Is Medication-Related Osteonecrosis of the Jaws (MRONJ) Associated to Cyclin-Dependent Kinase (CDK) 4/6 Inhibitors? A Word of Cautiousness. Comment on Marcianò et al. Medication-Related Osteonecrosis of the Jaws and CDK4/6 Inhibitors: A Recent Association. Int. J. Environ. Res. Public Health 2020, 17, 9509.

Marcianò et al. launched an alert in this journal about a possible association between medication-related osteonecrosis of the jaws (MRONJ) and cyclin-dependent kinase (CDK) 4/6 inhibitors in breast cancer patients [...].

Osteonecrosis of the Jaw (ONJ) in Osteoporosis Patients: Report of Delayed Diagnosis of a Multisite Case and Commentary about Risks Coming from a Restricted ONJ Definition.

Osteonecrosis of the jaws (ONJ) in osteoporosis patients has been defined as rare, but the number of reported cases is increasing. We report a case of delayed ONJ diagnosis in a patient, who was being treated with alendronate, developing bone alterations both in maxilla and in mandible. Underestimation of ONJ incidence and missed or delayed ONJ diagnosis in osteoporosis patients might derive from lack of awareness of health providers as well as from an ONJ definition that is too restricted. The more recent definition of medication-related osteonecrosis of the jaws (MRONJ) released in 2014 by the American Association of Oral Maxillofacial Surgeons (AAOMS) accept fistula, besides bone exposure, as a major sign of disease, but it seems to be insufficient since it excludes all cases of ONJ disease without bone exposure. A new MRONJ definition is needed to avoid missing or delayed diagnosis.

Osteonecrosis of the Jaws (ONJ) after Bisphosphonate Treatment in Patients with Multiple Myeloma: Decreasing ONJ Incidence after Adoption of Preventive Measures.

Bisphosphonates (BPs) are administered to Multiple Myeloma (MM) patients with bone lytic lesion. Osteonecrosis of the Jaw (ONJ) is a complication reported since 2003 in patients treated with intravenous (IV) BPs such as zoledronic acid and pamidronate, with 6%-26.3% frequency in early literature series, before some preventive measures were recommended. We evaluated the occurrence of ONJ with and without dental preventive measures in MM patients treated with BPs in our centre between 1996 and 2015. Since 2005, MM patients (already under treatment or before treatment) underwent a baseline mouth assessment (dental visit, Rx orthopantomography, and eventual tooth avulsion or dental care if necessary) and were followed by a multidisciplinary team. We reviewed the charts of 119 MM patients receiving IV BPs, classified into 3 groups: (a) "historic group" (21 patients who had started BP treatment in years before the awareness of ONJ); (b) "screening group" (20 patients starting BPs without baseline evaluation); and (c) "prevention group" (78 patients starting therapy only after baseline preventive assessment and eventual dental care measures). ONJ was observed in 3/21 patients (14.2%) from group a, in 2/20 patients (10%) from group b, and in no patients from group c (0%). Notably, the median number of IV BP administrations decreased after 2005. Our data confirmed a meaningful reduction of ONJ risk in MM patients treated with BPs if preventive measures are applied. Both implementation of prevention measures and reduction of cumulative doses of IV BPs could have contributed to a decreased incidence of ONJ.

Cellular trafficking, accumulation and DNA platination of a series of cisplatin-based dicarboxylato Pt(IV) prodrugs.

A series of Pt(IV) anticancer prodrug candidates, having the equatorial arrangement of cisplatin and bearing two aliphatic carboxylato axial ligands, has been investigated to prove the relationship between lipophilicity, cellular accumulation, DNA platination and antiproliferative activity on the cisplatin-sensitive A2780 ovarian cancer cell line. Unlike cisplatin, no facilitated influx/efflux mechanism appears to operate in the case of the Pt(IV) complexes under investigation, thus indicating that they enter by passive diffusion. While Pt(IV) complexes having lipophilicity comparable to that of cisplatin (negative values of log Po/w) exhibit a cellular accumulation similar to that of cisplatin, the most lipophilic complexes of the series show much higher cellular accumulation (stemming from enhanced passive diffusion), accompanied by greater DNA platination and cell growth inhibition. Even if the Pt(IV) complexes are removed from the culture medium in the recovery process, the level of DNA platination remains very high and persistent in time, indicating efficient storing of the complexes and poor detoxification efficiency.

Biological activity of a series of cisplatin-based aliphatic bis(carboxylato) Pt(IV) prodrugs: how long the organic chain should be?

The biological properties of a series of cisplatin-based Pt(IV) prodrug candidates, namely trans,cis,cis-[Pt(carboxylato)2Cl2(NH3)2], where carboxylato=CH3(CH2)nCOO(-) [(1), n=0; (2), n=2; (3), n=4; (4), n=6] having a large interval of lipophilicity are discussed. The stability of the complexes was tested in different pH conditions (i.e. from 1.0 to 9.0) to simulate the hypothetical conditions for an oral route of administration, showing a high stability (>90%). The transformation into their active Pt(II) metabolites was demonstrated in the presence of ascorbic acid, with a pseudo-first order kinetics, the half-time of which smoothly decreases as the chain length of carboxylic acid increases. Their antiproliferative activity has been evaluated in vitro on a large panel of human cancer cell lines. As expected, the potency increases with the chain length: 3 and 4 resulted by far more active than cisplatin on all cell lines of about one or two orders of magnitude, respectively. Both complexes retained their activity also on cisplatin-resistant cell line, and exhibited a progressive increase of the selectivity compared with non-tumor cells. These results were confirmed with more prolonged treatment (up to 14days) studied on multicellular tumor spheroids (MCTSs). In this case the Pt(IV) complexes exert a protracted antiproliferative action, even if the drug is removed from the culture medium. Finally, in a time-course experiment of the total platinum evaluation in mice blood (after a single oral administration of the title complexes), 2 gave the best results, representing a good compromise between lipophilicity and water solubility, that increase and decrease respectively on passing from 1 to 4.

Antiproliferative activity of Pt(IV)-bis(carboxylato) conjugates on malignant pleural mesothelioma cells.

The bifunctional Pt(IV) conjugate cis,cis,trans-diamminedichloridobis(valproato)platinum(IV), based on the cisplatin square-plane with two axial valproato (2-propylpentanoate, VPA) ligands, has been re-synthesized with a modified procedure and its biological activity was compared with that of its isomer cis,cis,trans-diamminedichloridobis(n-octanoato)platinum(IV). Both complexes showed a striking cytotoxic effect (in the micro or sub-micromolar range) on various human carcinoma cell lines (namely ovarian, colon, breast and lung cancer), and, in particular, on cells derived from malignant pleural mesothelioma. This remarkable activity is due to the action of the cisplatin metabolite only, generated by the intracellular Pt(IV)→Pt(II) reduction, which concentration is greatly increased by the enhanced cellular accumulation of the original, highly lipophilic Pt(IV)-bis(carboxylato) complexes. The two axial VPA ligands are released in a too low concentration to act as histone deacetylase inhibitor (HDACI), as VPA works in the millimolar range, so that no synergism can be claimed. Moreover, n-octanoic acid is substantially deprived of any HDACI propensity.

Evaluation of platinum-ethacrynic acid conjugates in the treatment of mesothelioma.

Malignant pleural mesothelioma (MPM) cells are characterized by chemoresistance associated with glutathione (GSH) metabolism. Ethacrynic acid (EA) is able to inhibit the detoxifying enzyme glutathione-S-transferase (GST), which catalyzes the conjugation between GSH and Pt-based drugs. With the aim of obtaining active bifunctional drugs, a Pt(II) complex containing two EA moieties as leaving groups, namely cis-diamminobis(ethacrynato)platinum(II), was synthesized, characterized, and tested on four MPM cell lines. The resulting antiproliferative activity was compared with that elicited by the analogue Pt(IV) complex, cis,cis,trans-diamminodichloridobis(ethacrynato)platinum(IV) (ethacraplatin) and by the co-administration of free EA and cisplatin. The Pt(II) and Pt(IV) bifunctional complexes showed poorer performance than the reference drug cisplatin alone or in combination with EA. After treatment, cellular GST activity remained consistently unchanged, while the GSH level increased.