Effect of diabetes on biodistribution, nephrotoxicity and antitumor activity of cisplatin in mice

Abstract

Both types of diabetes are associated with higher incidence of some types of cancer. Treating cancer in diabetic patients without aggravating diabetes-related complications is a challenge for clinicians. Additionally, little is known about how diabetes affects the treatment of cancer. One of the most effective chemotherapeutic drugs is cisplatin, which is nephrotoxic. Studies suggest that diabetes acts as a protective factor against the nephrotoxicity of cisplatin, but the mechanisms involved have not been elucidated yet. This renal protection has been attributed to decreased accumulation of cisplatin in the kidneys, which could be associated with deficient active transport of proximal tubular cells or to pharmacokinetic alterations caused by diabetes. However, it is uncertain if diabetes also compromises the antitumor activity of cisplatin. To address this issue, we developed a mouse model bearing cisplatin-induced nephrotoxicity, Sarcoma 180 and streptozotocin-induced diabetes. Four groups of treatment were defined: (i) control, (ii) diabetic, (iii) cisplatin and (iv) diabetic treated with cisplatin. The following parameters were evaluated: renal function, oxidative stress, apoptosis, renal histopathology, tumor remission, survival rate, genotoxicity and platinum concentration in tumor and several organs. Results indicate that diabetes protects against the renal damage induced by cisplatin, while also compromises its antitumor effectiveness. This is the first study to demonstrate this effect.

Pharmacokinetics and tissue distribution of novel platinum containing anticancer agent BP‐C1 studied in rabbits using sector field inductively coupled plasma mass spectrometry

“…reported blood plasma pharmacokinetics and tissue distribution of cisplatin, carboplatin and 5 experimental anti‐cancer agents; main deposition was found for kidney for investigated agents. Noteworthy, in most distribution studies, which concern platinum‐containing drugs, mainly intravenous (for human‐based designs) or also intra‐peritoneal (for non‐clinical studies) routes of administration are employed . That is why media such as skin and muscle tissue are not investigated as usual.…”

Comparison of therapeutic responses to an anticancer drug in three stocks of ICR mice derived from three different sources

“…Antitumor activity of Cis in the three ICR stocks was evaluated by using methods described in previous studies [1112], with some modifications. Briefly, Sarcoma 180 cells (5×10 6 cells) collected from ascetic tumors in Krol:ICR mice were subcutaneously injected into the groin region of six-week-old Korl:ICR, A:ICR, and B:ICR mice (n=28/group; Figure 1A).…”

In Vivo Antitumor Activity of Phytochemical Pitc-2 Obtained From Tissue Cultured Plant Pluchea Indica on Sarcoma-180 Solid Tumor Mice Model

“…It also prevents the release of cytochrome c into the cytosol which activates caspases by the mitochondrial pathway. Overexpression of Bcl-2 inhibits caspase-3 activation [30,26]. In our study, it was found that after treatment with PITC-2 on sarcoma-180 cells a significant decrease in Bcl-2 was observed whereas an increase in level Bcl-2 was observed in control group animals.…”