Dicycloplatin, a Novel Analog of Cisplatin and Carboplatin, May Provide Therapeutic Advancement in Cancer Chemotherapy

Chemistry and Pharmacology of DCP

Dicycloplatin is a platinum compound developed in China and approved by the State Food and Drug Administration of China (SFDA) in 2012. DCP is synthesized from platinum powder through 10 steps. The host part of DCP is carboplatin and the guest is an additional carboxylate ligand (cyclobutane-1,1-dicarboxylic acid - CBDCA), linked via 4 hydrogen bonds. It is a hydrogen-bond supramolecule, not a covalent-bond molecule (6, 7). This unique chemical structure contributes to its distinct pharmacological properties. DCP has a stable chemical structure, good water solubility, and an excellent safety profile. Unlike cisplatin, which rapidly hydrolyzes in the bloodstream, DCP demonstrates greater stability in plasma, potentially reducing off-target effects while maintaining cytotoxic activity against cancer cells (6, 7). The molecular mechanisms of DCP appear to parallel those of cisplatin and carboplatin. Like these conventional platinum compounds, DCP forms DNA adducts that disrupt cellular processes essential for cancer cell survival and proliferation (9-11). However, the kinetics of DNA binding and the specific adducts formed may differ, potentially explaining the altered toxicity profile observed in preclinical and clinical studies (8, 12). Pharmacokinetic studies have demonstrated that DCP has favorable distribution properties, with good penetration into tumor tissues. This compound exhibits a plasma half-life intermediate between cisplatin and carboplatin, potentially allowing for more sustained antitumor effects with less frequent dosing (9). Importantly, DCP is available in both intravenous and oral formulations, with the latter (An-Tuo-Ke-Jin) representing a significant advance in platinum drug delivery that could improve patient convenience and potentially reduce healthcare costs (13). Preclinical studies have demonstrated that DCP maintains cytotoxic activity against various cancer cell lines, including those resistant to conventional platinum compounds (6). This suggests potential utility in treating platinum-refractory tumors, a significant unmet need in oncology. Additionally, DCP has shown synergistic effects when combined with other chemotherapeutic agents, including taxanes and gemcitabine, mirroring the combination strategies commonly employed with conventional platinum compounds (14).

Molecular Mechanism Investigations

In vitro studies. In vitro investigation of DCP in human normal and cancer cells have shown the following. After 1-hr drug exposure at IC50 doses (3.79 μM), several kinases of the DNA-damage repair pathway were activated. The activated kinases - including p-p53, p-Chk2 and p-BRCA1 - were observed in ovarian cancer cells but not ovarian normal cells (12). Cells were exposed to different concentrations of DCP for 1-hour and cultured in drug-free media for 24-hour, Western blot analysis showed that DCP activated several crucial genes in the apoptosis pathway - including p53, Bax and Caspase-3 - in prostate cancer cells only but not in prostate normal cells. These findings suggest that DCP mainly affects tumor cells (12). These data indicate a possible molecular mechanism of DCP’s more bearable side effects.

In vivo studies. In vivo studies using Flow Cytometry analysis of bone marrow and spleen in mice treated with Cisplatin (CDDP), Carboplatin (Carbo), and DCP (at 1/2 LD50, IP for 7 days) shown that cisplatin induced more apoptosis (including early apoptosis and late apoptosis) in bone marrow than DCP, indicating that DCP is less toxic to bone marrow than cisplatin. Flow cytometry was carried out for cell-cycle analysis of mice spleen after 3-platinim drug treatment. The Results showed that cisplatin and carboplatin arrested more splenocytes in the G1 phase than DCP, suggesting that DCP caused less damage to spleen cells than cisplatin or carboplatin. Eight-color flow cytometry evaluation of the immune status of spleen in mice treated with cisplatin, carboplatin and DCP demonstrated that DCP retained more CD8 T cells and CD8 memory T cell than cisplatin; DCP also retained more CD4 memory T cells compared to cisplatin and carboplatin, suggesting immune status of mice treated with DCP is less compromised than those treated with cisplatin or carboplatin (12). In summary, in vivo findings showed that DCP was less toxic to bone marrow than cisplatin, DCP caused less damage to spleen cells than cisplatin or carboplatin, and that better immune status of mice treated with DCP than those treated with cisplatin and carboplatin.

Clinical Evidence for DCP in Cancer

Treatment phase I and II clinical trials. The clinical development of DCP began with phase I trials in China, which established its safety profile and determined appropriate dosing regimens (8). These early studies demonstrated that DCP could be administered at doses that achieved therapeutic plasma concentrations with manageable toxicity. The maximum tolerated dose was established, and dose-limiting toxicities were identified, primarily consisting of myelosuppression, which is also common with other platinum compounds but appeared less severe with DCP (6, 8). A pivotal phase II trial comparing DCP plus paclitaxel to carboplatin plus paclitaxel in advanced non-small cell lung cancer (NSCLC) demonstrated comparable efficacy with a more favorable toxicity profile in the DCP arm (14). Specifically, patients receiving DCP experienced less severe nephrotoxicity, neurotoxicity, and ototoxicity, maintaining while similar response rates and progression-free survival (14).

Case reports and real-world evidence. Beyond formal clinical trials, case reports and real-world evidence have provided valuable insights into the potential utility of DCP in clinical practice. Perhaps the most notable case is the first American patient treated with DCP for bladder cancer, as reported by Yu et al. (12, 13, 15, 16). This patient, diagnosed with non-invasive high-grade papillary urothelial carcinoma, received intravenous DCP for eight weeks and additional oral DCP capsules for 1 ½ months after declining standard BCG immunotherapy. There was no vomiting, no hair loss to this patient. Weekly monitoring showed that his red blood cell (RBC), white blood cell (WBC) and Platelet levels dropped slightly each week, indicating that DCP was working. However, all remained within normal limits. The patient did not suffer from serious myelosuppression, a common side effect of chemotherapeutic drugs (specifically, low platelets, low WBC count and anemia). In other words, the immune system of this patient was not compromised by DCP chemotherapy. The treatment resulted in complete remission that was maintained for five years with annual DCP “booster” treatments (15, 16). When the patient experienced tumor recurrence after 18 months without surveillance (due to the COVID-19 pandemic), a seven-week course of oral DCP capsules alone resulted in complete remission, as confirmed by cystoscopy and cytology (13). Remarkably, this treatment was well-tolerated, with minimal side effects and no significant impact on bone marrow, liver, or renal parameters. This case is particularly significant as it demonstrates the potential efficacy of oral DCP, which could represent a major advance in platinum drug delivery.

Comparative studies with conventional platinum compounds. Studies have directly compared DCP to conventional platinum compounds, providing the most robust evidence for its potential advantages. A randomized controlled trial comparing DCP plus paclitaxel to carboplatin plus paclitaxel in advanced NSCLC found similar objective response rates (36.44% vs. 30.51%) and median overall survival (14.9 vs. 12.9 months) between the two regimens (14). However, the DCP arm demonstrated significantly lower rates of grade 3-4 lymphopenia, hyperglycemia, and nausea/vomiting. And dicycloplatin may be more efficacious than carboplatin for the treatment of advanced squamous NSCLC (14).

Specific Applications in Cancer Types

Bladder cancer. Bladder cancer represents a particularly promising application for DCP, as highlighted by the case report discussed earlier (13, 15, 16). Cisplatin-based chemotherapy is standard for muscle-invasive bladder cancer, but many patients are ineligible due to impaired renal function or other comorbidities (17-19). The improved renal safety profile of DCP could potentially expand the population of patients able to receive platinum-based therapy. Additionally, the availability of an oral formulation could be particularly valuable in bladder cancer, where maintenance therapy might help prevent the high rate of recurrence that characterizes this disease. The successful use of oral DCP in treating recurrent bladder cancer, as demonstrated in the American patient case, suggests potential for both primary treatment and maintenance therapy in this setting (13, 16).

Lung cancer. Non-small cell lung cancer has been the most extensively studied indication for DCP, with both phase I and II trials demonstrating its efficacy and safety (8, 14). Platinum-based doublet chemotherapy remains standard first-line treatment for many NSCLC patients without actionable mutations, and DCP could potentially replace conventional platinum compounds in these regimens. A particular advantage in lung cancer might be the reduced ototoxicity and neurotoxicity of DCP, as these toxicities can be especially problematic in older patients who constitute a large proportion of the lung cancer population (20). Additionally, the potential for oral administration could be valuable in maintenance therapy or in patients with poor performance status who might benefit from less intensive treatment regimens.

Hepatocellular carcinoma. A phase II randomized, open-label, multicenter study was conducted to investigate the therapeutic potential and safety profile of DCP in transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) (21). The results indicated that DCP, whether used alone or in combination with epirubicin, achieved higher objective response rates (ORR) and disease control rates (DCR) compared to epirubicin monotherapy. The combination regimen (DCP plus epirubicin) demonstrated the most favorable progression-free survival (PFS). Importantly, all treatment arms exhibited acceptable safety profiles, with no significant increase in toxicity observed in the combination group. Overall, TACE incorporating DCP – especially in combination with epirubicin – showed encouraging anti-tumor efficacy and tolerability. These findings support the potential role of DCP as a viable alternative to standard agents like epirubicin in the TACE treatment of unresectable HCC, though confirmation in larger phase III studies remains essential (21).

Other solid tumors. In vitro studies suggested that DCP inhibits other cancer type cells, such as melanoma, ovarian carcinoma, prostate cancer (11, 12, 22, 23). DCP may be effective to treat other solid tumors like regular chemotherapy agents since DCP was showed better or similar efficacy to conventional platinum compounds with a significantly an improved safety profile. But in vivo and clinical studies are needed to confirm DCP tumor inhibitory effects in other tumor types.

Safety Profile and Quality of Life Considerations

The improved safety profile of DCP compared to conventional platinum compounds represents one of its most significant potential advantages. Across studies, DCP has consistently demonstrated reduced nephrotoxicity compared to cisplatin or carboplatin, with less impact on glomerular filtration rate and lower incidence of electrolyte disturbances (2, 10, 12, 24). This could potentially eliminate the need for aggressive hydration protocols that are standard with cisplatin administration. Neurotoxicity, a dose-limiting toxicity of both cisplatin and oxaliplatin, appears substantially reduced with DCP (13, 14). Studies have reported lower incidence and severity of peripheral neuropathy, potentially allowing for more prolonged treatment without functional impairment. Similarly, ototoxicity, a particularly problematic adverse effect of cisplatin that can cause permanent hearing loss, has been reported at lower rates with DCP (12, 14). Hematologic toxicities, including thrombocytopenia, neutropenia, and anemia, appear comparable to or slightly less severe than those observed with carboplatin (14, 16). This suggests that DCP may not offer as dramatic an advantage in this domain, but the overall toxicity profile remains favorable. Therefore, quality of life assessments in clinical trials have generally favored DCP over conventional platinum compounds, with patients reporting less fatigue, nausea, and sensory disturbances (12, 16). The availability of an oral formulation could further improve quality of life by reducing hospital visits and associated disruptions to daily activities (13).

Regulatory Status and Availability

DCP received approval from the State Food and Drug Administration of China (now the National Medical Products Administration) in 2012 for the treatment of solid tumors (6, 7). Both intravenous and oral formulations are commercially available in China and have been incorporated into clinical practice there. However, DCP has not yet received approval from regulatory authorities in Western countries, including the USFDA and European Medicines Agency. This limited availability has restricted its use primarily to Chinese patients, with exceptions like the 1st American bladder cancer patient who has involved in DCP investigations and traveled to China to receive treatment (13, 16). Efforts to expand the global availability of DCP are warranted, with several pharmaceutical companies exploring development and registration pathways in Western markets. The promising efficacy and safety data, particularly the potential for oral administration, make DCP an attractive candidate for global development despite the competitive landscape of platinum compounds.

Future Directions and Research Scope

Despite the promising data available for DCP, several important research questions remain unanswered. Large, multinational phase III trials are needed to definitively establish the efficacy and safety of DCP compared to conventional platinum compounds across various cancer types. These trials should include diverse patient populations to ensure generalizability of results beyond Chinese patients, who have constituted the majority of study participants to date. The oral formulation of DCP represents a particularly innovative aspect that warrants further investigation. Comparative studies of oral versus intravenous DCP are needed to establish bioequivalence and determine appropriate dosing regimens (13). Additionally, studies exploring maintenance therapy with oral DCP could potentially identify new treatment paradigms that improve outcomes while maintaining quality of life. Combination strategies involving DCP with targeted therapies and immunotherapies represent another important area for future research (25, 26). As these newer treatment modalities have transformed cancer care, understanding how DCP interacts with them could help optimize treatment sequencing and combinations. Biomarker studies to identify patients most likely to benefit from DCP versus conventional platinum compounds could help personalize treatment decisions. While platinum sensitivity is a well-established concept, specific markers predicting differential response or toxicity between platinum analogs remain limited. Lastly, new technologies, such as ADC Linker and prodrug-conjugated tumor-seeking commensals, maybe good options for DCP related therapy in cancer in the future as well as other platinum drugs (27-30).