Effect Of CCNU Research Articles

Malignant glioma subset from Actuate 1801: A phase 1/2 study of 9-ING-41, a glycogen synthase kinase 3 beta (GSK-3β) inhibitor, as a single agent and combined with chemotherapy, in patients with refractory hematologic malignancies or solid tumors.

2051 Background: GSK-3β, a serine/threonine kinase, is a key regulator of metabolism and glycogen biosynthesis. GSK-3β aberrant overexpression promotes tumor progression and chemotherapy resistance through NF-κB and p53-mediated apoptotic pathways. GSK-3β inhibition impacts immunomodulation through downregulation of checkpoints, such as PD-L1 and LAG-3, and increasing NK and T-cell mediated killing of tumor cells. 9-ING-41 is a small-molecule potent selective GSK-3β inhibitor with preclinical antitumor activity against several tumor types. In chemoresistant PDX models of glioblastoma (GBM), 9-ING-41 enhanced the antitumor effect of CCNU and CPT-11. Methods: In the first-in-human study (NCT03678883), patients (pts) with refractory malignancies received 9-ING-41 monotherapy (n = 65) or in combination with one of 8 cytotoxic regimens after prior treatment with the same chemotherapy (n = 162). We report the subset of pts with recurrent gliomas treated with 9-ING-41 monotherapy IV twice a week in 21-day cycles at different dose levels (3.3, 5, 9.3, 15mg/kg), or in combination with lomustine 30 mg/m² orally once weekly in 84-day cycles. Primary objective was safety and tolerability. Results: An RP2D of 15mg/kg IV was confirmed across all 9 regimens, no accentuation of chemotherapy-related toxicity noted. Of 18 glioma patients enrolled, 13 were GBM, 2 anaplastic astrocytomas, 1 diffuse astrocytoma, and 1 anaplastic oligodendroglioma. Four patients received single agent 9-ING-41, 14 treated concurrently with lomustine. Demographics: 6 female, 12 male; median age 52 (30-69) years; median ECOG was 1 (0-2). All received first-line radiation and temozolomide (18/18), prior therapies for recurrences included nitrosoureas (15/18), bevacizumab (8/18), TTFields (6/18), immune checkpoint inhibitor (4/18). Median recurrences 3 (1-6). Genomic alterations from available NGS reports included: IDH WT (11), IDH mutation (3), MGMT promoter unmethylated (11), MGMT promoter methylated (1), 1p19q co-deletion (10), EGFR amplification (6), EGFR v3 mutation (3), TERT promoter mutation (6), PTEN loss (3), NF1 rearrangement (2), ATRX loss (2), TP53 mutated (4), CDKN2A deletion (2), RB1 loss (1), PALB-2 mutation (10). No SAEs or grade 3/4 AEs attributed to 9-ING-41 were noted; AEs included G1/2 transient vision changes (9/18, 50%), infusion reactions (4/18, 22%). Side effects from lomustine included: G3/4 thrombocytopenia (3/14, 21%), and G1/2 fatigue (4/14, 28%). Best overall response: 1 minimal response (-43%) after 2 cycles of 9-ING-41 and lomustine. Median days on therapy was 55 (4-305), 4/18 (22%) were stable for 20 weeks or longer. Conclusions: These results show 9-ING-41 alone or in combination is safe and warrants further study in glioma patients. Clinical trial information: NCT03678883.

Stress and chemotherapy. Combined effects on tumor progression and immunity in animal models.

In mice bearing Lewis lung carcinoma, rotational and restraint stress specifically increases the formation of lung metastasis, and restraint stress markedly attenuates the antitumor effects of cyclophosphamide. The aim of this investigation was therefore to examine the effects of restraint stress on tumor metastasis in mice bearing MCa mammary carcinoma, and on the effectiveness of CCNU and DTIC. Restraint stress increases MCa mammary carcinoma metastasis, causes a marked reduction in cyclophosphamide activity, and a minor attenuation of the effects of CCNU and DTIC. The possible occurrence of seasonal factors, observed for the increase by rotational stress of Lewis lung carcinoma metastasis, was also determined for cyclophosphamide effectiveness. The survival time of control mice is longer in February than in June, and is not appreciably modified by rotational stress. The effects of cyclophosphamide are similar in both seasonal periods, and are similarly attenuated by rotational stress. The seasonal effects of rotational stress, and the reduction of the effects of cyclophosphamide caused by rotational stress, are accompanied by corresponding variations in the number of CD3+ and CD4+ splenic T-lymphocyte subsets and in the CD4+/CD8+ ratio, respectively. The reported effects of stress on tumor progression and on the effectiveness of cyclophosphamide thus appear to occur via modulation of immune responses of the host directed against the tumor. These data appear of interest for their experimental implications, and suggest the opportunity to consider the role that the stress during treatment may play in determining the effectiveness of clinical antitumor chemotherapy.

Effects of CCNU on monocyte phagocytosis

The effect of CCNU on human monocyte phagocytosis of yeast cells was measured in vitro. ‘Therapeutic’ CCNU concentrations had no measurable effect on monocyte phagocytosis. Higher concentrations of CCNU had a slight but statistically significant effect on the engulfment phase of monocyte phagocytosis. The results suggest that CCNU treatment is of minor importance for monocyte function.

In vitro activity of alkylating agents on human tumors as measured by a short-term antimetabolic assay.

The activity of some alkylating agents widely used in clinical practice was studied by an in vitro antimetabolic assay, which evaluates the interference of drugs on the incorporation of 3H-thymidine and 3H-uridine in short-term cultures of human tumors. The effect of CCNU, chlorambucil, cisplatin, melphalan, prednimustine, procarbazine and the pro-active derivatives of cyclophosphamide and ifosfamide, 4-hydroperoxycyclophosphamide and 4-hydroperoxyifosfamide, was tested on non-Hodgkin lymphomas, germ cell testicular tumors, breast and ovarian cancers. Similar effects were generally produced by the drugs on both DNA and RNA precursor incorporation, and the in vitro response rates were similar to those clinically obtained for the same tumor types by using the same drugs in monochemotherapy. The effects of different alkylating agents on the individual tumors were not significantly associated, except for the analogues 4-hydroperoxycyclophosphamide and 4-hydroperoxyifosfamide, for which a significant agreement rate was observed. No evidence of acquired resistance to 4-hydroperoxycyclophosphamide and cisplatin after clinical treatment with the same drug was found in samples from ovarian cancer and non-Hodgkin lymphoma, but there was a definite trend in germ cell testicular tumors to lower sensitivity to cisplatin in previously treated patients.

Potentiation by amphotericin B of the cytotoxicity of anticancer agents against MOPC-315 plasmacytoma and Lewis lung carcinoma.

The ability of amphotericin B (AmB) to potentiate the cytotoxicity of several different anticancer agents against two murine tumor models was examined. A spleen colony assay was used to quantitate the cytotoxicity of BCNU, CCNU, and L-PAM, either alone or in combination with AmB against the MOPC-315 plasmacytoma. A high level of potentiation of the effects of CCNU and L-PAM by AmB occurred, but AmB did not increase the cytotoxicity of BCNU. Tumor growth curves and calculation of cell survival demonstrated significant potentiation of the cytotoxicity of CCNU by AmB against SC Lewis lung carcinoma.

Karyometric, cytophotometric, and histoenzymatic studies on neuroglia of young rats subjected to CCNU ( Lomustine) action

Studies on the effects of CCNU on neuroglia cells of the central nervous system in young individuals were conducted on 19 Wistar strain rats, each given 2 mg doses of 0.25 CCNU in 7th and 12th d of life. Karyometric and cytophotometric studies proved that CCNU administered to young rats induced changes in oligodendroglia and astroglia of the central nervous system. The changes included significant increase in nuclei contour and in the area of nuclei cross-section in oligodendro- and astroglia cells, elongation of oligodendroglia nuclei and an augmented DNA content in the 2 neuroglia types. The observed karyometric and cytophotometric changes were more evident in oligodendroglia nuclei than in astroglia nuclei.

Effect of CCNU on survival rate of objective remission and duration of free interval in patients with malignant brain glioma—Final evaluation

The effect of CCNU on three clinical parameters was measured in patients with malignant brain gliomas, operated and treated by radiation therapy ( 5500–6000 rad). From 111 selected patients included in the first trial (No. 26741) 81 were avialable for the final evaluation. Four questions were answered by this study: 1. (a) Free interval can be measured in a selected group of patients with malignant brain glioma. 2. (b) CCNU (mean dosage actually given was over 100 mg/m 2 once every 6 weeks) does not prolong the free interval. 3. (c) Objective remission was observed in 8 out of 27 patients where this parameter was evaluable. The duration of the remission ranged from 3 to over 14 months. 4. (d) The median survival of patients who received CCNU only after relapse was 22.5 weeks from the recurrence and 62 weeks from the operation; the figures for patients treated earlier with CCNU were 11 and 43 weeks. These differences are significant at respectively 2 and 7% levels. Only survival time was measured in the second trial (No. 26742), it was 31 weeks in patients treated with CCNU and 21.5 in the control group. Although only 19 patients were evaluated, the difference is significant at 1% level. Combined results of both trials suggest so far that: CCNU prolongs the total survival time, produces objective remission in about 30% of cases and that it should be administered only after relapse, at least in patients with free interval.

Effect of CCNU on survival, rate of objective remission and duration of free interval in patients with malignant brain glioma—First evaluation

The effect of CCNU on three clinical parameters was measured in patients with malignant brain gliomas, operated and treated by radiation therapy ( 5500–6000 rads). From 100 selected patients included in the first trial (No. 26741) 81 were evaluable. Four questions were answered by this study: 1. (a) Free interval can be measured in a selected group of patients with malignant brain glioma. 2. (b) CCNU (mean dosage actually given was 106 mg/m 2 once every 6 weeks) does not prolong the free interval. 3. (c) Objective remission was observed in 4 out of 16 patients where this parameter was evaluable. 4. (d) Total survival time was 77 weeks in patients treated with CCNU only after relapse and 50 weeks in those treated within 3 weeks after operation until death. This difference is significant at the 5% level. Only survival time was measured in the second trial (No. 26742), it was 33 weeks in patients treated by CCNU and 17 in the control group. Although only 17 patients were evaluated, the difference is significant at 5% level. Combined results of both trials suggest so far that: CCNU prolongs the total survival time, produces objective remission in about 25% of cases, and that it should be administered only after relapse, at least in patients with free interval.