Chlorambucil

Interaction with Guanine and Adenine Bases

This compound exhibits a preference for certain sites on DNA bases for alkylation. The most frequent site of alkylation is the N7 position of guanine. patsnap.comnih.govacs.orgrsc.org Alkylation can also occur at the N3 position of adenine. nih.govrsc.orgmdpi.com The reaction of this compound with the N7 of guanine or N3 of adenine leads to the formation of mono-adducts. nih.govrsc.orgmdpi.com

Formation of Intrastrand and Interstrand Cross-links

As a bifunctional agent, this compound can form cross-links within or between DNA strands. patsnap.comnih.govacs.org Interstrand cross-links (ICLs), which form between the two opposite DNA strands, are considered particularly toxic DNA lesions. acs.orgnih.govacs.org These cross-links are potent blocks to DNA replication and can lead to the formation of DNA double-strand breaks. acs.orgnih.gov Intrastrand cross-links, formed within the same DNA strand, are also generated. acs.orgnih.govacs.org Studies have shown that while monofunctional alkylation with guanine is frequent, cross-linked adducts, particularly intrastrand cross-links, are major detected products, especially in tetranucleotides. nih.gov

Data on the types of adducts detected after this compound treatment of calf thymus DNA, analyzed at the oligonucleotide level, provides insight into the dynamics of alkylation and cross-linking. nih.gov

Based on research findings on this compound-adducts in DNA analyzed at the oligonucleotide level. nih.gov

p53-Dependent and p53-Independent Pathways

Apoptosis induced by DNA damaging agents like this compound can occur through both p53-dependent and p53-independent pathways. The tumor suppressor protein p53 plays a critical role in sensing DNA damage and initiating cell cycle arrest or apoptosis. wikipedia.org this compound-induced DNA damage can lead to the accumulation of cytosolic p53, which subsequently activates pro-apoptotic proteins. wikipedia.org However, apoptosis can also be triggered in cells with non-functional or absent p53, indicating the existence of p53-independent mechanisms. Research into the specific pathways activated by this compound in different cell types and contexts is ongoing.

Modulation of Apoptotic Regulators (e.g., Bax, Bcl-2)

The balance between pro-apoptotic and anti-apoptotic proteins, particularly members of the Bcl-2 family, is a key determinant of a cell's fate following cytotoxic insult. haematologica.orgtandfonline.com this compound-induced apoptosis involves the modulation of these regulators. Elevated levels of anti-apoptotic proteins like Bcl-2 and low levels of pro-apoptotic proteins like Bax have been linked to chemoresistance in chronic lymphocytic leukemia (CLL) cells treated with this compound. haematologica.orgtandfonline.comnih.govnih.govpsu.edu Conversely, a significant elevation of Bax protein has been observed in CLL cells undergoing apoptosis. haematologica.orgtandfonline.com The ratio of Bcl-2 to Bax is considered an important factor influencing sensitivity to this compound-induced apoptosis. tandfonline.comnih.govpsu.edu

Studies have investigated the correlation between Bcl-2 and Bax expression levels and this compound sensitivity in CLL cells.

Based on research findings on Bcl-2 and Bax expression and this compound-induced apoptosis in CLL cells. haematologica.orgtandfonline.comnih.govnih.govpsu.edu

Impact on Regulatory T Cells

Studies have indicated that this compound can influence the population of regulatory T cells (Tregs). Regulatory T cells are a subset of T lymphocytes that play a critical role in maintaining immune tolerance and suppressing immune responses. aacrjournals.orgfrontiersin.org Research has shown that this compound treatment can lead to a reduction in the number and function of CD25+, CD4+, and Foxp3+ regulatory T cells in the peripheral blood. mdpi.com While some studies on other alkylating agents like cyclophosphamide have shown a transient increase in Tregs followed by depletion or altered function, the specific and sustained impact of this compound on Treg subsets and their functional consequences in different contexts require further detailed investigation. aai.orgnih.gov

Data from a study comparing Ibrutinib and this compound in chronic lymphocytic leukemia (CLL) patients showed that this compound progressively reduced various circulating immune cells, including regulatory T cells. ascopubs.org

Angiogenesis Inhibition

This compound has been reported to possess anti-angiogenic properties, which can contribute to its anti-tumor activity by limiting the formation of new blood vessels required for tumor growth and metastasis. mdpi.comrsc.orgresearchgate.net Studies have shown that this compound can inhibit direct sprout formation in in vivo models of vascular occlusion. mdpi.comresearchgate.net Furthermore, it can induce selective cytotoxicity in human-immortalized endothelial cells, thereby impeding their viability. mdpi.comresearchgate.net Research on this compound derivatives has also demonstrated enhanced anti-angiogenic activity and effective inhibition of tumor growth in vivo. rsc.orgresearchgate.net

Programmed Death-Ligand 1 (PDL1) Depletion Mechanisms

Recent research highlights the ability of this compound to induce the depletion of programmed death-ligand 1 (PDL1) on tumor cells. bmj.comnih.govnih.govbmj.com This is a significant finding as tumor cell-intrinsic PDL1 can mediate resistance to treatment and suppress anti-tumor immunity. bmj.comnih.govnih.govmdpi.combmbreports.org this compound-mediated PDL1 reduction can occur through both transcriptional and post-translational mechanisms, and these mechanisms can be tumor cell-type-specific. bmj.comnih.govnih.gov Pharmacological depletion of tumor PDL1 with this compound has been shown to target tumor-intrinsic PDL1 signaling, potentially overcoming treatment resistance and enhancing anti-tumor immunity, including rendering some anti-PDL1-resistant tumors sensitive to anti-PDL1 therapy through effects on natural killer (NK) cells. bmj.comnih.govnih.govbmj.com

This compound-mediated tumor cell PDL1 depletion has been observed to phenocopy the effects of genetic PDL1 depletion in reducing tumor cell mTORC1 activation. bmj.comnih.govbmj.com The mTORC1 pathway is a key regulator of cell growth, proliferation, and survival, and its activation in tumor cells can contribute to pathogenesis and treatment resistance. bmbreports.orgfrontiersin.orgresearchgate.netmdpi.com By inhibiting mTORC1 signaling, this compound's effect on PDL1 can contribute to its anti-tumor potential. bmj.comnih.govbmj.com

This compound's effect on tumor cell PDL1 depletion is also associated with the augmentation of autophagy. bmj.comnih.govnih.govbmj.com Autophagy is a cellular process involved in the degradation and recycling of cellular components, and it can play a complex role in cancer, sometimes promoting survival and sometimes contributing to cell death. bmbreports.orgiu.edu Studies have shown that tumor cell-intrinsic PDL1 can suppress autophagy. bmj.comnih.govbmj.combmbreports.orgiu.edu Therefore, the depletion of PDL1 by this compound can lead to increased autophagic flux. bmj.comnih.govbmj.com

One of the post-translational mechanisms by which this compound promotes PDL1 degradation is through the activation of the GSK3β/β-TRCP pathway. bmj.comnih.govnih.govnih.gov Glycogen synthase kinase 3 beta (GSK3β) is a kinase that can phosphorylate PDL1, marking it for ubiquitination by the E3 ubiquitin ligase β-TRCP (beta-transducin repeat-containing protein), which leads to proteasomal degradation of PDL1. bmj.comnih.govnih.govtandfonline.commednexus.orgactuatetherapeutics.com Research indicates that this compound treatment can activate GSK3β, as evidenced by reduced phosphorylation of GSK3β, thereby promoting PDL1 ubiquitination and degradation in certain cancer cell lines. bmj.comnih.gov Blocking the GSK3β pathway has been shown to restore PDL1 expression despite this compound exposure. bmj.com

Passive Diffusion

Role of Human Glutathione Transferase Pi (GST P1-1)

Human Glutathione Transferase Pi (GST P1-1) is a key enzyme involved in the detoxification of electrophilic compounds, including certain chemotherapeutic agents like this compound researchgate.netmdpi.comnih.gov. GSTs catalyze the conjugation of reduced glutathione (GSH) to these compounds, forming more water-soluble conjugates that can be more easily excreted from the cell nih.govmdpi.com. This process can effectively neutralize the cytotoxic activity of alkylating agents such as this compound researchgate.netnih.gov.

Overexpression of GST P1-1 has been observed in various cancer tissues and has been linked to drug resistance researchgate.netnih.govjst.go.jp. Studies have shown that this compound can be detoxified by GST P1-1 through a GSH conjugation reaction researchgate.nettorvergata.it. The interaction between this compound and GST P1-1 involves the binding of this compound to the enzyme's substrate-binding site (H-site) torvergata.itpdbj.org. In the presence of GSH, a productive conjugation reaction occurs, leading to the formation of a GSH-chlorambucil conjugate torvergata.itpdbj.org. This conjugation is considered a detoxification process that protects cellular biomolecules from damage mdpi.com.

Allelic variants of GST P1-1 exist and are associated with differing efficiencies in catalyzing GSH conjugation reactions researchgate.netnih.govtorvergata.it. For instance, the GSTP1 105Val variant has been shown to have significantly lower catalytic activity towards this compound compared to the GSTP1 105Ile variant ashpublications.org. These differences in catalytic activity among variants can potentially influence an individual's susceptibility to certain cancers and their response to therapies involving GST substrates ashpublications.org.

Beyond its catalytic detoxification function, GST P1-1 has also been implicated in regulatory functions unrelated to detoxification, including interactions with kinase pathways nih.govjst.go.jp. For example, GST P1-1 can interact with c-Jun N-terminal kinase (JNK), potentially influencing cellular responses to stress and contributing to drug resistance nih.govjst.go.jppnas.org.

Data on the catalytic efficiency of GST P1-1 variants with this compound as a substrate highlights the enzyme's role in this compound metabolism. Research involving kinetic studies of GST P1-1 allelic variants demonstrates that their catalytic properties are highly substrate-dependent nih.govtorvergata.it.

Impact of p53 Mutations on Drug Sensitivity

Mutations in the tumor suppressor gene TP53 (which encodes the p53 protein) are among the most frequently observed genetic alterations in human cancers and are significantly associated with resistance to various standard chemotherapies, including alkylating agents like this compound oncotarget.comaacrjournals.orgkarger.comembopress.org. The p53 protein plays a critical role in the cellular response to DNA damage, regulating cell cycle arrest and apoptosis tandfonline.com. Functional p53 is essential for mediating the cytotoxic effects of DNA-damaging agents such as this compound tandfonline.comaacrjournals.org.

In cells with wild-type p53, this compound-induced DNA damage typically leads to the stabilization and activation of p53, triggering downstream pathways that result in cell cycle arrest or apoptosis tandfonline.comaacrjournals.org. However, in the presence of p53 mutations or dysfunction, this critical DNA damage response pathway is impaired tandfonline.comaacrjournals.org. Mutant p53 can lose its normal tumor suppressor function and, in some cases, acquire new functions that promote oncogenesis and contribute to chemoresistance oncotarget.comkarger.com.

Studies in chronic lymphocytic leukemia (CLL) have shown a strong association between p53 mutations and innate resistance to this compound aacrjournals.orgnih.gov. While p53 mutations are not present in all CLL patients, they are frequently linked to a poorer response to this compound therapy aacrjournals.org. The exact mechanism by which p53 mutations confer this compound resistance is not fully elucidated, but it is believed to involve the inability of cells with dysfunctional p53 to undergo appropriate cell cycle arrest or apoptosis in response to this compound-induced DNA damage embopress.orgtandfonline.com. Research has indicated that lymphocytes from individuals with p53 mutations show a marked resistance to this compound-induced apoptosis compared to those with wild-type p53 tandfonline.com.

Although p53 mutations are strongly associated with this compound resistance, drug-resistant samples have also been observed in patients with wild-type p53, suggesting that multiple mechanisms contribute to resistance in CLL nih.gov. Nevertheless, p53 status is considered a significant predictor of response to this compound and other DNA-damaging agents karger.comembopress.org.

Table 1: Median LD50 Values of Chemotherapeutic Drugs in Untreated CLL Patient Samples

Data derived from in vitro chemosensitivity testing using the MTT assay in samples from untreated CLL patients nih.gov.

Table 2: Association of p53 Mutation Status with this compound Resistance in CLL

Data based on a study examining p53 gene mutations and in vitro drug sensitivity in CLL nih.gov.

Enhanced Cross-link Repair

Increased efficiency in repairing the DNA cross-links induced by this compound is a significant mechanism of resistance. Studies have shown that resistant cells can exhibit accelerated removal of these cross-links compared to sensitive cells. aacrjournals.orgaacrjournals.org This enhanced repair capacity reduces the accumulation of cytotoxic DNA lesions, allowing cancer cells to survive and proliferate despite exposure to the drug.

Recombinational Repair

Homologous recombinational repair (HRR) is a major pathway involved in the repair of DNA double-strand breaks and interstrand cross-links. Research has highlighted the emerging role of recombinational repair in this compound resistance, particularly in CLL. aacrjournals.orgaacrjournals.orgnih.govnih.gov Increased activity of HRR, often indicated by elevated levels of proteins like HsRad51 and Xrcc3, has been correlated with a this compound-resistant phenotype. nih.gov This suggests that an enhanced ability to utilize HRR to fix this compound-induced DNA damage contributes to treatment failure.

Bcl-xL and MCL1 Expression

Members of the Bcl-2 family of proteins are key regulators of apoptosis. Overexpression of anti-apoptotic proteins such as Bcl-xL and MCL1 has been implicated in resistance to various chemotherapeutic agents, including potentially this compound. ashpublications.orgdovepress.comnih.govresearchgate.netashpublications.org These proteins can sequester pro-apoptotic proteins, preventing the activation of the apoptotic cascade even in the presence of significant DNA damage. Studies in CLL have suggested that elevated Bcl-2/Bax ratios may correlate with chemoresistance. nih.govtandfonline.com While the direct link between this compound resistance and the expression levels of Bcl-xL and MCL1 is an area of ongoing research, their role in promoting cell survival pathways suggests their potential contribution to overcoming drug-induced apoptosis. ashpublications.orgdovepress.comnih.govashpublications.orgnih.govresearchgate.netoncotarget.com

PI3-kinase Pathway Activity

The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is a key regulator of various cellular processes, including apoptosis, proliferation, differentiation, motility, and metabolism um.es. Activation of the PI3K/Akt axis has been implicated in conferring therapeutic resistance to various anti-neoplastic agents, including classical chemotherapeutic drugs um.es.

Studies suggest that the PI3K/Akt axis may be important for resistance to this compound-induced apoptosis in B-CLL lymphocytes um.es. While this hypothesis had been suggested, the precise mechanisms and the effect of selective pharmacological inhibitors on this compound resistance via this pathway have been areas of investigation um.es.

The PI3K pathway can be activated through various mechanisms, and its aberrant activation is often associated with the onset of cancer and resistance to therapy nih.gov. Inhibitors targeting key regulatory proteins within this pathway, such as PI3K, Akt, and mTOR, are being explored as potential strategies to overcome resistance, either alone or in combination with existing therapies um.es.

Synergistic Interactions with Other Chemotherapeutic Agents

Preclinical studies have demonstrated synergistic interactions between this compound and various other chemotherapeutic agents. For instance, in vitro studies using lymphocytes from patients with B-cell chronic lymphocytic leukemia (B-CLL) showed that DNA synthesis inhibitors like aphidicolin (PubChem CID: 26919) and 1-beta-D-arabinofuranosylcytosine (Cytarabine, PubChem CID: 5978) displayed synergy with this compound, enhancing its potency in this clinically relevant model. nih.gov This synergy was observed across a range of inhibitor concentrations and was not limited to samples from patients with established resistance. nih.gov

Another preclinical basis for novel combination therapy involved pentostatin (PubChem CID: 446411) and theophylline (PubChem CID: 2723625). nih.gov In vitro studies with human chronic lymphocytic leukemia cells indicated that theophylline, a phosphodiesterase inhibitor, downregulated bcl-2 and induced apoptosis. nih.gov This provided the rationale for a combination therapy involving pentostatin, this compound, and theophylline for relapsed chronic lymphoproliferative disorders. nih.gov

Combinations of nucleoside analogs and alkylating agents, including this compound, have shown activity in preclinical settings. nih.gov For example, the combination of pentostatin, a purine nucleoside analog, with this compound demonstrated activity in B-CLL patients in preclinical studies. nih.gov

Preclinical studies have also explored combining this compound with mercaptopurine (PubChem CID: 6691) for anti-cancer effects. nih.gov

Modulating DNA Repair for Potentiation

Modulating DNA repair pathways represents a strategy to overcome acquired resistance to genotoxic agents like nitrogen mustards, including this compound. researchgate.net These agents induce DNA inter-strand cross-links, which can lead to double-strand breaks. researchgate.net Enhanced cross-link repair has been identified as a primary mechanism of resistance to nitrogen mustards in B-CLL. nih.gov

Preclinical research has investigated the therapeutic potential of modulating DNA repair using agents like aphidicolin and Cytarabine to enhance this compound toxicity in B-CLL lymphocytes. nih.gov Both agents showed synergy with this compound, suggesting that inhibiting DNA synthesis can potentiate the effects of this compound by interfering with the cell's ability to repair the DNA damage it causes. nih.gov

Studies have also assessed the effect of oxidative stress on the non-homologous end joining (NHEJ) pathway, a DNA repair mechanism, finding that reduced repair capacity can be caused by modulation of DNA-PK activity. researchgate.net The kinase activity of DNA-PKcs was observed to increase after this compound treatment in both sensitive and resistant cells, but it subsequently decreased only in sensitive cells, consistent with increased levels of DNA double-strand breaks. researchgate.net

Rational Combination Design Based on Resistance Mechanisms

Designing rational drug combinations based on known resistance mechanisms is a key approach in preclinical research. Understanding the signaling pathways associated with resistance can help maximize the selective induction of cancer cell death. nih.gov

For instance, preclinical studies investigating resistance to venetoclax (PubChem CID: 49846572) in lymphoma cell lines demonstrated that resistance was associated with increased expression of BCLxL and MCL1, increased activity of the PI3-kinase pathway, and changes in cellular energy metabolism. oaepublish.com This understanding highlights how overcoming these alternative pro-survival mechanisms can rationalize novel drug combinations. oaepublish.com While this example focuses on venetoclax resistance, the principle applies to understanding and overcoming this compound resistance as well.

Preclinical data in lymphoma suggest that upregulation of PI3K is commonly seen in ibrutinib (PubChem CID: 24821595) resistance, suggesting that combinations targeting PI3K might be effective in this scenario. ashpublications.org Although this is related to ibrutinib, it illustrates the strategy of targeting resistance pathways in combination therapy.

Pharmacological depletion of tumor PDL1 with this compound has been explored as a strategy to treat ovarian cancer and melanoma in preclinical models. bmj.com This approach improved antitumor immunity and rendered anti-PDL1-resistant tumors sensitive to anti-PDL1 therapy through NK cell effects. bmj.com this compound-mediated tumor PDL1 depletion suppressed tumor mTORC1 signals and stemness, suggesting potential mechanisms for this effect. bmj.com

Enhancing Specificity and Reducing Toxicity

A major goal in developing this compound analogs and hybrid molecules is to enhance their specificity for cancer cells and reduce toxicity to normal tissues. mdpi.comresearchgate.net this compound itself is limited by a lack of specificity, which contributes to its side effects. mdpi.com

Hybrid compounds incorporating this compound with different pharmacophores have been synthesized to address these limitations. mdpi.com For example, this compound-based hybrid compounds have been developed with the aim of improving specificity and reducing toxicity. mdpi.com

Studies have reported the synthesis of this compound combined with D- and L-tyrosine analogues, which showed enhanced anticancer activity compared to this compound alone in breast cancer cell lines in vitro. mdpi.com L-hybrids generally demonstrated superior activity. mdpi.com

Another approach involves creating hybrid molecules that combine DNA targeting and DNA damaging moieties. oup.com Tallimustine, a hybrid of a benzoyl nitrogen mustard and a DNA minor groove binder, is an example of this strategy, possessing enhanced sequence-selectivity and cytotoxicity. oup.com

Preclinical investigations of fluorodeoxyglucose-coupled this compound alkylating agents have shown high specificity towards cancer cells in a mouse leukemia model. researchgate.net These glycoconjugated drugs demonstrated increased cytotoxicity in vivo compared to unconjugated this compound in human cancer cell lines. researchgate.net

Boronic acid analogs of nitrogen mustard prodrugs, such as CWB-20145 and Fan-NM-CH3, have shown reduced toxicity compared to this compound while retaining potent antitumor effects in preclinical studies. uwm.edu Fan-NM-CH3 further improved in vivo efficacy and tumor specificity. uwm.edu

An olaparib-chlorambucil hybrid molecule (C2) has been developed, exhibiting potent PARP1 inhibitory activity and broad-spectrum anticancer potency in vitro against various cancer cell lines, including those that are BRCA-unmutated. frontiersin.org This hybrid showed significant potency compared to both olaparib and this compound alone. frontiersin.org

Mitochondrial Targeting Strategies

Targeting mitochondria is an emerging strategy in cancer therapy, and preclinical research has explored conjugating this compound to mitochondria-targeting moieties to enhance its cytotoxic effects. mdpi.comfrontiersin.orgdovepress.comnih.gov Cancer cells often exhibit altered mitochondrial metabolism, making mitochondria a potential therapeutic target. mdpi.comnih.gov

Triphenylphosphonium (TPP) is a commonly used moiety for mitochondrial targeting due to the negative mitochondrial membrane potential in cancer cells, which facilitates its accumulation. mdpi.comdovepress.comnih.gov A TPP-Chlorambucil conjugate (Mito-Chlor) has been synthesized and shown to accumulate in mitochondria, leading to mtDNA damage and significant suppression of tumor progression in a pancreatic tumor model in vivo. mdpi.comnih.gov Mito-Chlor exhibited increased anticancer efficacy compared to free this compound. nih.gov

Another study involving a TPP-Chlorambucil conjugate demonstrated about an 80-fold enhancement of cancer cell-killing activity in breast and pancreatic cancer cell lines that were largely insensitive to the parent drug. mdpi.com

Peptide-based strategies for mitochondrial targeting have also been investigated. nih.gov For example, a peptide-conjugated this compound (mtCbl) was obtained and confirmed to localize in mitochondria, showing potential for improved therapeutic effect. frontiersin.org

The rationale behind mitochondrial targeting is to leverage the differences in mitochondrial membrane potential between cancer and normal cells to selectively deliver cytotoxic agents, potentially increasing efficacy and reducing off-target toxicity. nih.gov

Table of Compounds and PubChem CIDs

Preclinical Combination Therapy Data (Illustrative Example based on search results)

Overcoming Drug Resistance with Hybrid Compounds

Drug resistance is a significant challenge in cancer therapy. Research efforts are directed towards synthesizing hybrid compounds that combine this compound with other agents to circumvent resistance mechanisms and enhance cytotoxic effects. One strategy involves conjugating this compound with platinum-based compounds. Studies have explored platinum(IV) complexes, such as those combining cisplatin with this compound moieties, demonstrating improved cytotoxicity in vitro against certain cancer cell lines, including cisplatin-resistant human ovarian cancer cells (A2780/CP70). These hybrid molecules have shown enhanced cellular uptake and increased DNA platination levels compared to cisplatin alone. nih.govmdpi.comnih.gov Compound 9, a platinum(IV) complex with two this compound moieties, efficiently entered cells and released both cisplatin and this compound upon reduction, leading to enlarged DNA damage and increased apoptosis in MDA-MB-231 cells. nih.gov

Another approach involves conjugating this compound with glucose analogs, such as 2-fluoro-2-deoxyglucose (FDG). This strategy aims to increase drug accumulation in tumor cells that exhibit high glucose uptake. Preclinical studies with FDG-Chlorambucil conjugates (compounds 21a and 40a) in murine melanoma (B16F0) and colon carcinoma (CT-26) cell lines showed antiproliferative activity in the micromolar range. researchgate.netscispace.com These conjugates were found to be less toxic than free this compound in vivo and demonstrated promising antitumor activity in tumor-bearing mice models, with Log Cell Kill (LCK) values exceeding 1.3. researchgate.net

Hybrid molecules incorporating this compound with other pharmacophores are also being investigated. For instance, a this compound–methionine hybrid (compound 12) was synthesized and evaluated against the MCF-7 breast cancer cell line, showing similar anticancer effects to this compound but with reduced toxicity in vitro. mdpi.comnih.gov This hybrid appeared to induce apoptosis. mdpi.com Additionally, a hybrid molecule combining olaparib and this compound (molecule C2) has shown potent PARP1 inhibitory activity and broad-spectrum anticancer potency in vitro, including against BRCA-unmutated cell lines. researchgate.netnih.gov This hybrid induced higher rates of apoptosis in K562 cells at lower doses compared to olaparib and this compound and caused G2/M phase cell cycle arrest. nih.gov

Preclinical data on the in vitro cytotoxicity of selected this compound hybrid compounds against various cancer cell lines:

Polymeric Nanoparticles for Encapsulation

Polymeric nanoparticles are widely studied as carriers for anticancer drugs due to their biocompatibility and biodegradability. frontiersin.org this compound has been encapsulated in various polymeric nanoparticles to improve its properties. Poly(DL-lactide-co-glycolide) (PLGA) nanoparticles loaded with this compound have shown higher activity against non-Hodgkin's lymphoma compared to the free drug. nih.gov this compound-loaded poly(butyl cyanoacrylate) preparations have demonstrated increased drug stability, preventing hydrolysis. nih.gov Redox-responsive heparin–this compound conjugated polymeric prodrugs have been designed to enhance antitumor activities. mdpi.com These conjugates could self-assemble into spherical vesicles with a this compound grafting efficiency of 61.33%. mdpi.com Cell viability tests showed that these prodrugs were biocompatible with normal cells (HaCaT) and selectively killed tumor cells (HeLa cells), with increased uptake by HeLa cells over time. mdpi.com

Self-Assembling Peptide-Drug Conjugates

Self-assembling peptide-drug conjugates represent a novel strategy for this compound delivery, forming supramolecular hydrogels or nanoparticles that can enhance drug solubility, cellular uptake, and potentially provide targeted delivery. researchgate.netnih.govdoi.orgrsc.org A self-assembling peptide-drug conjugate was developed by conjugating this compound and cyclen to a self-assembling peptide, forming a supramolecular hydrogel with improved aqueous solubility. researchgate.net This hydrogel exhibited favorable inhibitory activities against A549, HeLa, and MCF-7 cancer cell lines and showed lower toxicity towards normal 3T3 cells. researchgate.net It also induced significantly more DNA damage compared to free this compound. researchgate.net Another study explored conjugating this compound to the cell-penetrating peptide BP16, which enhanced its cellular uptake and improved cytotoxicity against various cell lines (CAPAN-1, MCF-7, PC-3, 1BR3G, and SKMEL-28) with IC50 values ranging from 8.7 to 25.5 µM, compared to >100 µM for free this compound. researchgate.net Incorporating a cathepsin B-cleavable sequence (Gly-Phe-Leu-Gly) further increased the efficacy, with IC50 values between 3.6 and 16.2 µM, attributed to selective release in the lysosomal compartment. researchgate.net Self-assembly of an amphiphilic drug-drug conjugate of irinotecan and this compound formed nanoparticles around 88 nm in diameter, capable of releasing both drugs upon hydrolysis. doi.org

Chitosan Nano-Conjugates

Chitosan, a natural polymer, is explored as a carrier for this compound to enhance its uptake and potentially reduce toxicity. nih.goveurekaselect.comeurekaselect.com A this compound-chitosan nano-conjugate was developed and investigated for its therapeutic effects on the MCF-7 breast cancer cell line. nih.goveurekaselect.comeurekaselect.com MTT assay results indicated that this nano-conjugate retained the anticancer effect of this compound while showing less abnormal toxicity. nih.goveurekaselect.comeurekaselect.com In vitro cellular uptake studies by flow cytometry demonstrated better uptake of the nano-conjugate into MCF-7 cells. nih.goveurekaselect.comeurekaselect.com Apoptosis induction was confirmed by RT-PCR. nih.goveurekaselect.com Chitosan has also been used as a polymeric shell for iron oxide nanoparticles (IONPs) to carry this compound (Chloramb-CS-IONPs), resulting in nanocomposites with an average size of 15 nm and a drug loading of 19%. nih.govresearchgate.net These nanocomposites showed controlled release of this compound, with approximately 89.9% released within about 5000 minutes at pH 7.4. nih.govresearchgate.net The Chloramb-CS-IONPs nanocomposite was found to be more efficient against leukemia cancer cell lines (WEHI) compared to free this compound and exhibited good biocompatibility in hematology analysis experiments. nih.govresearchgate.net

Chronic Lymphocytic Leukemia (CLL)

This compound has historically played a significant role in the management of CLL, especially in specific patient populations.

This compound was considered a standard of care for frontline treatment in CLL, particularly before the advent of more effective agents. Early trials utilizing this compound as a monotherapy or in combination aimed to control lymphocytosis and improve symptoms. Studies have shown that the efficacy of this compound as a single agent in CLL is low. haematologica.org Combination treatments incorporating this compound have shown improved outcomes compared to this compound monotherapy. haematologica.org

The treatment landscape for CLL has evolved significantly with the introduction of novel targeted therapies. Studies have compared this compound-based regimens with newer agents and combinations.

Data from comparative studies are summarized in the table below:

Despite the emergence of novel agents, this compound combined with an anti-CD20 antibody is still considered a legitimate frontline treatment option for unfit CLL patients with low-risk disease (non-del(11q) and IGHV-mutated). ashpublications.org

Comparison with Newer Agents and Regimens

Hodgkin Lymphoma

This compound has been used in the treatment of Hodgkin lymphoma (HL), although its role has largely been superseded by more intensive multi-agent chemotherapy regimens. Historically, this compound was used as a single agent in the palliative treatment of advanced disease. mims.com More modern approaches for HL involve combinations like ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). cancer.gov Novel agents and combinations, such as brentuximab vedotin and PD-1 inhibitors, are also now part of the treatment landscape for HL, including in relapsed/refractory settings. cancer.govascopubs.org

Non-Hodgkin Lymphoma

This compound has also been utilized in the treatment of certain types of non-Hodgkin lymphoma (NHL), particularly indolent B-cell lymphomas like follicular lymphoma. wikipedia.orgresearchgate.net It has been used as a single agent and in combination regimens. A study investigating interferon alfa-2b and this compound in pre-treated or relapsed NHL patients reported responses in both follicular and diffuse lymphoma subtypes. nih.gov In indolent B-cell lymphoma, the combination of this compound with rituximab has been investigated, showing feasibility and efficacy in newly diagnosed and relapsed/refractory patients. researchgate.net However, similar to CLL, the treatment of NHL has evolved with the use of more effective combination chemotherapies and targeted agents. theoncologynurse.comucsd.eduresearcherprofiles.org

Waldenström Macroglobulinemia

This compound has been an effective agent for the treatment of Waldenström Macroglobulinemia (WM). nih.govopenaccessjournals.com Studies have compared different administration schedules, such as continuous versus intermittent therapy. In a prospective study comparing continuous (0.1 mg/kg/d) and intermittent (0.3 mg/kg/d for 7 days every 6 weeks) oral this compound in untreated WM patients, objective improvement was observed in a significant proportion of patients. nih.gov Nineteen out of 24 patients (79%) on continuous therapy showed objective improvement, compared to 15 out of 22 patients (68%) on intermittent therapy. nih.gov Objective improvement was defined by criteria including a 50% or more reduction of serum M-protein or an increase in hemoglobin level of at least 2 g/dl without transfusion. nih.gov Reductions in organomegaly were also noted, with liver size decreasing by 2 cm or more in 55% of patients, spleen size decreasing by 2 cm or more in 67%, and lymphadenopathy decreasing in 71%. nih.gov The median duration of survival in this study was 5.4 years, with no significant difference between the continuous and intermittent regimens. nih.gov

Here is a summary of response rates from the WM1 study:

Responses to this compound in WM can be slow, and patients may require treatment for at least 6 months before therapy is considered ineffective. nih.govopenaccessjournals.com While this compound is considered effective for WM, newer agents like purine analogues or rituximab may be compared with it in prospective studies. nih.gov Single-agent this compound may still be a valid option for elderly, non-fit patients. openaccessjournals.com

Colorectal Cancer

Randomized Controlled Trials

Randomized controlled trials (RCTs) have been instrumental in comparing this compound to other treatment regimens in patients with CLL and other B-cell malignancies. These trials involve random allocation of participants to different treatment arms, minimizing bias and allowing for direct comparisons of outcomes.

More recent Phase 3 randomized trials have compared this compound, often in combination with anti-CD20 antibodies, to novel agents. The CLL11 trial, a multicenter, open-label, randomized phase 3 study, compared obinutuzumab plus this compound, rituximab plus this compound, and this compound alone in previously untreated CLL patients. fda.gov This trial was designed in two stages, initially randomizing patients to all three arms and subsequently randomizing between the obinutuzumab/chlorambucil and rituximab/chlorambucil arms. fda.gov The iLLUMINATE study, another randomized phase III trial, compared ibrutinib combined with obinutuzumab versus this compound combined with obinutuzumab as first-line therapy for patients with CLL/SLL. haematologica.org

RCTs have also investigated this compound in other conditions, such as scleroderma, in a 3-year, parallel, randomized, double-blind study comparing this compound to placebo. nih.gov

Here is a summary of selected randomized controlled trials involving this compound:

Systematic Reviews and Meta-Analyses

Systematic reviews and meta-analyses have synthesized findings from multiple clinical trials to provide a comprehensive overview of this compound's efficacy and its place in therapy. These studies pool data from various sources, increasing the statistical power to detect treatment effects and assess consistency across different trials.

Another systematic review focused on the recent evidence for the efficacy and safety of this compound in B-cell malignancies, including CLL, low-grade non-Hodgkin lymphoma, and Waldenström macroglobulinemia. nih.gov This review summarized results from prospective, randomized, controlled trials. nih.gov

Here is a summary of key findings from systematic reviews and meta-analyses:

Dose-Finding and Optimization Studies

Dose-finding and optimization studies are crucial in determining the appropriate dosage and schedule of a drug to maximize efficacy while minimizing toxicity. While this compound has been used for many years, the optimal dose and treatment duration have been subjects of investigation. nih.govnih.gov

Dose-finding studies have also been conducted for this compound in combination regimens. A phase I study investigated escalating doses of 2-chlorodeoxyadenosine combined with a fixed dose of oral this compound in patients with relapsed or refractory CLL or low-grade lymphoma to evaluate the toxicity of the combined regimen and determine the maximal-tolerated dose. nih.gov

Mathematical modeling and in silico simulations are also being explored as tools for dose finding and optimizing combined therapies involving this compound. researchgate.netmdpi.com

The concept of relative dose intensity (RDI) has been evaluated in real-world settings for this compound-containing regimens, such as obinutuzumab-chlorambucil, to understand the impact of dose modifications on outcomes outside of controlled clinical trials. ashpublications.orgericll.org

Here is a summary of findings related to this compound dose and optimization: