Development of novel anticancer platinum drugs

Cisplatin-based combination chemotherapies display significant anticancer activity and are routinely used in systemic treatment of diverse solid tumors. Nevertheless, next to unwanted side effects like nephrotoxicity, especially resistance of tumor cells against platinum drugs is still one of the major handicaps for successful systemic treatment in oncology. While a large subset of tumors exhibit intrinsic insensitivity against chemotherapy, also those cancer types initially responsive to platinum drugs often develop resistant recurrences or metastases during treatment. In order to reduce unwanted side effects and to circumvent resistance development, multiple novel platinum compounds have been synthesised during the last decades with only a few of them being clinically approved so far. One of these compounds is oxaliplatin with activity against some cisplatin-resistant tumors. However, also against this compound drug-resistance might develop. Consequently, during the last years several approaches have been taken at the Institute of Inorganic Chemistry at the University Vienna to generate platinum compounds of improved activity, enhanced targeting to the malignant tissues and reduced adverse effects. In a close cooperation with this institution, the proposed project executed at the Institute of Cancer Research, Department of Medicine I, Medical University Vienna, now aims to further develop two promising strategies to enhance the quality of experimental platinum compounds based on cell biological investigations and xenotransplantation experiments using immunocompromised mice (SCID). Firstly, five lead substances from a panel of oxaliplatin analogs (substituted at the cyclohexane ring) with promising anticancer activity will be investigated. Secondly, a tumor-targeting approach is taken based on the synthesis of bis(aminoalcoholato)platinum II compounds with closed configuration and thus reduced cytotoxicity at neutral pH which should be activated at the acidic, hypoxic environment within solid tumor nodules. The six most promising drug candidates of this chemical structure will be investigated. Both substance classes will be analysed in vitro with regard to cytotoxic/cytostatic activities taking advantage of a large cell line and tumor primary culture panel available at the Institute of Cancer Research. Furthermore, the underlying molecular targets and the impact of intrinsic and acquired drug resistance mechanisms will be determined using diverse molecular and cell biological methods. For the most promising metal complexes in vivo anticancer activities will be established against several solid tumor xenografts. In summary, the obtained data will establish the quality of pH-sensitive platinum drugs and oxaliplatin analogs as anticancer agents against solid tumors and allow selecting ideal candidate molecules. Moreover, the preparation of early clinical development should be fostered by the information gained with regard to the impact of drug resistance mechanisms and the potency to hinder therapeutic success. Consequently, the data should allow predicting which tumor types/patient collective are prone to benefit from these new anticancer agents.

The fight against cancer is one of the major challenges in modern medicine. Chemotherapy is a major backbone of cancer therapy and significantly contributes to enhanced patient survival especially in combination with novel targeted anticancer biological. Nevertheless severe adverse effects and profound resistance development limit the success of cancer therapy also e.g. with the widely used platinum substances cisplatin and oxaliplatin. Consequently, we aimed in this project to develop novel anticancer platinum drugs with limited side effects and less vulnerability by resistance mechanisms and thus an improved therapeutic window. Indeed, in three of the four different strategies we succeeded to generate candidates for improved anticancer therapy. Improvements were either caused by limited adverse effects based on inactive and thus non-toxic prodrugs shown to be activated in the tumour tissues or on derivatives with reduced neurotoxic effects but strong anticancer activity. Within the first approach, we developed derivatives of the widely used anticancer drug oxaliplatin containing methyl groups at the cyclohexane ring. Interestingly, the novel compounds are characterised by better tolerability at comparable activity as the parental compound. The severe neurotoxicity of oxaliplatin including hypersensitivity against cold was significantly reduced based on a less pronounced accumulation in neuronal tissue. Consequently, application of higher and more effective doses is possible with still reduced adverse effects. In a second approach, we have developed oxaliplatin prodrugs which are inactive in the circulation but then preferentially accumulated and specifically activated in the tumour tissue. To do so, a platinum(IV) prodrug version of oxaliplatin was established and linked to a maleimide moiety known to very efficiently bind to serum albumin and other cysteine-containing serum proteins. By both strategies the drug is inactivated in the healthy tissue. Blood vessels within the tumour are incomplete and leaky leading to enhanced accumulation of serum proteins, in our case loaded with the platinum prodrug. Within the acidic and reductive environment of the tumour or even within the tumour cells platinum(IV) is reduced to platinum(II) and oxaliplatin locally released. The validity of the approach has been proven in model systems. The third approach is also based on platinum(IV) prodrugs. Several asymmetric mono- and dinuclear platinum(IV) complexes were synthesized featuring an ethylene glycol moiety to optimise drug accumulation and allow oral application. Also this strategy has delivered interesting lead drug candidates currently evaluated in preclinical model systems. In the fourth approach, we generated and analysed ring-closed 2-aminoalcoholatoplatinum(II) complexes widely inactive at physiological pH but activated under slightly acidic pH conditions. This strategy worked in cell culture but did not prove valid in the living organism. In summary, we have generated in this project several novel platinum anticancer drug candidates with enhanced activity and/or reduced side effects. Several candidates are covered by patents and are currently heading for further (pre)clinical development to contribute to the fight against cancer.