Biological and biochemical properties of the 2-hydroxyl metabolites of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea.

The lethal and bone marrow toxicity and antitumor activity of the cis- and trans-2-hydroxylated metabolites of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) have been correlated with their relative in vitro alkylating and carbamoylating activities. Both the isomers have considerably greater alkylating activity and shorter chemical half-lives than the parent compound and on a molar basis have greater antitumor activity against i.p. L1210 leukemia. However, in terms of molar doses resulting in the death of 10% of normal mice, the cis- and trans-2 isomers were 2- and 3-fold more toxic than was CCNU in normal mice. In comparing the antitumor activity produced by a maximum nonlethal dose for each compound, we found that the trans isomer had activity identical to that of CCNU (413 and 410% increased life span compared to control), and the cis isomer had considerably less (152%). Like chlorozotocin, both isomers possess low carbamoylating activity and increased water solubility, two features that have been considered possible contributors to the bone marrow-sparing character of chlorozotocin. However, in the murine model the human bone marrow colony formation (CFU-C) assay neither hydroxylated metabolite of CCNU was associated with reduced myelotoxicity.     

E7449: A dual inhibitor of PARP1/2 and tankyrase1/2 inhibits growth of DNA repair deficient tumors and antagonizes Wnt signaling

Inhibition of Poly(ADP-ribose) Polymerase1 (PARP1) impairs DNA damage repair, and early generation PARP1/2 inhibitors (olaparib, niraparib, etc.) have demonstrated clinical proof of concept for cancer treatment. Here, we describe the development of the novel PARP inhibitor E7449, a potent PARP1/2 inhibitor that also inhibits PARP5a/5b, otherwise known as tankyrase1 and 2 (TNKS1 and 2), important regulators of canonical Wnt/β-catenin signaling. E7449 inhibits PARP enzymatic activity and additionally traps PARP1 onto damaged DNA; a mechanism previously shown to augment cytotoxicity. Cells deficient in DNA repair pathways beyond homologous recombination were sensitive to E7449 treatment. Chemotherapy was potentiated by E7449 and single agent had significant antitumor activity in BRCA-deficient xenografts. Additionally, E7449 inhibited Wnt/β-catenin signaling in colon cancer cell lines, likely through TNKS inhibition. Consistent with this possibility, E7449 stabilized axin and TNKS proteins resulting in β-catenin de-stabilization and significantly altered expression of Wnt target genes. Notably, hair growth mediated by Wnt signaling was inhibited by E7449. A pharmacodynamic effect of E7449 on Wnt target genes was observed in tumors, although E7449 lacked single agent antitumor activity in vivo, a finding typical for selective TNKS inhibitors. E7449 antitumor activity was increased through combination with MEK inhibition. Particularly noteworthy was the lack of toxicity, most significantly the lack of intestinal toxicity reported for other TNKS inhibitors. E7449 represents a novel dual PARP1/2 and TNKS1/2 inhibitor which has the advantage of targeting Wnt/β-catenin signaling addicted tumors. E7449 is currently in early clinical development.     

Antitumor activity of delta 7-prostaglandin A1 and delta 12-prostaglandin J2 in vitro and in vivo

Cyclopentenone prostaglandins (PGs) such as prostaglandin A1 (PGA1) and prostaglandin J2 (PGJ2) significantly increased the life span of Ehrlich ascites tumor-bearing mice. In order to obtain PG derivatives which have more potent antitumor activity than PGA1 and PGJ2, we synthesized a number of alkylidenecyclopentenone PGs and studied the antitumor activity of these compounds in vitro and in vivo. delta 7-PGA1, 12-epi-delta 7-PGA1, and delta 12,14-PGJ2 showed 50% inhibitory concentrations of 0.3 microgram/ml against the growth of L1210 culture cells. These compounds are several times more cytotoxic than parent compounds. From a structure-activity relationship analysis, we concluded that, as for PGA derivatives: (a) a double bond in C7-8 potentiates the cytotoxicity; (b) a 15-hydroxy group is not essential for cytotoxicity; (c) the stereochemistry of R2 chain is not essential, while 12-epi derivatives also have full activity; (d) a double bond in C12-13 seems to be essential for full activity, and for PGJ derivatives a double bond in C12-13 and C14-15 potentiates the cytotoxicity. These compounds showed marked antitumor activity against Ehrlich ascites tumor in vivo. At doses of 20-30 mg/kg/day three or five consecutive i.p. treatments with these compounds resulted in a 66 to 111% increase in life span with long-term survivors. A single i.p. injection with 12-epi-delta 7-PGA1 (100 mg/kg) resulted in 73% increase in life span with 33% of long-term survivors, indicating an activity comparable to that of cyclophosphamide (200 mg/kg). However, delta 7-PGA1 and 12-epi-delta 7-PGA1 were marginally effective against P388 leukemia. Treatment with delta 7-PGA1 (10 mg/kg/day i.p.) and 12-epi-delta 7-PGA1 (20 mg/kg/day i.p.) on Days 1-9 resulted in 25.8 and 29.6% increases in life span, respectively. delta 7-PGA1 and delta 12-PGJ2 derivatives may be a potential new class of antitumor agents.     

Antitumor activity of two derivatives from 2-acylamine-1, 4-naphthoquinone in mice bearing S180 tumor

Drugs containing a quinone moiety, such as anthracyclines, mitoxantrones and lapachol, show excellent anticancer activity. In this study, 2-butanoylamine-1,4-naphthoquinone (1) and 2-propanoylamine-1,4-naphthoquinone (2) derivatives from 2-amine-1 ,4-naphthoquinone were synthesized, and their antitumor activity in mice bearing Sarcoma 180 tumor were examined. In addition, hematology and biochemistry analyses, as well as, histopathological and morphological analyses were performed in order to evaluate the toxicological aspects of the naphthoquinones treatment. Both naphthoquinones showed potente antitumor activity. The inhibition rates were 33.48 and 42.35% for (1) and 37.65 and 55.24% for (2) at the dose of 25 and 50 mg/kg/day, respectively. In the histopathological analysis, the naphthoquinones showed only weak toxicity. Neither enzimatic activity of transaminases (aspartate aminotransferase-AST nor alanine aminotransferase-ALT), urea level nor hematological paramenter were significantly modified after naphthoquinones treatment. These data reinforce the anticancer potential of naphthoquinones derivatives.     

Enhanced Antitumor Activity and Reduced Toxicity of 1,3-Bis(2-chloroethyl)-1-nitrosourea Administered in Lipid Microspheres to Tumor-bearing Mice

Stable lipid microspheres (LM) and lipid nanospheres (LN) with average diameters of 200 nm and 50 nm, respectively, were used to encapsulate an lipophilic antitumor agent, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). LM and LN containing BCNU (lipo BCNU and s-lipo BCNU, respectively) were prepared by homogenizing a soybean oil solution of BCNU with egg yolk lecithin, and their antitumor activity via the intravenous route was tested against L1210 leukemia in mice and compared with that of BCNU dissolved in saline. Both lipo-BCNU and s-lipo BCNU showed significantly enhanced antitumor activity with reduced toxicity, when compared with the corresponding doses of BCNU alone. These results suggest that LM and LN may be suitable carriers for lipophilic antitumor agents and may enhance their efficacy.     

Antitumor activity and toxicity of ACNU, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride,comparing two divided doses and a single dose

Summary In order to determine whether it is possible to reduce the toxicity of the nitrosoureas, including the delayed type of hematologic toxicity, without diminishing antitumor activity by administering the drug according to a new treatment schedule other than the single high-dose treatment schedule, we examined the antitumor activity against murine tumors and toxicities to host mice of a nitrosourea derivative, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU), which was administered according to two divided doses schedule. Experimental results indicated that the toxicity of ACNU with respect to lethality, as well as weight loss of host mice, was alleviated by administering ACNU (IV) at one-half of LD₁₀ (20 mg/kg) on 2 successive days. However, no impairment of the antitumor activity of ACNU in various murine tumor systems was observed in comparison with that of ACNU administered according to the single high-dose schedule. The delayed type of hematologic toxicity (leukopenia) could not be alleviated by this treatment schedule.     

Determinants in chemosensitivity of oncogene-transformed NIH3T3 cells to 2'-C-cyano-2'-deoxy-1-beta-D-arabinofuranosylcytosine

2'-C-Cyano-2'-deoxy-1-beta-D-arabinofuranosylcytosine (CNDAC) is a novel 2'-deoxycytidine (dCyd) analogue with potent antitumor activity. To elucidate the determinants of chemosensitivity to CNDAC, the intracellular accumulation of CNDAC and the activities of dCyd kinase and cytidine deaminase were investigated in transformed NIH 3T3 cells with different genetic bases. The results indicate that the primary determinants of chemosensitivity to CNDAC are different in each cell type, but membrane transportation and the enzyme activities of dCyd kinase and cytidine deaminase are critical factors underlying the antitumor action of CNDAC. Moreover, the expression or function of these factors appears to be influenced by the activation of various oncogenes.     

Antitumor activity of a new platinum complex, 2-aminomethyl-pyrrolidine (1, 1-cyclobutanedicarboxylato) platinum (II)

One hundred cis-diamminedichloroplatinum (II) (CDDP) analogs have been evaluated for antitumor activity in male CDF1 mice subcutaneously (s.c.) implanted with tumor fragments of Colon 26 carcinoma. Among the complexes tested, 2-aminomethyl-pyrrolidine (1, 1-cyclobutanedicarboxylato) platinum (II) (DWA 2114) had the best antitumor effect. The mice intraperitoneally (i.p.) injected with DWA 2114 at a dose of 40 mg/kg/day on days 4, 6 and 8 after inoculation showed a 97% growth inhibitory ratio (GIR) on day 14 compared to the non-treated control mice. We evaluated the inhibitory effects of DWA 2114 on other tumors, such as Colon 38 carcinoma, Ca 755 mammary adenocarcinoma and L1210 leukemia, and found that it also had antitumor effects on various kinds of tumors. The nephrotoxicity-inducing activity of DWA 2114 and CDDP was evaluated in normal BDF1 mice, as indicated by changes in blood urea nitrogen (BUN) at almost the maximum tolerated dose (MTD) (DWA 2114: 100 mg/kg, CDDP: 12 mg/kg). DWA 2114 had no effect on BUN levels, while CDDP elevated BUN levels. These results indicate that DWA 2114 represents a second generation platinum antitumor complex.     

Effect of various substitutions in positions 1, 2, 3, and 4 of 4-demethoxydaunorubicin and 4-demethoxyadriamycin

Summary Previous studies on structure-activity relationships of anthracycline antitumor antibiotics have shown that removal of the methoxyl group at position 4 of the aglycone causes a marked increase in the potency of the compounds: 4-demethoxydaunorubicin and 4-demethoxyadriamycin had an antitumor effect similar to that of the parent compound at doses five to eight times lower, and they were active even when administered orally. This paper reports the effects of further substitutions at positions 1, 2, 3, and 4 of 4-demethoxy aglycone. The introduction of methyl groups at positions 2 and 3, or 1 and 4 resulted in decreased cytotoxicity and biological activity. The addition of a benzoyl ring at positions 2 and 3 decreased the activity further. 1,4-Dichloro-4-demethoxydaunorubicin and 2,3-dichloro-4-demethoxydaunorubicin were respectively as active and 2.5 times less active than was daunorubicin against HeLa cells in vitro while they were inactive against P388 and L1210 leukemias in vivo. 2,3-Dimethyl-4-demethoxyadriamycin showed an antitumor activity against mouse leukemias that was slightly higher than was that of adriamycin.     

Synergistic antitumor effects of interleukin 2 and the monoclonal Lym-1 against human Burkitt lymphoma cells in vitro and in vivo

Interleukin 2 (IL-2) regulates immune responses by inducing proliferation and differentiation of T-cells into cytotoxic cells, inducing lymphokine activated killer activity and enhancing antibody dependent cellular cytotoxicity (ADCC). Lym-1, a monoclonal antibody, recognizes a membrane antigen present on the surface of B-lymphoma cells and can be used for ADCC. We therefore used Raji (human Burkitt lymphoma) cells to study the efficacy of combination therapy with IL-2, lymphokine activated killer activity, and Lym-1. In vitro ADCC assays using Lym-1 showed that preincubation of peripheral blood lymphocytes with IL-2 had a synergistic antitumor effect. The maximum synergism was achieved when peripheral blood lymphocytes were incubated with IL-2 for 3 days as compared to 1 or 2 days, with the optimal concentration of IL-2 being 1000 units/ml. This effect was specific for Lym-1 as demonstrated by experiments using an irrelevant (antimelanoma) monoclonal antibody or an irrelevant target cell (A375). The ADCC was blocked by an anti-Fe receptor antibody (3G8). In vivo experiments performed by growing Raji tumors in nude mice also demonstrated the increase in ADCC and the synergism between IL-2 and Lym-1 in terms of decreased tumor size and growth. The mechanism of this synergy is probably from activation of cells mediating ADCC. This raises the possibility that treatment of patients with low doses of IL-2 in combination with Lym-1 may enhance immune responses and thereby antitumor activity.     

Antitumor activity of L/1C2-4-desacetylvinblastine-3-carboxhydrazide immunoconjugate in xenografts

The murine IgG3 monoclonal antibody L/1C2 is reactive with a high percentage of human carcinomas and has preferentially strong reactivity with tumors of squamous differentiation. This antibody was tested for antitumor activity in vitro and in xenograft models as a carbohydrate-linked immunoconjugate with the Vinca derivative 4-desacetylvinblastine-3-carboxhydrazide (DAVLBHYD). The conjugate retained good immunoreactivity and was highly active in a cytotoxicity assay. In human tumor nude mouse xenograft studies, L/1C2-DAVLBHYD antitumor activity was superior to that seen with free drug, free antibody, mixtures of free drug and free antibody, or control DAVLBHYD conjugates prepared with non-tumor-binding IgGs. With well-established tumors, potent antitumor activity was observed, including the ability to specifically regress greater than 400-mg tumors to 0 mg. In some cases, apparent long-term cures were effected. In studies using six different human tumor xenografts, the level of potency of L/1C2-DAVLBHYD was related to L/1C2 antigen expression, although the growth rate probably also contributes to the conjugate sensitivity of the tumors.     

Increased antitumor activity in combined treatment TS-1 and docetaxel. A preclinical study using gastric cancer xenografts

As TS-1 and docetaxel (TXT) have different mechanisms of antitumor activity, the combination therapy is expected to have a higher response. Human gastric cancer xenografts SC-2, St-40, and SC-4 inoculated into nude rats were treated with TS-1 alone (TS-1 12 mg/kg/day, day 1-14), TXT alone (TXT 2 mg/kg/day, day 1 or day 8), and combination of both drugs. TS-1 alone showed antitumor activity against three tumors (growth inhibition rate (IR): SC-2 (38.6 and 40.5%), St-40 (54.5%), SC-4 (55.1%)). TXT was effective with minimal toxicity, especially on day 1 of administration (IR at day 1 administration: SC-2 (51.7%), St-40 (42.1%), SC-4 (46.3%)). In the combined TS-1 and TXT group, antitumor activity increased at day 1 and at day 8 TXT administration (IR at day 1 administration: SC-2 (68.4%), St-40 (72.5%), SC-4 (76.0%)). Weight loss of TS-1 and day 1 TXT administration was the same as that of TS-1 alone. TS-1 and TXT showed no pharmacokinetic interaction. Compared with 5-fluorouracil and cisplatin treatment, combined therapy with TS-1 and TXT showed the same antitumor activity and toxicity. Combined therapy with TS-1 and TXT showed enhanced antitumor activity compared with monotherapy of each drug. The outpatient-based treatment of this combination is worth investigating.     

In vitro and in vivo pharmacological characterizations of the antitumor properties of two new olivacine derivatives, S16020-2 and S30972-1.

S16020-2, a new olivacine derivative and a topoisomerase II inhibitor, has recently entered clinical trials. New analogues and derivatives have been synthesized from the S16020-2 compound. Preliminary data indicate that S30972-1, one of these S16020-2 derivatives, may exhibit a comparatively higher level of antitumor potency associated with an improved therapeutic index than does S16020-2. The antitumor activities of S16020-2 and S30972-1 were therefore characterized both in vitro and in vivo, with Adriamycin and etoposide chosen as reference compounds. The in vitro data show that S30972-1 is a topoisomerase II inhibitor, mediating its activity through an ATP-dependent mechanism such as S16020-2. The two olivacine derivatives exhibited similar activities in vitro at the levels of the global growth of six human cancer cell lines, of the induction of apoptosis, and of the G2 cell cycle phase arrest. The in vivo antitumor activity characterization included the use of two murine leukemia types (P388-LEU and L1210-LEU), two murine lymphoma-like models (P388-LYM and L1210-LYM), two mammary adenocarcinomas (MXT-HI and MXT-HS), and one melanoma (B16). The data show that S30972-1 is actually more efficient in vivo than S16020-2, a feature that may relate to the fact that S30972-1 is less toxic than S16020-2. The S30972-1 compound exhibited in vivo a level of antitumor activity that was also actually higher than that exhibited by Adriamycin and similar to that exhibited by etoposide.     

BOF-A1 and BOF-A2, new 5-FU degradation-inhibitory agents

2, 6-Dihydroxy-3-cyano pyridine (CNDP) was found from the study of inhibitory effects of pyrimidine and pyridine derivatives on 5-FU degradation catalyzed by dihydrouracil dehydrogenase. CNDP, a new inhibitor on 5-FU degradation was 300 times more effective than uracil. Co-administration of an equi-molar CNDP with some fluorinated pyrimidine preparations potentiated their antitumor activity. Tegafur (FT-207) and EM-FU in combination with CNDP were found most effective. This potentiation was exhibited not only to 5-FU derivatives but also to FdUrd and its derivatives. BOF-A1 and BOF-A2, new compounds combined with CNDP were markedly active against mouse sarcoma 180 and rat Yoshida sarcoma.     

Trastuzumab in combination with PEGylated interferon-α1b exerts synergistic antitumor activity through enhanced inhibition of HER2 downstream signaling and antibody-dependent cellular cytotoxicity

The anti-HER2 monoclonal antibody trastuzumab is the mainstay of treatment for HER2-positive breast and gastric cancer, and its combination with multiple chemotherapeutic agents has represented an effective and rational strategy in the clinic. In this study, we report that trastuzumab in combination with PEGylated interferon-α1b (IFN-α1b), a polyethylene glycol (PEG)-conjugated form of a subtype of interferon alpha (IFN-α), synergistically inhibited the proliferation of HER2-positive cells, including BT-474 and SK-BR-3 breast cancer cells and NCI-N87 gastric cancer cells, and also induced their apoptosis, but had no effect on HER2-negative MDA-MB-231 breast cancer cells. Trastuzumab inhibited phosphorylation of HER2, AKT and ERK, an effect that was enhanced by PEGylated IFN-α1b, likely owing to PEGylated IFN-α1b-mediated downregulation of HER2 through the lysosomal degradation pathway. Moreover, PEGylated IFN-α1b significantly enhanced trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) in HER2-positive cells. Importantly, trastuzumab combined with PEGylated IFN-α1b exhibited significant synergistic antitumor activity in HER2-positive BT-474 xenografts, an effect that was associated with enhanced inhibition of HER2 expression and AKT and ERK phosphorylation. Strikingly, depletion of natural killer cells with anti-Asialo GM1 antibody abrogated the synergistic antitumor activity, indicating that augmented ADCC is essential for this synergy. Taken together, our findings indicate that both enhanced inhibition of HER2 downstream signaling and augmented ADCC contribute to the synergistic antitumor activity of trastuzumab with PEGylated IFN-α1b, and imply that combining trastuzumab with PEGylated IFN-α1b could be a promising strategy for HER2-positive cancers.     

Prostaglandin E2 regulation of tumoristatic factor production by macrophage-like P388D1 cells

Macrophage-like P388D1 cells, when stimulated with lipopolysaccharide (LPS), produced a factor(s) whose activity was inhibitory to growth of Lewis lung carcinoma cells. Indomethacin, a prostaglandin-synthesis inhibitor, augmented the production of tumoristatic activity by LPS-stimulated P388D1 cells, whereas exogenous prostaglandin E2 (PGE2) suppressed its secretion. These results suggest that P388D1 cells regulate their antitumor abilities by producing PGE2, which inhibits production of soluble factor(s) with tumoristatic activities.     

Enhancement of the anticancer activity of bis(2-chloroethyl)nitrosourea in mice by coadministration of 2'-deoxyuridine, 2'-deoxycytidine, or thymidine

The previous observation that the coadministration of a single dose of thymidine with the 3'-chloroethylnitrosourea analog of thymidine (3'-[3-(2-chloroethyl-3-nitrosoureido]-3'-deoxythymidine, 3'-CTNU) to mice bearing the L1210 or P388 leukemia enhanced the antitumor activity of 3'-CTNU, has led to a similar study of the potential effect on antitumor activity where thymidine, 2'-deoxyuridine, or 2'-deoxycytidine is coadministered with 1,3-bis(2-chloroethyl)-1-nitrosourea. Three levels of 1,3-bis(2-chloroethyl)-1-nitrosourea (10, 15, and 20 mg/kg) were coadministered to mice bearing the L1210 leukemia or the B16/F10 melanoma with each of the deoxyribonucleosides (2 g/kg). There was not only an increase in average days of survival of those that perished, but also a marked increase in the number of greater than 60-day survivors. The present report is a result of a determination of whether the augmented anticancer activity produced by a single injection of thymidine with 3'-CTNU was restricted to nitrosourea analogs of thymidine. The present study reveals not only that the phenomena of enhanced anticancer activity by the coadministration of thymidine can be extended to non-thymidine-containing nitrosoureas, but also that the coadministration of thymidine with 1,3-bis(2-chloroethyl)-1-nitrosourea produced an even more marked enhancement of antitumor activity than that previously observed when thymidine was coadministered with 3'-CTNU.     

Importance of Lyt 1+ T-cells in the antitumor activity of an immunomodulator, SSM, extracted from human-type Tubercle bacilli

An arabinomannan lipid extracted from Mycobacterium tuberculosis strain Aoyama B (SSM) is an immunopotentiating agent with interferon-inducing and antitumor activities. In the present study, the possible role(s) of various immunocompetent cells on the antitumor effect of SSM was investigated in mice bearing syngeneic (RL male 1 leukemia) and allogeneic (Ehrlich carcinoma) ascites tumors. When Thy 1+ T-cells were depleted from tumor-bearing mice by the administration of monoclonal anti-Thy 1.2 antibody, the protective effect of SSM was eliminated. However, when macrophage (M phi) and natural killer (NK) cell activities were depleted by treatment with M phi blockers (trypan blue and carrageenan) or a blocker for NK cells (anti-asialo GM1 antiserum), no alteration of the antitumor activity of SSM was observed. Therefore, T-lymphocytes, but not M phi or NK cells, were required for the expression of the antitumor efficacy of SSM. The antitumor activity of SSM was also abrogated by Lyt 1+ T-cells being depleted by treatment with monoclonal anti-Lyt 1.2 antibody, whereas the administration of monoclonal anti-Lyt 2.2 antibody had no effect on the antitumor activity. Independent of M phi, NK cells, or Lyt 2+ T-cells, Lyt 1+ T-lymphocytes appear to play an important role in the expression of the antitumor effects of SSM.     

YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo

Angiogenesis is an important process in cell development, especially in cancer. Vascular endothelial growth factor (VEGF) signaling is an important regulator of angiogenesis. Several therapies that act against VEGF signal transduction have been developed, including YN968D1, which is a potent inhibitor of the VEGF signaling pathway. This study investigated the antitumor activity of YN968D1 (apatinib mesylate) in vitro and in vivo. YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ. YN968D1 effectively inhibited proliferation, migration and tube formation of human umbilical vein endothelial cells induced by FBS, and blocked the budding of rat aortic ring. In vivo, YN968D1 alone and in combination with chemotherapeutic agents effectively inhibited the growth of several established human tumor xenograft models with little toxicity. A phase I study of YN968D1 has shown encouraging antitumor activity and a manageable toxicity profile. These findings suggest that YN968D1 has promise as an antitumor drug and might have clinical benefits.