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Accurate neutron-capture cross sections on unstable nuclei near the line of beta stability are crucial for understanding the s-process nucleosynthesis. However, neutron-capture cross sections for short-lived radionuclides are difficult to measure due to the fact that the measurements require both highly radioactive samples and intense neutron sources. Essential ingredients for describing the γ decays following neutron capture are the γ-ray strength function and level densities. We will compare different indirect approaches for obtaining the most relevant observables that can constrain Hauser-Feshbach statistical-model calculations of capture cross sections. Specifically, we will consider photon scattering using monoenergetic and 100% linearly polarized photon beams. Challenges that exist on the path to obtaining neutron-capture cross sections for reactions on isotopes near and far from stability will be discussed., SCOPUS: cp.p, ND 2016: International Conference on Nuclear Data for Science and Technology, info:eu-repo/semantics/published

Background: One-phonon mixed-symmetry quadrupole excitations are a well-known feature of near-spherical, vibrational nuclei. Their interpretation as a fundamental building block of vibrational structures is supported by the identification of multiphonon states resulting from a coupling of fully-symmetric and mixed-symmetric quadrupole phonons. In addition, the observation of strong M1 transitions between low-lying 3(-) and 4(+) states has been interpreted as an evidence for one-phonon mixed-symmetry excitations of octupole and hexadecapole character. Purpose: The aim of the present study is to identify collective one-and two-phonon excitations in the heaviest stable N = 52 isotone Ru-96 based on a measurement of absolute M1, E1, and E2 transition strengths. Methods: Inelastic proton-scattering experiments have been performed at the Wright Nuclear Structure Laboratory (WNSL), Yale University, and the Institute for Nuclear Physics (IKP), University of Cologne. From the acquired proton-gamma and gamma gamma coincidence data we deduced spins of excited states, gamma-decay branching ratios, and multipole mixing ratios, as well as lifetimes of excited states via the Doppler-shift attenuation method (DSAM). Results: Based on the new experimental data on absolute transition strengths, we identified the 2(+) and 3(+) members of the two-phonon mixed-symmetry quintuplet (2(1,ms)(+) circle times 2(1,s)(+)). Furthermore, we observed strong M1 transitions between low-lying 3(-) and 4(+) states suggesting one-phonon symmetric andmixed-symmetric octupole and hexadecapole components in their wave functions, respectively. The experimental results are compared to sdg-IBM-2 and shell-model calculations. Conclusions: Both the sdg-IBM-2 and the shell-model calculations are able to describe key features of mixed-symmetry excitations of Ru-96. Moreover, they support the one-phonon mixed-symmetry hexadecapole assignment of the experimental 4(2)(+) state.

Background: Nuclear fission is a complex large-amplitude collective decay mode in heavy nuclei. Microscopic density functional studies of fission have previously concentrated on adiabatic approaches based on constrained static calculations ignoring dynamical excitations of the fissioning nucleus, and the daughter products. Purpose: To explore the ability of dynamic mean-field methods to describe fast fission processes beyond the fission barrier, using the nuclide $^{240}$Pu as an example. Methods: Time-dependent Hartree-Fock calculations based on the Skyrme interaction are used to calculate non-adiabatic fission paths, beginning from static constrained Hartree-Fock calculations. The properties of the dynamic states are interpreted in terms of the nature of their collective motion. Fission product properties are compared to data. Results: Parent nuclei constrained to begin dynamic evolution with a deformation less than the fission barrier exhibit giant-resonance-type behaviour. Those beginning just beyond the barrier explore large amplitude motion but do not fission, whereas those beginning beyond the two-fragment pathway crossing fission to final states which differ according to the exact initial deformation. Conclusions: Time-dependent Hartree-Fock is able to give a good qualitative and quantitative description of fast fission, provided one begins from a sufficiently deformed state., Amended version, accepted for publication in Phys. Rev. C. 22 pages, 20 figures, 7 tables

Background: Nuclear fission is a complex large-amplitude collective decay mode in heavy nuclei. Microscopic density functional studies of fission have previously concentrated on adiabatic approaches based on constrained static calculations ignoring dynamical excitations of the fissioning nucleus, and the daughter products. Purpose: To explore the ability of dynamic mean-field methods to describe induced fission processes, using quadrupole boosts in the nuclide $^{240}$Pu as an example. Methods: Quadrupole constrained Hartree-Fock calculations are used to create a potential energy surface. An isomeric state and a state beyond the second barrier peak are excited by means of instantaneous as well as temporally extended gauge boosts with quadrupole shapes. The subsequent deexcitation is studied in a time-dependent Hartree-Fock simulation, with emphasis on fissioned final states. The corresponding fission fragment mass numbers are studied. Results: In general, the energy deposited by the quadrupole boost is quickly absorbed by the nucleus. In instantaneous boosts, this leads to fast shape rearrangements and violent dynamics that can ultimately lead to fission. This is a qualitatively different process than the deformation-induced fission. Boosts induced within a finite time window excite the system in a relatively gentler way, and do induce fission but with a smaller energy deposition. Conclusions: The fission products obtained using boost-induced fission in time-dependent Hartree-Fock are more asymmetric than the fragments obtained in deformation-induced fission, or the corresponding adiabatic approaches., Amended version, accepted for publication in Phys. Rev. C. 22 pages, 20 figures, 3 tables

Background: Excitations with mixed proton-neutron symmetry have been previously observed in the $N=52$ isotones. Besides the well established quadrupole mixed-symmetry states (MSS), octupole and hexadecapole MSS have been recently proposed for the nuclei $^{92}$Zr and $^{94}$Mo. Purpose: The heaviest stable $N=52$ isotone $^{96}$Ru was investigated to study the evolution of octupole and hexadecapole MSS with increasing proton number. Methods: Two inelastic proton-scattering experiments on $^{96}$Ru were performed to extract branching ratios, multipole mixing ratios, and level lifetimes. From the combined data, absolute transition strengths were calculated. Results: Strong $M1$ transitions between the lowest-lying $3^-$ and $4^+$ states were observed, providing evidence for a one-phonon mixed-symmetry character of the $3^{(-)}_2$ and $4^+_2$ states. Conclusions: $sdg$-IBM-2 calculations were performed for $^{96}$Ru. The results are in excellent agreement with the experimental data, pointing out a one-phonon hexadecapole mixed-symmetry character of the $4^+_2$ state. The $\big< 3^-_1||M1||3^{(-)}_2\big>$ matrix element is found to scale with the $$ matrix element.

The dipole response of 76 34 Se in the energy range from 4 to 9 MeV has been analyzed using a (γ ,γ ′ ) polarized photon scattering technique, performed at the High Intensity γ -Ray Source facility at Triangle Universities Nuclear Laboratory, to complement previous work performed using unpolarized photons. The results of this work offer both an enhanced sensitivity scan of the dipole response and an unambiguous determination of the parities of the observed J=1 states. The dipole response is found to be dominated by E1 excitations, and can reasonably be attributed to a pygmy dipole resonance. Evidence is presented to suggest that a significant amount of directly unobserved excitation strength is present in the region, due to unobserved branching transitions in the decays of resonantly excited states. The dipole response of the region is underestimated when considering only ground state decay branches. We investigate the electric dipole response theoretically, performing calculations in a three-dimensional (3D) Cartesian-basis time-dependent Skyrme-Hartree-Fock framework.

The near-yrast structure of the near-magic, odd-odd nucleus, ${}_{39}^{88}$Y${}_{49}$, has been studied into the high-spin regime. Investigations were performed at the Wright Nuclear Structure Laboratory, Yale University, using the ${}^{74}$Ge(${}^{18}$O,$p3n$) and ${}^{76}$Ge(${}^{18}$O,$p5n$) fusion-evaporation reactions at beam energies of 60 and 90 MeV, respectively. Gamma-ray energy coincidence analyses using both double (${\ensuremath{\gamma}}^{2}$) and triple (${\ensuremath{\gamma}}^{3}$) fold coincidences, together with angular correlation measurements, have been used to extend the previously reported level scheme to an excitation energy of 8.6 MeV and a spin and parity of 19${}^{(\ensuremath{-})}$. The presented level scheme is compared with predictions of a truncated valence space shell-model calculation, which assumes an inert ${}^{56}$Ni core with proton and neutron excitations allowed within the ${f}_{5/2}$, ${p}_{3/2}$, ${p}_{1/2}$, and ${g}_{9/2}$ single-particle states. The shell-model calculations show a reasonable comparison with the experimental data for the yrast, positive-parity states up to spin 18 $\ensuremath{\hbar}$, with larger variations evident for negative-parity states with spins greater than 16 $\ensuremath{\hbar}$. In spite of a significant increase in angular momentum input associated with the thin target ${}^{76}$Ge(${}^{18}$O,$p5n$) reaction channel, as compared to the backed target data using the ${}^{74}$Ge target, no additional discrete states were identified in the former data set, suggesting that the level scheme for this nucleus fragments significantly above the observed states, possibly indicating cross-shell excitations becoming dominant for $Ig$19 $\ensuremath{\hbar}$.

Excited states in 74Se were populated following the e/β + decay of 74Br, mainly from the J=K=4, 13.8-keV β-decaying isomer. Off-beam γ-ray spectroscopy was performed with the array of Clover HPGe detectors at WNSL Yale. Many new transitions were observed and rigorous spin assignments were made based on γ-γ angular correlations. The β-decay strength was found to proceed almost entirely to a few high-lying states near 4500 keV, which are consistent with deformed two-quasineutron high-K configurations. These doorway states then provide an effective tool for populating and identifying the lower prolate structures. Once categorized, the low-lying states of 74Se can be described as a set of near-spherical vibrational levels mixing strongly with a spectrum of prolate states which have an unperturbed bandhead near 1350 keV. © 2013 American Physical Society.

We discuss the mechanism causing the `kink' in the charge radius isotope shift at the N=126 shell closure. The occupation of the 1$i_{11/2}$ neutron orbital is the decisive factor for reproducing the experimentally observed kink. We investigate whether this orbital is occupied or not by different Skyrme effective interactions as neutrons are added above the shell closure. Our results demonstrate that several factors can cause an appreciable occupation of the 1$i_{11/2}$ neutron orbital, including the magnitude of the spin-orbit field, and the isoscalar effective mass of the Skyrme interaction. The symmetry energy of the effective interaction has little influence upon its ability to reproduce the kink., Comment: 4 pages, 4 figures, to be submitted to proceedings of INPC 2013

A shortlist of Skyrme force parameterizations, recently found to have passed a series of constraints relating to nuclear matter properties is analyzed for their ability to reproduce data in finite nuclei. We analyse binding energies, isotope shifts and fission barriers. We find that the subset of forces have no common ability to reproduce (or otherwise) properties of finite nuclei, despite passing the extensive range of nuclear matter constraints., Comment: 7 Pages, submitted for proceedings of XXXV Reuni\~ao de Trabalho sobre F\'isica Nuclear no Brasil

We revisit the problem of the kink in the charge radius shift of neutron-rich even isotopes near the N=126 shell closure. We show that the ability of a Skyrme force to reproduce the isotope shift is determined by the occupation of the neutron 1i orbital beyond N=126 and the corresponding change it causes to deeply-bound protons orbitals with a principal quantum number of 1. Given the observed position of the single-particle energies, one must either ensure occupation is allowed through correlations, or not demand that the single-particle energies agree with experimental values at the mean-field level. © 2013 American Physical Society.

Background: The evolution of and interplay between single-particle and collective excitations in the 40 $\ensuremath{\leqslant}N\ensuremath{\leqslant}$ 50 range for ${}_{38}$Sr and ${}_{40}$Zr isotopes have been studied.Purpose: Measurement of the $g$ factor of the 2${}_{1}^{+}$ and 4${}_{1}^{+}$ states in radioactive ${}^{88}$Zr while simultaneously remeasuring the $g({2}_{1}^{+})$ factors in the Sr isotopes and extention of the measurements to higher energy states in the Sr isotopes. Lifetimes of states in these nuclei are determined.Methods: The transient field technique in inverse kinematics and line-shape analysis using the Doppler-shift attenuation method are applied. The ${}^{88}$Zr nuclei were produced by the transfer of an $\ensuremath{\alpha}$ particle from the ${}^{12}$C nuclei of the target to ${}^{84}$Sr nuclei in the beam. The excited states in the stable ${}^{84}$Sr isotopes were simultaneously populated via Coulomb excitation by ${}^{12}$C in the same target. Coulomb excitation measurements on ${}^{86,88}$Sr were carried out with the same apparatus.Results: The resulting $g$ factors and $B(E2)$ values of these nuclei reveal similarities between the two chains of Zr and Sr isotopes. Large-scale shell-model calculations were performed within the ${p}_{3/2},{f}_{5/2},{p}_{1/2},{g}_{9/2}$ orbital space for both protons and neutrons and yielded results in agreement with the experimental data.Conclusions: In this paper the magnetic moments and lifetimes of several low-lying states in ${}^{88}$Zr and ${}^{84.86,88}$Sr have been measured and compared to large-scale shell-model calculations.

Background: The experimental study of $g(Ig2)$ factors of nuclear states can provide information about the evolution of collectivity in certain regions of the nuclear chart, and assist in obtaining a microscopic description of the nuclear wave functions. The measurements and explanations of $g(Ig2)$ factors are still a challenge for experiments and theory.Purpose: Measurement of the $g({2}_{1}^{+})$ and $g({4}_{1}^{+})$ factors, the latter for the first time, in the ${\phantom{\rule{0.16em}{0ex}}}_{44}^{96}$Ru nucleus. Comparison of the experimental results with calculations using the shell model and collective models.Methods: The experiments made use of the transient field technique, using a Coulomb-excitation reaction in inverse kinematics. Large scale shell model calculations were performed; comparisons with previous theoretical predictions, using the tidal-wave model and the hydrodynamical model, were carried out.Results: The values of $g({2}_{1}^{+})=+0.46(2)$ and $g({4}_{1}^{+})=+0.58(8)$ were experimentally obtained. While the $g({2}_{1}^{+})$ value agrees with the hydrodynamical model prediction of $g=Z/A=+0.46$, the $g({4}_{1}^{+})$ is in agreement with the shell model predictions. The trend of the experimental $g$ factors, as a function of nuclear spin, is not reproduced by the theoretical models discussed.Conclusions: Measurements of $g({2}_{1}^{+})$ and $g({4}_{1}^{+})$ in ${}^{96}$Ru were performed. Further theoretical efforts are necessary to explain the trend of the $g$ factors as a function of nuclear spin for the ${}^{96}$Ru nucleus. Future measurements of $g({4}_{1}^{+})$ should reduce the uncertainty of the result.

Octupole vibrational states were studied in the nucleus (150)Nd via inelastic proton scattering with 10.9-MeV protons, which are an excellent probe to excite natural parity states. For the first time in (150)Nd, both the scattered protons and the gamma rays were detected in coincidence, giving the possibility to measure branching ratios in detail. Using the coincidence technique, the B(E1) ratios of the decaying transitions for 10 octupole vibrational states and other negative-parity states to the yrast band were determined and compared to the Alaga rule. The positive and negative-parity states revealed by this experiment are compared with interacting boson approximation calculations performed in the spdf boson space. The calculations are found to be in good agreement with the experimental data, for both positive and negative-parity states.

Mixed-symmetry states of octupole (L = 3) and hexadecapole (L = 4) character have been recently proposed in the N = 52 isotones Zr-92 and Mo-94, based on strong M1 transitions to the lowest-lying 3(-) and 4(+) states, respectively. In order to investigate similar excitations in the heaviest stable N = 52 isotone Ru-96, two inelastic proton-scattering experiments have been performed at the Wright Nuclear Structure Laboratory (WNSL), Yale University, USA and the Institute for Nuclear Physics, University of Cologne, Germany. From the combined data of both experiments, absolute E-1, M-1, and E2 transition strengths were extracted, allowing for the identification of candidates for MS octupole and hexadecapole states. The structure of the low-lying 4(+) states is investigated by means of sdg-IBM-2 calculations.

A novel sterically hindered platinum complex, AMD473 [cis-amminedichloro(2-methylpyridine) platinum(II)], designed primarily to be less susceptible to inactivation by thiols, has shown in vitro activity against several ovarian carcinoma cell lines. Notably, AMD473 has shown activity in vitro in human carcinoma cells that have acquired cisplatin resistance due to reduced drug transport (41M/41McisR) or enhanced DNA repair/increased tolerance of platinum-DNA adducts (CH1/CH1cisR). In this study, we show that AMD473, at its maximum tolerated dose of 35-40 mg/kg i.p. administration, produced marked in vivo antitumor activity against a variety of murine (ADJ/PC6 plasmacytoma, L1210 leukemia) and human ovarian carcinoma xenograft models, including several possessing acquired resistance to cisplatin [ADJ/PC6cisR, L1210cisR, CH1cisR, and HX110 (carboplatin-resistant)]. In the ADJ/PC6 model, an increased therapeutic index was noted following oral as opposed to i. p. administration. In a head-to-head comparison using CH1cisR xenografts and equitoxic doses (q7dx4 schedule), comparative growth delays were as follows: AMD473, 34 days; cisplatin, 10.4 days; carboplatin, 6.4 days; and JM216 (p.o. administration), 3.5 days (in a previous experiment, the trans-platinum complex JM335 induced a growth delay of 5.4 days against this model). In this model, oral activity was also noted with a growth delay of 34 days at 400 mg/kg every 7 days (total of four doses). In addition, AMD473 showed promising activity against CH1 xenografts that had regrown following initial treatment with cisplatin (additional growth delay of 30 days over that observed for retreatment with cisplatin). Across the whole panel of cisplatin-sensitive to cisplatin-resistant human ovarian carcinoma xenografts, AMD473 showed improved or at least comparable activity to that observed for an equitoxic dose (4 mg/kg) and schedule of cisplatin. Platinum pharmacokinetics showed that following i.v. administration of 20 mg/kg AMD473 in saline to Balb/c- mice bearing murine plasmacytoma (ADJ/PC6), a biexponential decay was observed in the plasma with a rapid distribution t1/2alpha of 24 min followed by a slow elimination t1/2beta of 44 h. Platinum accumulated in various organs with platinum tissue to plasma area under the curve ratios of 8.6 for liver and kidney, 5.7 for spleen, 3.7 for heart, 5.2 for lung, and 5 for tumor. The plasma and tissue concentration time curve following i.p. administration was similar to that observed following i.v. administration, with a bioavailability of 89%. When AMD473 was given p.o., the platinum absorption was rapid (K01 of 30 min) and the bioavailability was 40%. A less than proportional increase in area under the curve and Cmax was noted in tissue, plasma, and plasma ultrafiltrate following increasing oral doses of AMD473. In vitro, with AMD473, the rate of binding to different plasma proteins was approximately half of that of cisplatin. Following administration of 45 mg/kg i.p. in oil, 33% of the administered platinum was eliminated in the urine after 24 h, and 40% was eliminated after 72 h. Fecal recovery represented 13% of the administered dose after 3 days. Similar results were observed following oral and i.v. administration of 20 mg/kg, but significantly more was excreted in the feces (over 50% of the administered dose) following oral administration of 400 mg/kg, showing that absorption might be a limiting factor by this route of administration. The dose-limiting toxicity for AMD473 in mice was myelosuppression, and no renal toxicity was observed. The promising antitumor activity of AMD473, together with its lack of nephrotoxicity and favorable pharmacokinetic profile, suggests that AMD473 is a good candidate for clinical development. AMD473 is entering Phase I clinical trials under the auspices of the United Kingdom Cancer Research Campaign in 1997.

An 18-mer full-phosphorothioate oligonucleotide with sequence antisense to the first six codons of the open reading frame of bcl-2 (G3139) has shown efficacy against the DoHH2 lymphoma implanted in severe combined immunodeficient mice. This study evaluated the pharmacokinetics of 35S-labeled G3139 in female BALB/c mice after single i.v. bolus administration or s.c. infusion for 1 week. After 100 microg i.v. bolus (approximately 5 mg/kg), the radioactivity was rapidly distributed and eliminated, with low blood levels 6 hr after administration. Most of the initial plasma radioactivity was protein bound (98% at 5 min). Tissue to plasma ratios were 87 for kidney, 17 for liver, 5 for spleen, 2.5 for heart and lung and 3.5 for gut. High-performance liquid chromatographic determination of G3139 showed triexponential kinetics, with alpha, beta and gamma half-lives of 5 min, 37 min and 11 hr, respectively. After 106 microg/day s.c. infusion, plasma steady state was reached by day 3, when half of the radioactivity was protein bound and 66 to 86% of the radioactivity was associated with parent drug (0.9 microg/ml). The plasma half-life of elimination for G3139 was 22 hr. Tissue to plasma ratios were similar to those after i.v. bolus administration, but accumulation was observed in all organs including bone marrow, where the levels reached were in the cytotoxic range. G3139 was metabolized to at least three different products, all observed in plasma, liver and kidney. Two metabolites eluted before the parent compound and one after the parent compound. There was greater degradation in the liver 6 hr after i.v. administration than at 24 hr, 48 hr, 3 days and 7 days after s.c. administration. In the kidney, most radioactivity was G3139. All degradation products were found in the urine but only traces of parent drug were eliminated. After both routes of administration, most of the radioactivity was eliminated in the urine and to a lesser extent in the feces. Significantly more radioactivity was excreted in the urine after i.v. bolus, compared with s.c. infusion (33% on day 1 and 55% by day 3 for i.v. vs. 7.2% on day 1 and 12.9% by day 3 for s.c.). These data show that s.c. infusion resulted in less excretion and metabolism of the administered dose.

Formulation difficulties prevented the otherwise promising clinical development of the anti-tumour agent trimelamol (TM; tris-[hydroxymethyl]trimethylmelamine]). A synthetic analogue programme resulted in the identification of CB 7646 (bis N-[hydroxymethyl]trimethylmelamine) as a compound with improved stability and favourable formulation characteristics. The in vitro and in vivo activity of CB 7646 was shown to be very similar to that of TM. In addition, curative activities were shown in the PXN/65 human ovarian cancer xenograft and the MX-1 and T-61 human breast cancer xenograft models. The effectiveness of the N-(hydroxymethyl)melamines against platinum-refractory disease was noted in the phase I clinical trial of TM. In line with this finding, the present study confirmed the effective activity of both TM and CB 7646 against various forms of platinum resistance in in vitro models. Curative activity for TM and CB 7646 was seen in the HX110P human ovarian cancer xenograft with acquired carboplatin resistance. Animal studies indicated less neurotoxicity for CB 7646 than for TM. The pharmacokinetic profile of CB 7646 indicated a decreased plasma elimination, indicative of slower in vivo degradation than for TM. CB 7646, therefore, represents a promising candidate for clinical development, designed to supersede TM.

Trimelamol (TM) was developed as a water soluble analogue of the oral chemotherapeutic agent hexamethyl-melamine (HMM), to be administered i.v., in an effort to avoid dose limiting emesis. Because of formulation difficulties due to its inherent instability the development of TM was halted. In vivo studies using a human ovarian cancer xenograft model PXN/65 showed TM to be curative in the dose range of 15-60 mg/kg i.p. daily x 5, for 4 weeks. Conversely, HMM given at the highest dose (60 mg/kg i.p., or 90 mg/kg p.o.) indicated only very modest tumour growth delays. In vitro chemosensitivity testing using primary ovarian tumour cultures showed that in 12/23 cases indicating reduced sensitivity to cisplatin or carboplatin, sensitivity to TM was increased. TM was curative in the carboplatin-resistant HX 110P human ovarian cancer xenograft and promising activity was seen in the MX-1 human breast cancer xenograft. In spite of enhanced stability in aqueous solution and good in vitro cytotoxicity, the TM analogues CB 7669 (triscyanomethyl) and CB 7639 (tristrifluoroethyl) showed disappointing in vivo antitumour activity which may be explained by the need for prolonged exposure. TM analogues with intermediate stability are currently under development in an effort to further the clinical development of this promising group of antitumour agents.

Two pairs of cis/trans platinum complexes, JM118 (cis-ammine(cyclohexylamine) dichloro platinum(II)) and its trans counterpart, JM334 and JM149 (cis-ammine(cyclohexylamine) dichloro-dihydroxo platinum(IV)) and its trans counterpart JM335 have been evaluated (both in vitro and in vivo) against two murine tumour models of historical importance in the discovery of novel platinum drugs; the ADJ/PC6 plasmacytoma and the L1210 leukaemia and sublines selected for resistance to platinum drugs. In vitro, results showed that the trans complexes induced comparable growth inhibitory properties to those observed for cisplatin and their respective cis isomers. Moreover, retention of activity was observed in a series of 5 acquired platinum drug (cisplatin, carboplatin, iproplatin, tetraplatin and JM149)-resistant L1210 sublines whereas at least partial cross-resistance was observed to the cis isomer JM149 in the acquired carboplatin and iproplatin-resistant lines (in addition to being 11-fold resistant in the line selected for resistance to JM149 itself). In vivo, JM355 showed activity against both the ADJ/PC6 and L1210 models of acquired cisplatin resistance. Furthermore, JM355 was active against an ADJ/PC6 subline possessing resistance to iproplatin and a L1210 subline possessing resistance to its cis isomer JM149. Interestingly, the trans platinum(II) counterpart of JM335(JM334) was inactive in vivo. These data indicate that the trans platinum(IV) complex JM335 possess several in vitro growth inhibitory- and in vivo antitumour properties which are distinct from those observed for cisplatin (or its cis isomer). Thus, JM335 contravenes the original structure-activity rules determined for platinum-containing compounds and, because of its level of activity against cisplatin-resistant tumours, establishes the complex as of interest in the search for new platinum drugs active against cisplatin-resistant disease.

As part of a drug discovery program to discover more effective platinum-based anticancer drugs, a series of platinum complexes of trans coordination geometry centered on trans-ammine(cyclohexylaminedichlorodihydroxo)platinum(IV) (JM335) has been evaluated in vitro against a panel of cisplatin-sensitive and cisplatin-resistant human tumor cell lines (predominantly ovarian). In vitro, against 5 human ovarian carcinoma cell lines, JM335 was comparably cytotoxic to cisplatin itself and over 50-fold more potent than transplatin (mean 50% inhibitory concentrations: JM335, 3.1 microM; cisplatin, 4.1 microM; transplatin, 162 microM). With the use of seven pairs of human tumor cell lines (parent and subline with acquired resistance to cisplatin and encompassing all of the known major mechanisms of resistance to cisplatin) JM335 exhibited a different cross-resistance pattern to that of its cis isomer (JM149). JM335 showed non-cross-resistance in six of the seven resistant lines, cross-resistance in the A2780cisR line possibly being associated with high levels of glutathione. Preliminary intracellular DNA binding studies showed that in contrast to transplatin, JM335 was efficient at forming DNA-DNA interstrand cross-links. In vivo, JM335 produced growth delays in excess of 15 days against 4 of 6 human ovarian carcinoma xenografts and was unique among the complexes studied in retaining some efficacy against a cisplatin-resistant subline of the murine ADJ/PC6 plasmacytoma. JM335 is the first trans-platinum complex to demonstrate marked antitumor efficacy against both murine and human s.c. tumor models and represents a significant structural lead to complexes capable of circumventing cross-resistance to cisplatin.

JM216 is a novel antitumor platinum(IV) complex displaying oral activity, dose-limiting myelosuppression, and a lack of nephro- and neurotoxicity in rodents. It has been selected for clinical evaluation. The schedule dependency of its antitumor action against a murine (ADJ/PC6 plasmacytoma) and a human tumor model (PXN109T/C ovarian carcinoma xenograft) was studied in vivo. Single dose (q21d), once a day dosing for 5 consecutive days (q21d or q28d), and once a day dosing indefinitely (chronic daily dosing) administration schedules were compared. Against the murine ADJ/PC6 plasmacytoma, daily x5 administration improved the tolerance, antitumor potency, and therapeutic index of oral JM216, compared to single dose administration, whereas no advantage was found for fractionating cisplatin dosages. Against the PXN109T/C human ovarian carcinoma xenograft, oral JM216, given at dose levels delivering a equivalent total dose on single dose (200 mg/kg q21d), daily x5 (40 mg/kg/day q21d) and chronic daily dosing (9.5 mg/kg/d) schedules, showed superior tumor growth delays (55 +/- 15 days; P0.05) and maximal tumor regression (10 +/- 11% of initial tumor volume; P0.001) with the daily x5 schedule. Gastrointestinal toxicity (P0.05) and mild nephrotoxicity (P0.01) complicated the chronic daily dosing schedule, while leukopenia (P0.02) and thrombocytopenia (P0.01) were dose-limiting for the single dose and daily x5 administration, respectively. Peak plasma ultrafiltrate (PUF) platinum levels were below cytotoxic levels (PUF Cmax, 0.11 +/- 0.066 mg/l) at the maximally tolerable dose for the chronic dosing schedule (9.5 mg/kg). Peak PUF platinum levels did not increase significantly with a 5-fold increase in dosage from 40 mg/kg (PUF Cmax 1.5 +/- 0.11 mg/l) to 200 mg/kg (PUF Cmax, 2.4 +/- 0.44 mg/l; P0.05). In conclusion, these data demonstrate antitumor schedule dependency for oral JM216 in vivo, independently in two tumor model systems, and with nonlinear pharmacokinetics after its oral administration to mice. Optimal antitumor activity, tolerance, and pharmacokinetics occurred with daily x5 dosing, and this has prompted the clinical evaluation of this administration schedule.

The cytotoxicity of a novel platinum(IV) complex, bis-acetato-amminedichloro-cyclohexylamine platinum(IV) (JM216), has been evaluated in vitro against a panel of human tumor cell lines (predominantly ovarian) representative of models of intrinsic and acquired to cisplatin. In addition, the activity of JM216 administered by the p.o. route has been determined in vivo using the murine ADJ/PC6 plasmacytoma and four human ovarian carcinoma xenograft lines. In vitro, against seven human ovarian carcinoma cell lines, JM216 showed similar cytotoxicity and pattern of cytotoxicity to cisplatin (mean 50% inhibitory concentrations of 3.5 microM for cisplatin and 1.7 microM for JM216). The cytotoxicity of JM216 was more dependent on the time of drug exposure than that of cisplatin, suggesting that extended split-dosing rather than a single bolus administration might be a more appropriate schedule in patients. Using six pairs of acquired cisplatin-resistant and parent human tumor cell lines (four ovarian, one testicular, and one cervical) JM216 exhibited non-cross-resistance (resistance factor of1.5) in three whereas tetraplatin exhibited partial or full cross-resistance in all six pairs. Notably, in two of the acquired cisplatin-resistant lines (41McisR and HX/155cisR) where JM216 retained activity, resistance has previously shown to be due primarily to reduced platinum uptake. In vivo, following p.o. administration using the cisplatin-sensitive murine ADJ/PC6 plasmacytoma, JM216 showed antitumor selectivity far superior to that observed for either cisplatin, carboplatin, or tetraplatin. Across four human ovarian carcinoma xenografts of widely differing sensitivity to cisplatin and carboplatin, JM216 exhibited p.o. activity, broadly comparable to that observed for i.v. administered cisplatin and carboplatin and markedly superior to i.p. administered tetraplatin. These antitumor properties suggest that JM216 provides a structural lead to platinum complexes which may circumvent transport-determined acquired resistance to cisplatin and is a suitable candidate as an p.o. administrable platinum complex for phase I clinical trial.

A series of derivatives of the anti-tumour hydroxymethyltriazenes have been investigated for activity in vivo and in vitro. Acetoxymethyltriazenes are active in vivo against the TLX5, P388 and PC6 tumours in mice, and inhibit the growth of TLX5, Np and Li cells in vitro without metabolic activation. The acetoxymethyltriazenes are comparable with the hydroxymethyltriazenes and monomethyltriazenes in their spectrum of activity and thus appear to be prodrugs for these species. On the other hand, a methoxymethyltriazene was found to be active on the TLX5 tumour in vivo, but did not inhibit the growth of Np cells in vitro. This latter observation is consistent with the anticipated chemical stability of the methoxymethyltriazene and the requirement for metabolic O-demethylation to generate an active species. Acetoxymethyltriazenes do not require metabolic intervention and break down chemically in phosphate buffer to the hydroxymethyltriazene, which in turn loses formaldehyde to give the incipient methylating agent, the monomethyltriazene.

Cisplatin and its analogues, cis-diammine(1,1-cyclobutanedicarboxy lato)platinum II (CBDCA, JM8) and cis-dichloro-trans-dihydroxy-bis(isopropylamine)platinum IV (CHIP, JM9), are active against a number of experimental rodent neoplasms when administered parenterally. This is the first report to describe the antitumour activity of this class of compounds following oral administration via a stomach tube. The complexes were tested against the ADJ/PC6A plasmacytoma grown s.c. in female Balb C- mice, and the Walker 256 carcinosarcoma grown i.m. in male Wistar rats. Cisplatin had a TI (therapeutic index; LD50/ED90) of 4–5 against the ADJ/PC6A and a TI of 2 against the Walker 256. Comparable or lower activity against the ADJ/PC6A has also been demonstrated for CBDCA and CHIP. Following an oral dose of 50mg/kg in mice of the three complexes, maximum platinum levels in blood (1.5–2.4µg/ml) are achieved 1–4 hours after drug administration. Urinary excretion is greatest for cisplatin (15% of dose in 48 hours), followed by CHIP (13%) and CBDCA (9%). The major part (60–80&) of the dose, however, is excreted in the faeces. These results indicate that the orally administered cisplatin and the two analogues are absorbed to an appreciable extent into the systemic circulation. This is probably important in producing the observed antitumour activities of the complexes when given by this route of administration.