Main research findings

Topotecan is a chemotherapy drug used to treat various types of cancer, either alone or in combination with other chemotherapy drugs. 16 is a retrospective study that evaluated the efficacy and toxicity of topotecan followed by cisplatin in patients with persistent or recurrent cervical cancer. 1 is a phase I study that assessed the feasibility of combining oral topotecan and intravenous cisplatin, the pharmacokinetic interaction, and sequence-dependent effects. 3 showed that combining topotecan with a Tdp1 inhibitor enhanced the DNA-damaging effect of topotecan, which is used clinically to treat cancer. 22 showed that topotecan combined with cisplatin is effective in treating advanced squamous cell lung cancer and head and neck cancer. 13 is a study that evaluated the short-term efficacy and toxicity of topotecan and cyclophosphamide as maintenance chemotherapy for stage IV neuroblastoma in complete remission. 8 is a phase III trial that compared the efficacy of cisplatin-topotecan followed by carboplatin-paclitaxel (Arm 1) versus paclitaxel-carboplatin (Arm 2) in women with newly diagnosed stage IIB or greater ovarian cancer. This study found that the experimental arm had a significantly lower response rate compared to standard treatment, and a lower likelihood of normalized CA125 within the first 3 months. However, at 43 months follow-up, there were no significant group differences in progression-free survival. The experimental arm also had significantly more side effects. 23 showed that co-administration of phenoxodiol and topotecan exhibited significant anti-tumor activity without major adverse side effects. 14 showed that topotecan affects retinal vessels in newborn rats. Topotecan is a topoisomerase I inhibitor with the ability to inhibit tumoral growth in animal models of retinoblastoma, and the physiological system of the rodent retina during vessel formation and hierarchical organization was used to assay its antiangiogenic properties. We specifically analyzed possible differences in effectiveness and side effects among different drug dosages and administration methods. Qualitative analyses were undertaken for this study. After preliminary experiments in which suckling animals treated subcutaneously with topotecan dosages between 9 and 3 mg/kg experienced high lethality and extremely severe systemic damages, 7-day-old rats were injected subcutaneously, intravenously, or peribulbarly with a single dose of 1 mg/kg. Retinal vessels were visualized in retinal fluorescein angiograms taken 1 and 2 weeks after treatment. The most important and frequent alterations were found to affect radial vessels, which showed non-perfused and/or regionally mislocated segments, along with abnormal branching and enlargements in the retinal periphery. The persistence of capillary-free periarteriolar regions, non-vascularized regions, and spots of extravascular FITC were also detected. Despite the high individual variability, the alterations were substantially similar among the different drug administration methods, while they appeared milder in 21-day-old rats compared to younger ones. The extensive vascular remodeling found after topotecan administration, in addition to demonstrating the antiangiogenic properties of this chemotherapeutic drug, confirms the rodent retina as a highly valuable model system for studying angiogenesis modulation. 7 showed that melphalan, topotecan, and carboplatin are toxic to retinal pigment epithelial cells. Clinical evidence of retinal pigment epithelium (RPE) alterations after intra-arterial (IAC) and intravitreal chemotherapy (IViC) of retinoblastoma has been reported. We therefore investigated the cellular toxic effects of melphalan, topotecan, and carboplatin on the RPE in a cell culture model. 17 showed that the anticancer drug topotecan induces structural and dynamic effects on the human topoisomerase I-DNA complex. Human topoisomerase I catalyzes the relaxation of DNA supercoils in fundamental cellular processes such as transcription, replication, and chromosomal segregation. It is the only target of the camptothecin family of anticancer drugs. Among these, topotecan has been used to treat lung and ovarian carcinoma for several years. Camptothecins reversibly bind to the covalent intermediate DNA-enzyme, stabilizing the cleavable complex and reducing the religation rate. The stalled complex then collides with the progression of the replication fork, producing lethal double-strand DNA breaks and eventually cell death. 19 is a study that developed a semi-physiologically-based pharmacokinetic/pharmacodynamic model to describe the effects of topotecan on B-lymphocyte lineage cells. 15 evaluated the anti-cytogenotoxic effects of quercetin in animals treated with topotecan. This study examined the possible chemoprotective activity of orally administered quercetin against topotecan-induced cyto- and genotoxicity towards mouse somatic cells in vivo. DNA strand breaks, micronuclei formation, and mitotic activity were undertaken in this study as markers of cyto- and genotoxicity. Oxidative stress markers such as intracellular reactive oxygen species generation, lipid peroxidation, and reduced and oxidized glutathione were assessed in bone marrow as a possible mechanism underlying this amelioration. Quercetin was neither cytotoxic nor genotoxic in mice at the doses tested. Pretreatment of mice with quercetin significantly reduced topotecan-induced genotoxicity and cytotoxicity in bone marrow cells, and these effects were dose-dependent. Moreover, prior administration of quercetin before topotecan challenge ameliorated oxidative stress markers. In conclusion, quercetin plays a protective role in the abatement of topotecan-induced cyto- and genotoxicity in the bone marrow cells of mice, at least in part due to its antioxidant effects. Based on the data presented, strategies can be developed to decrease the topotecan-induced bone marrow suppression and secondary malignancy in cancer patients and medical personnel exposed to topotecan. 20 is a prospective, randomized, phase II trial that reported the effects of concurrent topotecan and radiation on 6-month progression-free survival in the primary treatment of glioblastoma. 4 showed that celecoxib and topotecan have cytotoxic and apoptotic effects on AGS and HEK 293 cell lines. This study aimed to assess the anti-cancer effects of celecoxib and topotecan against the human gastric cancer cell line (AGS) in comparison to the control in an in-vitro study. 12 predicted the effects of 8C2, a monoclonal anti-topotecan antibody, on the plasma and tissue disposition of topotecan. We are investigating an inverse targeting strategy to reduce the dose-limiting systemic toxicities resulting from intraperitoneal administration of topotecan, a model chemotherapeutic drug. This approach utilizes the systemic co-administration of anti-topotecan antibodies to alter the plasma and tissue disposition kinetics of topotecan. To better predict the effects of 8C2, a high-affinity anti-topotecan monoclonal antibody, on the pharmacokinetics of topotecan, two mathematical models have been developed and evaluated. Model 1 is a hybrid physiologically based pharmacokinetic (PBPK) model that was created by merging a PBPK model for topotecan with a simple two-compartment model of 8C2 pharmacokinetics. Model 2 is a comprehensive PBPK model developed by merging a PBPK model for IgG with a PBPK model for topotecan. To help validate the simulation results from both models, a tissue distribution experiment was conducted in which topotecan and 8C2 were co-administered in mice. Experimental and simulated data were compared by calculating the median percent prediction error (%PE) for all tissues. For both models, the median %PE values for all tissues were less than 100%, indicating that the predicted values were, on average, less than twofold the observed plasma and tissue topotecan concentration values. In general, model 2 was found to be more predictive of the data set than model 1, as the overall median %PE value for model 2 (%PE = 63) was less than model 1 (%PE = 73). 2 is a review article that explored the use of topotecan to treat ovarian cancer. 5 examined the effects of pazopanib monotherapy vs. pazopanib and topotecan combination on anaplastic thyroid cancer (ATC) cells. The purpose of this study was to examine pazopanib/topotecan combination activity vs. pazopanib monotherapy on anaplastic thyroid cancer (ATC) cells. Proliferation analyses were performed on ATC cell lines administered for 72 h with pazopanib and topotecan alone and in their simultaneous combination. Pazopanib and topotecan produced strong synergism on ATC cells, calculated by the combination index, increasing the intracellular concentrations of topotecan lactone measured by high-performance liquid chromatography. Furthermore, a significant decrease in the gene expression of ATP-binding cassette transporter G2 (ABCG-2), vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1α (HIF-1α), and colony stimulating factor-1 (CSF-1) was presented in combination-treated ATC cells by real-time PCR tests. In summary, the simultaneous association of pazopanib and topotecan established a highly synergistic ATC antiproliferative effect, suggesting a new possibility to translate this schedule into clinical trials. 11 is a study that developed a PK/TD modeling for prediction of the effects of 8C2, an anti-topotecan mAb, on topotecan-induced toxicity in mice. To facilitate the development of an inverse targeting strategy, where anti-topotecan antibodies are administered to prevent systemic toxicity following intraperitoneal topotecan, a pharmacokinetic/toxicodynamic (PK/TD) model was developed and evaluated. The pharmacokinetics of 8C2, a monoclonal anti-topotecan antibody, were assessed following IV and SC administration, and the data were characterized using a two-compartmental model with nonlinear absorption and elimination. A hybrid PK model was constructed by combining a PBPK model for topotecan with the two-compartment model for 8C2, and the model was employed to predict the disposition of topotecan, 8C2, and the topotecan-8C2 complex. The model was linked to a toxicodynamic model for topotecan-induced weight-loss, and simulations were conducted to predict the effects of 8C2 on the toxicity of topotecan in mice. Increasing the molar dose ratio of 8C2 to topotecan resulted in a dose-dependent decrease in the unbound (i.e. not bound to 8C2) topotecan exposure in plasma (AUCf) and a decrease in the extent of topotecan-induced weight-loss. Consistent with model predictions, toxicodynamic experiments showed a substantial reduction in the percent nadir weight loss observed with 30 mg/kg IP topotecan after co-administration of 8C2 (20 ± 8% vs. 10 ± 8%). The investigation supports the use of anti-topotecan mAb to reduce the systemic toxicity of IP topotecan chemotherapy. 9 showed that topotecan in combination with thymoquinone has antiproliferative and proapoptotic effects on acute myelogenous leukemia. Topotecan has shown promising antineoplastic activity in solid tumors and acute leukemia. Because of the primary dose-limiting toxicity of topotecan, it is necessary to identify other agents that can work synergistically with topotecan, potentially increasing its efficacy while limiting its toxicity. Many studies showed synergism in combination of topotecan with gemcitabine and bortezomib. Other studies report an increase in growth inhibition of gemcitabine or oxaliplatin when cells were preexposed to naturally occurring drugs such as thymoquinone. The aim of this project was to study the mode of action of topotecan along with thymoquinone on survival and apoptosis pathways in acute myelogenous leukemia (AML) cell lines and to investigate the potential synergistic effect of thymoquinone on topotecan. 6 described the preparation and use of magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) labeled thermosensitive liposomes for imaging and tracking of biodistribution and drug release in a murine cancer model. Image-guided drug delivery using imageable thermosensitive liposomes (iTSLs) and high-intensity focused ultrasound (FUS or HIFU) has attracted interest as a novel and non-invasive route to targeted delivery of anti-cancer therapeutics. FUS-induced hyperthermia is used as an externally applied “trigger” for the release of a drug cargo from within thermosensitive drug carriers. It is suggested that sub-ablative hyperthermia significantly modifies the permeability of tumor vasculature and enhances nanoparticle uptake. We prepared iTSLs to encapsulate topotecan (Hycamtin®), a chemotherapeutic agent which when released in tumors can be monitored by an increase in its intrinsic drug fluorescence. FUS was applied using feedback via subcutaneously placed fine-wire thermocouples to maintain and monitor hyperthermic temperatures. iTSL accumulation was detected within tumors using NIRF imaging immediately after liposome administration. Mild FUS-induced hyperthermia (3 min at 42°C, 30 min post i.v. administration) greatly enhanced iTSLs uptake. A co-localized enhancement of topotecan fluorescence emission was also observed immediately after application of FUS, indicating rapid triggered drug release. The phenomena of increased iTSL accumulation and concomitant topotecan release appeared to be amplified by a second mild hyperthermia treatment applied one hour after the first. MRI in vivo also confirmed enhanced iTSLs uptake due to the FUS treatments. Our imaging results indicate the effects of hyperthermia on the uptake of carriers and drugs. FUS-induced hyperthermia combined with real-time imaging could be used as a tool for tumor-targeted drug delivery. 18 addressed the low-lying valence electronic excitations of the topotecan anticancer drug, in two stable lactone forms, in infinite dilute aqueous solution by combining time-dependent density functional theory calculations with nanoseconds time-scale classical molecular dynamics simulations at 298 K. The effects of the surrounding and fluctuating classical environment on the investigated topotecan forms are included in a perturbed electronic Hamiltonian, which is computed and then diagonalized at each frame stored during the molecular dynamics sampling in explicit solution. Current results clearly indicate that, at moderately acidic and physiological conditions, the valence UV-Vis absorption spectra of topotecan drug are strongly affected by the surrounding dielectric media and by its perturbing trajectory as arising from finite-temperature fluctuations and supramolecular interactions. Furthermore, the extension of the proposed computational study to hydrated topotecan complexes in liquid water shows that all of the experimentally detected UV-Vis spectroscopic features in solution are accurately reproduced only when direct solute-solvent intermolecular interactions are also explicitly taken into account in our simulating scenario. Finally, the present investigation opens up a chance regarding the computational prediction of the UV-Vis absorption spectra of topotecan interacting, in silico, with the topoisomerase-DNA binary complex in physiological conditions (i.e. water dilute solution, room temperature). 21 investigated the effects of topotecan, a topoisomerase I-inhibiting anticancer agent, on hematologic parameters and serum levels of trace elements. The study was conducted on three groups consisting of 16 and 18 rabbits in the study groups and 15 rabbits in the control group. Rabbits in group I (n = 16) received high-dose topotecan intravenously (i.v.; 0.5 mg/kg once daily), while rabbits in group II (n = 18) received low-dose topotecan i.v. (0.25 mg/kg once daily) for 3 days. The 15 rabbits comprising the control group did not receive topotecan. Serum samples were collected from each rabbit on the first day, before treatment, and on the 15th day of treatment. Erythrocytes, hemoglobin, white blood cell count, thrombocyte count, and trace elements such as selenium, copper, lead, zinc, and cobalt were analyzed. Hemoglobin levels and erythrocyte counts were lower in both study groups than in the control group. However, thrombocyte and leukocyte counts were similar in all three groups (p > 0.005). Serum trace element levels (copper, lead, zinc, and cobalt) did not differ significantly between groups. However, serum selenium levels were significantly lower in both study groups than the control group (p < 0.001). The results revealed that topotecan treatment causes a decrease in erythrocyte counts and hemoglobin levels due to bone marrow suppression, and these effects must be taken into account during treatment. In addition, selenium supplementation might be helpful in cancer patients receiving topotecan to increase the effect of the chemotherapeutic agent. 10 investigated the chemotherapeutic agents that produce the strongest synergistic effects when combined with trabectedin against ovarian clear cell carcinoma (CCC), which is regarded as an aggressive chemoresistant histological subtype.

Benefits and Risks

Benefits Summary

Topotecan is a chemotherapy drug used to treat various types of cancer, either alone or in combination with other chemotherapy drugs. 16 suggests that topotecan followed by cisplatin is effective in treating persistent or recurrent cervical cancer. 22 suggests that topotecan combined with cisplatin is effective in treating advanced squamous cell lung cancer and head and neck cancer. 13 suggests that topotecan and cyclophosphamide are effective as maintenance chemotherapy for stage IV neuroblastoma in complete remission. 5 showed that combining pazopanib and topotecan demonstrated a highly synergistic ATC antiproliferative effect, suggesting a new possibility to translate this schedule into clinical trials. 6 showed that using high-intensity focused ultrasound (FUS) to irradiate thermosensitive liposomes encapsulating topotecan can enhance drug delivery to tumors.

Risks Summary

Topotecan can cause various side effects. 16 , 1 suggest that combining topotecan and cisplatin can cause hematologic side effects, especially neutropenia and thrombocytopenia. 8 suggests that combining topotecan and cisplatin could cause more side effects than standard treatment. 14 showed that topotecan affects retinal vessels in newborn rats. 7 showed that topotecan can be toxic to retinal pigment epithelial cells. 21 showed that topotecan decreased erythrocyte counts and hemoglobin levels in rabbits, which is thought to be due to bone marrow suppression. Topotecan can also cause selenium deficiency. 17 showed that topotecan affects the human topoisomerase I-DNA complex. This effect is concerning because it could cause topotecan to inhibit DNA replication and repair, leading to cell death.

Comparison Between Studies

Commonalities Among Studies

These studies suggest that topotecan is a potentially effective anticancer agent for various cancer types. They also suggest that topotecan can cause side effects. These studies suggest that topotecan may be an effective anticancer agent for various cancer types, but it is important to consider the risk of side effects.

Differences Between Studies

These studies investigated various aspects of topotecan, including combination therapy with other chemotherapy drugs, side effects of topotecan, and the mechanism of action of topotecan. 16 is a retrospective study evaluating the combination of topotecan and cisplatin. In contrast, 1 is a phase I study of combining oral topotecan and intravenous cisplatin. Additionally, 8 is a phase III trial comparing the efficacy and side effects of combining topotecan and cisplatin with standard treatment. 14 evaluated the effects of topotecan on retinal vessels in newborn rats. 7 evaluated the potential toxicity of topotecan to retinal pigment epithelial cells. 17 evaluated the effects of topotecan on the human topoisomerase I-DNA complex. These studies used different designs and methods, leading to different results.

Consistency and Contradictions in Results

The results of these studies suggest that topotecan could be an effective anticancer agent, but it also carries a risk of side effects. However, there are contradictions between the studies regarding the efficacy and severity of topotecan’s side effects. For example, 8 suggests that combining topotecan and cisplatin could cause more side effects than standard treatment. On the other hand, 23 suggests that co-administration of phenoxodiol and topotecan exhibited significant anti-tumor activity without major adverse side effects. These contradictions can be explained by differences in study design, patient populations, and treatment methods.

Notes on Applying the Results to Real Life

These studies suggest that topotecan is a potentially effective anticancer agent, but it also carries a risk of side effects. Therefore, it is essential to carefully consider the benefits and risks when using topotecan in treatment. It is important to select the appropriate dosage and administration method when using topotecan in treatment, considering the patient’s condition and disease state. It is also important to monitor for side effects and provide appropriate care when necessary.

Limitations of Current Research

All of these studies used specific designs and methods, and each has limitations. For example, 16 is a retrospective study, which may be subject to bias. 1 is a phase I study with a limited number of patients. 8 is a phase III trial, but the follow-up period is limited to 43 months. These limitations could restrict the generalizability of the research findings.

Directions for Future Research

More research is needed to better understand the efficacy and side effects of topotecan. In particular, studies are needed to investigate combination therapy with other chemotherapy drugs, new administration methods for topotecan, and methods to reduce the side effects of topotecan to maximize its effectiveness while minimizing side effects. It is also essential to study how topotecan works against different types of cancer.

Conclusion

These studies suggest that topotecan is a potentially effective anticancer agent, but it also carries a risk of side effects. It is essential to carefully consider the benefits and risks when using topotecan in treatment. Further research is needed to better understand the efficacy and side effects of topotecan.