancer patient management and outcome. The most typical manifestation of cardiotoxicity is a hypokinetic cardiomyopathy leading to heart failure. However, the spectrum of the toxic effects that can impair the cardiovascular system may also include acute coronary syndromes, hypertension, arrhythmias, and thromboembolic events. Patients undergoing cancer treatment are more vulnerable to cardiovascular injuries, and their risk of premature cardiovascular disease and death is higher than that of the general population. Prevention of cardiotoxicity remains the most important strategy, and several measures, including cardiac function monitoring, limitation of chemotherapy dose, use of anthracycline analogues and cardioprotectants, and early detection of myocardial cell injury by biomarkers, have been proposed. The response to modern heart failure therapy of cancer treatment-induced cardiomyopathy has never been evaluated in clinical trials, and currently there are no definitive guidelines. Although it is likely that medications used for other forms of cardiomyopathy, particularly angiotensin-converting enzyme inhibitors and β-blockers, may be highly effective, there is still some unjustified concern regarding their use in cancer patients. Specific guidelines that take cardiologic conditions of cancer patients into account are currently lacking and need to be developed.

The impact of age on a mitoxantrone-based tumor vaccine

Meeting abstracts Several chemotherapies, including the anthracycline analog mitoxantrone, are known to induce an immunogenic cell death in tumor cells that can produce a protective anti-tumor immune response in mice. Although the anti-tumor immune response mediated by mitoxantrone tumor cell death

Topical valrubicin application reduces skin inflammation in murine models

Valrubicin is a cytostatic anthracycline analogue, lacking toxicity by skin and tissue contact, and represents a new drug with potential for topical treatment of psoriasis and nonmelanoma skin cancer (NMSC); the beneficial effects have been partly explained by its antiproliferative and proapoptotic characteristics. To assess the effect of valrubicin on skin inflammation as inflammation also plays a key role in psoriasis and NMSC. The effect of topical valrubicin treatment on skin inflammation in vivo was addressed in skin inflammation mouse models, where 12-O-tetradecanoylphorbol 13-acetate was used to induce irritant contact dermatitis. An acute and a chronic model were included, to investigate the effect of valrubicin in short-term inflammation and in more persistent inflammation. Inflammation-associated ear oedema was evaluated by measuring ear thickness, infiltration of neutrophil cells, and expression of inflammatory cytokines, interleukin (IL)-1β and IL-6. Topical valrubicin treatment effectively reduced the inflammatory response in the acute and the chronic models. The present data document an anti-inflammatory effect of valrubicin, and may suggest an interesting new role for valrubicin in other debilitating skin diseases in which inflammation is a significant factor.

Effect of berubicin, the 4'-o-benzylated doxorubicin analog, on growth inhibition and apoptosis in multiple myeloma.

e18557 Background: Doxorubicin (DOX), an anthracycline, topoisomerase II inhibitor, is routinely used for hematologic malignancies including multiple myeloma (MM); however, its efficacy is limited by drug resistance and cardiotoxcity. To overcome these limitations, we designed, synthesized and tested Berubicin (BRN). BRN has been evaluated in clinical trials in neuroblastoma multiforme. It is a representative of a novel class of mechanistically altered anthracycline analogs. The data obtained from this study will serve as the basis for the rapid translation of BRN from the bench to the clinic in a phase I clinical trial for patients with MM at MD Anderson Cancer Center. Methods: We investigated the effects of BRN, DOX and Bortezomib (BTZ) in 3 human MM cell lines, MM1S, ARP-1, U266, and freshly isolated primary samples from patients with MM. MM cells were treated with BRN, DOX, and BTZ. The effects of these compounds on cell proliferation, apoptosis, and the cell cycle were analyzed using MTS assay and flow cytometry analysis. Results: BRN potently inhibited the growth of the established MM cell lines, as well as the freshly isolated primary MM cells in a dose-dependent manner. It showed growth inhibition at IC50 of 5.99 nM (U266), 5.21 nM (MM1S) and 3.99 nM (ARP-1), and was more potent than doxorubicin (IC50 14.63 nM, 7.24 nM and 11.06 nM) and bortezomib (IC50 304.9 nM, 15.47 nM and 53.19 nM). In contrast, BRN did not affect the proliferation of patient-derived normal bone marrow cells (CD138- cells) at the concentrations that were lethal to MM cells. Conclusions: Berubicin not only induced apoptosis in 3 cell lines in dose-dependent manners but also induced G2/M cell cycle arrest in 3 cell lines. In conclusion, BRN was effective against MM cells in vitro and will be applied to our planned clinical trial.

Doxorubicin- and Daunorubicin-Induced Regulation of Ca2+ and H+ Fluxes Through Human Bax Inhibitor-1 Reconstituted into Membranes

Bax inhibitor-1 (BI-1) is an evolutionarily conserved cell death suppressor in both animals and plants. We examined the effect of doxorubicin (DXR) and daunorubicin (DNR), which are clinically important anthracycline compounds, on the functional regulation of BI-1 reconstituted into membranes. DXR and DNR inhibited the proton-induced efflux of encapsulated Ca(2+) from membranes in a drug concentration-dependent manner. Both compounds also reduced the H(+) influx activity of BI-1. The proteoliposomes containing BI-1 increased the quenching of DXR fluorescence by Cu(2+), and the fluorescence energy transfer between pyrene-labeled BI-1 and DXR was enhanced with increasing DXR concentrations. The dissociation constants and the number of binding sites for both drugs in BI-1 were determined to be in the range of 3.7-4.5 × 10(-6) m and approximately 4-5/BI-1 molecule, respectively, using a proteomicelle system. DXR also induced secondary structural changes in reconstituted BI-1 and abolished the ability of BI-1-overexpressing cells to protect against endoplasmic reticulum stress-induced cell death. However, when mitoxantrone was used instead of DNR and DXR as an anthracycline analog, no significant effects were observed. These results suggest that BI-1 can be considered to be a new cancer therapeutic target by anthracyclines because of its stimulatory effects in cancer/tumor progression.

Exploration of small hydroxy‐9,10‐anthraquinones as anthracycline analogues: physicochemical characteristics and DNA binding for comparison

Hydroxy‐9,10‐anthraquinones resemble anthracycline‐based anticancer drugs. By varying the pH of the solution, the proton dissociation constants of 1,2,5,8‐tetrahydroxy‐9,10‐anthraquinone (THAQ) were determined. Interaction of THAQ with calf thymus DNA (ct DNA) was studied by UV–Vis spectroscopy to determine the overall binding constant and site size of interaction. The binding constant values (~104) for THAQ interacting with ct DNA at different pH were an order less than that known for anthracyclines. From knowledge of the overall binding constants at different pH values and the first pK of THAQ, the contribution of each form (neutral and monoanionic) towards overall binding with ct DNA could be obtained under physiological conditions. Hence, knowing the contributions of the neutral and monoanionic forms, it now becomes possible to know the overall binding constant for an interaction of THAQ with ct DNA at any pH. The calculated parameters help in understanding the role of the negative charge on the monoanionic form during interaction and suggests suitable chemical modifications that could prevent the development of such negative charges. This could lead to an increase in binding of THAQ to ct DNA. The study also helps to recognize the importance of sugar units in anthracycline anticancer drugs in DNA interaction. Copyright © 2011 John Wiley &amp; Sons, Ltd.

The role of reactive oxygen species in WP 631-induced death of human ovarian cancer cells: A comparison with the effect of doxorubicin

In the present study, we investigated the anticancer activity of WP 631, a new anthracycline analog, in weakly doxorubicin-resistant SKOV-3 ovarian cancer cells. We studied the time-course of apoptotic and necrotic events: the production of reactive oxygen species (ROS) and changes in the mitochondrial membrane potential in human ovarian cancer cells exposed to WP 631 in the presence and absence of an antioxidant, N-acetylcysteine (NAC). The effect of WP 631 was compared with the activity of doxorubicin (DOX), the best known first-generation anthracycline.Cytotoxic activity was determined by the MTT assay. The morphological changes characteristic of apoptosis and necrosis in drug-treated cells were analyzed by double staining with Hoechst 33258 and propidium iodide (PI) using fluorescence microscopy. The production of reactive oxygen species and changes in mitochondrial membrane potential were studied using specific fluorescence probes: DCFH2-DA and JC-1, respectively.The experiments showed that WP 631 was three times more cytotoxic than DOX in the tested cell line. It was found that the new anthracycline analog induced mainly apoptosis and, marginally, necrosis. Apoptotic cell death was associated with morphological changes and a decrease in mitochondrial membrane potential. In comparison to DOX, the novel bisanthracycline induced a significantly higher level of ROS and a greater drop in the membrane potential.The results provide direct evidence that the novel anthracycline WP 631 is considerably more cytotoxic to human SKOV-3 ovarian cancer cells than doxorubicin. The drug can produce ROS, which are immediately involved in the induction of apoptotic cell death.

Treatment and prevention of cardiotoxicity due to anticancer therapy

Abstract Cardiotoxicity induced by anticancer treatment still remains an unanswered problem strongly affecting the quality of life and the overall survival of cancer patients. The most typical form of cardiotoxicity, a dilated cardiomyopathy, usually becomes manifest late in the course of the disease and it is classically considered to be refractory to therapy. Prevention of cardiotoxicity remains the most important strategy and several measures, including cardiac function monitoring, limitation of chemotherapy dose, use of anthracycline analogues and cardioprotectants, and early detection of cardiotoxicity by biomarkers, have been proposed. The response to modern heart failure therapy of chemotherapy-induced cardiomyopathy has never been evaluated in clinical trials, and evidence-based recommendations for its treatment are still lacking. Although it is likely that angiotensin-converting-enzyme inhibitors and beta-blockers, used for other forms of cardiomyopathy may be highly effective also in this setting, there is still some unjustified concern to use them in asymptomatic cancer patients, and current management mainly focuses on treatment of only symptomatic patients.

Effects of three new anthracyclines and doxorubicin on the rat isolated heart.

The acute cardiac toxicity of three second-generation anthracycline analogues and doxorubicin was compared in a model of the rat isolated Langendorff perfused heart. The drugs, doxorubicin (DX), 4-epi-doxorubicin (4'EDX), 4-demethoxy-daunorubicin (4DMDR) and 4'-deoxy-doxorubicin (4'dxDX) were infused for 40 min at a concentration of 26 microM into the isolated hearts. All four compounds significantly reduced cardiac work and its first derivative. The time to 50% decrease in work (TW50) was respectively 36, 23, 9 and 7 min for DX, 4'EDX, 4'dxDX and 4DMDR. The three anthracycline derivatives, but not DX, significantly increased coronary resistance. Heart rate was reduced by all compounds compared with baseline, but not compared with controls. Rhythm disturbances were seen with all five hearts perfused with 4DMDR, which stopped beating before 40 min; 2/5 hearts in the 4'EDX group and 1/5 hearts in the 4'dxDX group also stopped before the end of perfusion. All the compounds reached concentrations in the myocardium 8 to 50 times higher than in the perfusing medium. The more cardiotoxic the compound, the higher was its myocardial concentration; a significant correlation was found for all four agents. Noradrenaline was never measurable in the perfusate of control and DX hearts; perfusion with the three anthracycline derivatives caused some release, but the pattern was not clearcut and the maximum concentrations attained in the perfusate were relatively low (less than or equal to 1.6 X 10(-9) M). In conclusion, in the rat isolated perfused heart, the early cardiotoxicity induced by equimolar concentrations of the three anthracycline compounds was greater than that induced by DX and was directly related to drug accumulation in the myocardium. Catecholamines do not seem to have a major role in the development of toxicity in this model.

Interaction of 1,4-Dihydroxy–9,10-Anthraquinone with Calf Thymus DNA: A Comparison with Anthracycline Anticancer Drugs

The anthracycline drugs adriamycin and daunorubicin, efficient in the treatment of various human cancers, form strong intercalation complexes with DNA. The therapeutic efficacy and toxicity of such anticancer drugs are governed by biochemical reactions of the core dihydroxy-9,10-anthraquinone unit. The high cost and toxic side effects of anthracycline drugs limit their use in cancer therapy. For a few decades, efforts have been made to find cheap, less toxic yet efficient analogues of anthracyclines. This work on 1,4-dihydroxy-9,10-anthraquinone (QH2), a simple analogue of the anthracyclines, was carried out to compare its biochemical properties with anthracyclines. UV-Vis and fluorescence spectroscopic methods were used to analyze interaction of the compound with calf thymus DNA. The data were used to evaluate the binding constant and site size.

Inhibitory activity of four demethoxy fluorinated anthracycline analogs against five human-tumor cell lines

Four anthracycline analogs synthesized in our laboratory were evaluated in comparison with adriamycin (doxorubicin) for their growth-inhibitory effect against five human-tumor cell lines, including lung carcinoma, colon adenocarcinoma, breast adenocarcinoma, melanoma, and glioblastoma. The compounds included 4-demethoxy-7- O-(2,6-dideoxy-2-fluoro-- l-talopyranosyl)daunomycinone ( 2), its 3′,4′-diacetate ( 1), its 14-bromo derivative 3, and its 14-hydroxy analog, namely 4-demethoxy-7- O-(2,6-dideoxy-2-fluoro-α- l-talopyranosyl)adriamycinone ( 4). Compounds 1, 2, and 3 showed moderate cytotoxic effect in most of the cell lines, while compound 4 had a strong effect, comparable to or better than that of adriamycin in most of the cell lines.

Determination of the absolute configurations of synthetic daunorubicin analogues using vibrational circular dichroism spectroscopy and density functional theory

The absolute configurations of three synthesized anthracycline analogues have been determined using vibrational circular dichroism (VCD) spectroscopy and the density functional theory (DFT) calculations. The experimental VCD spectra of the three compounds have been measured for the first time in the film state, prepared from their CDCl(3) solutions. Conformational searches for the monomers and some dimers of the three compounds have been performed at the DFT level using the B3LYP functional and the 6-311G** and 6-311++G** basis sets. The corresponding vibrational absorption and VCD spectra have been calculated. The good agreement between the experimental and the calculated spectra allows one to assign the absolute configurations of the three compounds with high confidence. In addition, the dominant conformers of the three compounds have also been identified.

SZ‐685C, a marine anthraquinone, is a potent inducer of apoptosis with anticancer activity by suppression of the Akt/FOXO pathway

The aims of this study were to investigate the anti-cancer activity of SZ-685C, an anthracycline analogue isolated from marine-derived mangrove endophytic fungi, and to explore the molecular mechanisms underlying such activity. The effect of SZ-685C on the viability of cancer cell lines was investigated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. SZ-685C-induced apoptosis was assessed by Annexin V-fluorescein isothiocyanate/propidium iodide staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling assay and analysis of caspase activation. The effect of SZ-685C on the Akt/FOXO pathway was studied using Western blotting analysis, and the in vivo anti-tumour efficacy was examined in an MDA-MB-435 breast cancer xenograft model. SZ-685C suppressed the proliferation of six cancer cell lines derived from human breast cancer, prostate cancer, glioma and hepatoma (IC(50) values ranged from 3.0 to 9.6 microM) and the growth of breast cancer xenografts in mice. SZ-685C had a direct apoptosis-inducing effect through both the extrinsic and intrinsic apoptotic pathways, as shown by activation of caspase-8 and 9 as well as effector caspase-3 and poly (ADP-ribose) polymerase. Phosphorylation of Akt and its downstream effectors, forkhead box protein O1 and forkhead box protein O3a, was down-regulated in SZ-685C-treated cancer cells. Furthermore, the pro-apoptotic protein Bim was up-regulated by SZ-685C treatment consistent with FOXO dephosphorylation. SZ-685C could induce apoptosis through the Akt/FOXO pathway, which consequently leads to the observed anti-tumour effect both in vitro and in vivo. Our data suggest that SZ-685C may be a potentially promising Akt inhibitor and anti-cancer drug candidate.

A rational approach to the synthesis of template inhibitory antitumor drugs

A rational synthesis of template inhibitory antitumor drugs (that is, the anthracyclines) is described which is based on the results of (a) in vitro studies (the interaction specificities of the drugs with template DNA), (b) pharmacological properties of the anthracyclines, and (c) the known differential physical properties of cancer versus normal cells. It appears that for most cases the in vitro studies of (a) the rates of dissociation of DNA-drug complexes, (b) the extent of inhibition of DNA-dependent RNA polymerase, and (c) the determination of the distribution coefficients of the drugs (a measure of cellular permeability) provide a fairly reliable and rapid estimate of the in vivo biological activity of the anthracycline. This conclusion is based on the comparison of the in vitro data with the results obtained from the antitumor activity of anthracycline analogs against the P-388 mouse lymphocytic tumor. In addition, it is found that enhanced chemotherapeutic indexes of the anthracyclines are obtained when administered in the form of a DNA complex. However, it is not possible to conclude that a lysosomotropic principle (as postulated by Trouet and coworkers [3-5]) is the mechanism responsible for this effect.