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5HTP - serotonin
- Repression or downregulation of programmed death-ligand 1 (PD-L1)
- Can release its inhibition of T cells
- Activate antitumor immune responses
- PD-1 and PD-L1 antibodies
- Are promising treatments for diverse tumor types
Cell-based screen of 200 metabolic molecules flow cytometry assay of PD-L1 surface expression was conducted
- L-5-hydroxytryptophan (L-5-HTP) was found to suppress PD-L1 expression induced by interferon gamma (IFN-gamma)
2 syngeneic mouse tumor models
- L-5-HTP suppressed IFN-gamma-induced PD-L1 expression in tumor cells transcriptionally
- Effect was directly due to itself
- L-5-HTP inhibited IFN-gamma-induced expression of RTK ligands
- Thus suppressed phosphorylation-mediated activation of RTK receptors
- The downstream MEK/ERK/c-JUN signaling cascade
- Leading to decreased PD-L1 induction
- Mouse tumor models, treatment with 100 mg/kg L-5-HTP (intraperitoneal)
- Inhibited PD-L1 expression and exhibited antitumor effect
- L-5-HTP upregulated the ratio of granzyme B+ CD8+ activated cytotoxic T cells
- Intact immune system and PD-L1 expression
- Was critical for L-5-HTP to exert its antitumor effects
- L-5-HTP acted synergistically with PD-1 antibody to improve anticancer effect.
Poznámka:
- serotonin mohou produkovat v GIT různé bakterie
- serotonin vznika z tryptofanu (co tryptofan a tumor ? )
- Inhibitory zpětného vychytávání serotoninu (SSRI antidepresiva) mohou zvyšovat hladiny serotoninu
- serotonin může ale i podporovat množení některých nádorových buněk - dohledat další pokusy a různé formy zvýšení hladin na tento typ nádoru
Arsenic trioxide (ATO)
- Chemotherapy drug that has been used to treat a variety of cancers, including small-cell lung cancer (SCLC). ATO is a metalloid that works by damaging the DNA of cancer cells, which can lead to the death of the cells.
Several studies effectiveness of ATO in treating SCLC
- Some of these studies have shown that ATO can improve survival rates for patients with SCLC.
- For example, one study found that patients with SCLC who were treated with ATO had a median survival time of 18 months
- Compared to 12 months for patients who were not treated with ATO.
- Safety of ATO
- ATO is a relatively safe drug overall, but it can cause some side effects, such as nausea, vomiting, diarrhea, and bone marrow suppression. ATO can also cause more serious side effects, such as peripheral neuropathy, which is damage to the nerves that can cause numbness, tingling, and pain in the hands and feet.
- Overall, ATO can be a beneficial treatment for SCLC, but it is important to be aware of the potential side effects. Patients should talk to their doctor about the risks and benefits of ATO before starting treatment.
- Here are some additional things to keep in mind about ATO and SCLC:
- ATO is typically used in combination with other chemotherapy drugs to treat SCLC.
- ATO is not a cure for SCLC, but it can help to control the cancer and improve survival rates.
- ATO is a relatively new drug, so more research is needed to fully understand its long-term effects.
Cyclophosphamide + epirubicin to the standard treatment with EP
- Led to higher response rates
- Modestly prolonged survival
- Cost of increased toxicity
- Insufficient data to justify the addition of a third or even fourth drug to the platinum–etoposide backbone for ES-SCLC.
- erj.ersjournals.com/content/35/1/202
Cyclosporin A (CsA) or verapamil (VER)
- Synergistically enhanced the antitumor effects of ADM and VCR on SBC-3/ADM cells.
- MS-209 restored ADM incorporation and this effect was enhanced by CsA and VER,
- Suggesting that these synergistic effects were due to competitive inhibition of P-gp function.
- Conclusion: MS-209 in combination with CsA or VER might increase the efficacy of these chemotherapeutic agents against MDR human SCLC cells.
- link.springer.com/article/10.1007/s002800050849
Dynamin
- Involved in EGFR- and PD-L1 endocytosis
- A reversible small molecular weight inhibitor of dynamin, dyngo4A, shows its efficacy if added to anti-EGFR mAb.
- The drug combination increases EGFR expression on the cell surface and, at the same time, ADCC is both responsive and refractory in EGFR SCC lines. Dyngo4a also increases the expression of p-Akt, which is involved in mTOR phosphorylation of PRAS40, a powerful inhibitor of mTORC1 complex.
- This inhibition translates into a blockage of cell transcription
- Despite promising results in preclinical studies, the agent has not yet been tested in clinical trials.
- www.ncbi.nlm.nih.gov/pmc/articles/PMC7352732/
Endostatin
- Mr 20,000 COOH-terminal fragment of collagen XVIII, is the first such molecule undergoing Phase I clinical trials (15, 16). Recently, studies have shown that the NC1 domain of type IV collagen, which plays a crucial role in influencing basement membrane organization (17, 18, 19), has antiangiogenic and tumor growth delay properties in animal models
- aacrjournals.org/cancerres/article/62/3/789/509611/Antineoplastic-Effects-of-Chemotherapeutic-Agents
Equipoise
- I have a lot of equipoise
- United States, there’s almost a religion in re-treating with platinum if they’ve hit at least 6 months
- But the survival isn’t improved by doing that.
- Response rate is PFS [progression-free survival], not OS [overall survival].
- I don’t think that’s mandatory, but I do it in my practice.
- If you use the 6-month cutoff and we’re in an era of triplet, it’s only 22% of patients.
- I pulled that off
- It’s not controversial for most.
- In my practice, lurbinectedin
- Is used more than topotecan.
- I hate lurbinectedin less than I hate topotecan for toxicity profile.
- It’s a little more patient-friendly.
- In the forbidden but omnipresent cross-trial comparisons
- I find the data perhaps superior. I have equipoise.
- I’m in the minority of small cell doctors in not being a particular lover of temozolomide.
- I found it to be a bit of a stem cell toxic substance
- Hard to give anything else after it
- Penetration of the blood-brain barrier is a clear advantage
Jared Weiss, MD
Imunoterapie u SCLC
- Morrison enrolled 11 patients with SCLC who received immunotherapy
- All patients who responded to immunotherapy, the number of PD-L1 positive CTCs decreased or remained unchanged
- Number of PD-L1 positive CTCs in all patients with disease progression increased
- Expression of PD-L1 could be detected on all CTCs
- Dynamic increase in the number of PD-L1 positive CTCs
- Can be an effective marker for predicting the resistance of SCLC patients to immunotherapy
- After 6 months of immunotherapy
- All patients with H-FBS expression in the peripheral blood had disease progression
- Those with no H-FBS expression were affected by immunotherapy
- Neagu first detected the expression of PD-L1 on the peripheral blood CTC of patients with metastatic breast cancer
- Confirmed the expression of PD-L1 protein on the CTC cell membrane - H-FBS detection
- Burgos-Ojeda D showed that radiotherapy
- Can induce an increase in the expression of H-FBS
- no association between H-FBS and prognosis was found
- Ali also observed an increase in H-FBS expression in patients receiving radiotherapy or concurrent chemo radiation
- Patients with positive baseline H-FBS had a poor prognosis
- Expression of H-FBS before and after chemotherapy
- Detection rate has increased
- H-FBS is considered to be an independent predictor of poor prognosis of chemotherapy
- Stage Ia lung adenocarcinoma, Boldrini selected 4 acinar lung adenocarcinomas with good prognosis and 4 solid lung adenocarcinomas with poor prognosis
- C5orf34 as an up-regulation difference of the genes
- Dynamic change of H-FBS expression
- Can be an effective marker for evaluating treatment response during immunotherapy
- Hesperetin-fiber bronchoscope
- Artificial intelligence fiber bronchoscope combined with hesperetin derivatives, and then the slice observation results were verified by CTC technology
- C5orf34 in the tissue is detected separately
- aimspress.com/article/doi/10.3934/mbe.2021423?viewType=HTML
Irinotecan + carboplatin
- A camptothecin
- Topoisomerase I inhibitor
Cisplatin plus irinotecan - 2002, a Japanese phase III trial
- Significantly more effective than EP
- Trial was prematurely stopped because, at an interim analysis
- 154 patients treated with irinotecan plus cisplatin showed a significantly higher
- Response rate (84 versus 68%)
- Longer median survival (12.8 versus 9.4 months) and
- Higher 2-yr survival rate (19 versus 5%)
- Than those with the etoposide-based regimen
- Although haematological toxicity
- Was less pronounced with irinotecan
- Significantly more grade 3 or 4 diarrhoea was reported in this group
Results could not be confirmed in a large phase III trial in USA, Australia and Canada
- Study included 322 patients
- Could not safely administer the same doses as in Japan
- Thus used a different regimen for the administration of both EP and cisplatin/irinotecan
- But with a similar if not higher dose intensity
Southwest Oncology Group (SWOG) trial S0124
- Randomly assigned 671 patients with ES-SCLC to regimens identical to those used in the Japanese trial
- Results of this trial were published recently
- No significant differences were found
4th study from Norway addressing this issue in 2008
- Moderate benefit of a treatment with carboplatin and irinotecan
- Over carboplatin with oral etoposide
- Conflicting results have been obtained with the combination of platinum and irinotecan
- Probably due to pharmacogenomic differences between study populations
- Differences in the studied treatment regimens
SWOG S0124 trial of cisplatin/irinotecan toxicity
- TT genotype of the 3435C>T ABCB1 (ATP-binding cassette, subfamily B (MDR/TAP), member 1 gene) polymorphism
- Associated with cisplatin/irinotecan-related diarrhoea
- AA genotype of the -3156G>A UGT1A1 polymorphism (drug metabolism)
- Was associated with cisplatin/irinotecan-related neutropenia
- Half of the variation in toxicity and drug exposure remains unexplained by the UGT1A1 genotype.
- Other polymorphisms and single nucleotide polymorphisms also influence the disposition
- erj.ersjournals.com/content/35/1/202
Irinotenkan
Toxicity of irinotecan
- Genetic differences metabolic enzyme uridine-diphosphate glucuronosyltransferase (UGT) 1A1
- Might influence the degree of expected drug toxicity
- erj.ersjournals.com/content/35/1/202
Pemetrexed
- folic acid metabolism antagonist
- Place in the first-line treatment of malignant mesothelioma
- Possibly also of nonsquamous NSCLC
Phase I and II trials
- Antitumoural activity
- Toxicity comparable to standard treatment regimens with EP or cisplatin/irinotecan
- Interim analysis of a phase III trial revealed inferiority of carboplatin/pemetrexed compared to carboplatin/etoposide
- Led to the interruption of that trial
- erj.ersjournals.com/content/35/1/202
Poznámka:
- Nepodávat kyselinu listovou v žádném doplňku
Sorafenib
- Multikinase inhibitor
- Affecting pathways involved in tumour progression and angiogenesis
- Some promising activity in ES-SCLC
- Antiangiogenic agent cediranib (an inhibitor of the VEGFR-1, -2 and -3 tyrosine kinases) does not appear to be beneficial when added to standard chemotherapy
- erj.ersjournals.com/content/35/1/202
Topotecan
- Camptothecin family
Several phase II and III trials as first-line therapy for ES-SCLC x standard treatment of EP
- Noninferiority of cisplatin/topotecan compared to EP
- Overall survival
- Eckardt et al. 23 demonstrated that both regimens were similarly tolerable.
- Grade 3/4 neutropenia occurred more frequently with EP (84 versus 59%)
- Grade 3/4 anaemia and thrombocytopenia occurred more frequently with cisplatin/topotecan (38 versus 21% and 38 versus 23%, respectively)
- Study of Heigener et al. 24, increased haematological toxicity was observed with topotecan.
- Toxicity-related deaths was numerically higher with cisplatin/topotecan (5%) compared to EP (3%)
- Topotecan and etoposide was abandoned
- Due to an increased number of treatment-related deaths.
- erj.ersjournals.com/content/35/1/202
Amrubicin
Phase I and phase II trials (mainly in Japan) with amrubicin
- Synthetic anthracycline
- Randomised trials are currently recruiting patients in order to confirm these findings and to evaluate whether there is a role for amrubicin, in first-line therapy as well as in relapsed disease
- erj.ersjournals.com/content/35/1/202
Drugs Approved for Small Cell Lung Cancer
Afinitor (Everolimus)
Atezolizumab
Doxorubicin Hydrochloride
Durvalumab
Etopophos (Etoposide Phosphate)
Etoposide
Etoposide Phosphate
Everolimus
Hycamtin (Topotecan Hydrochloride)
Imfinzi (Durvalumab)
Lurbinectedin
Methotrexate Sodium
Nivolumab
Opdivo (Nivolumab)
Tecentriq (Atezolizumab)
Topotecan Hydrochloride
Trexall (Methotrexate Sodium)
Zepzelca (Lurbinectedin)
Ifosfamide + standard treatment with EP
- Led to higher response rates
- Modestly prolonged survival
- Cost of increased toxicity
- Insufficient data to justify the addition of a third or even fourth drug to the platinum–etoposide backbone for ES-SCLC.
- erj.ersjournals.com/content/35/1/202
Verapamil + combined chemotherapy
- Overrides resistance in small cell lung cancer xenografts
- Ability of verapamil, a reverser of P-glycoprotein (Pgp)-related resistance
- Improve the efficacy of CyCAV combined chemotherapy (Cy, cyclophosphamide (CPA); C, cisplatin (CDDP); A, doxorubicin (ADM);V, etoposide (VP16)), as currently administered to SCLC patients at Institut Gustave-Roussy, France
Treatment of nude mice implanted with these tumours
- Pgp encoded by the MDR1 (multidrug resistance) gene is not the only mechanism for multidrug resistance (MDR)
- Not all drugs included in this regimen are recognised by Pgp
- Efficacy of the CyCAV regimen, associated with or without verapamil (given 24 h before CyCAV on days 1–5)
- Verapamil (25 mg/kg) improved the antitumour effect of CyCAV in mice bearing SCLC-6T, SCLC-41T and SCLC-75 tumours, although toxicity was observed.
- Verapamil modestly delayed the plasma clearance of ADM.
- Two daily injections of 10 mg/kg of verapamil, administered at a 3 h interval, proved to be effective
- The same total dose administered as a bolus was not
- Results indicate that the association of some reversers of MDR, including drugs possibly interacting with Pgp, might potentiate SCLC combined chemotherapy.
- www.sciencedirect.com/science/article/abs/pii/095980499500386W
Verapamil (VER) Enhances the Cytotoxic Effects of Docetaxel and Vinblastine Combined Therapy Against Non-Small Cell Lung Cancer Cell Lines
- Combination therapy reduced drug-induced up-regulation of mdr-1 significantly (p<0.05).
- VER with the drug combination increased P-gp expression (p<0.05).
- Data provide evidence showing combined therapy is a better approach to improve the efficacy of chemotherapy and decreasing drug resistance.
- www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0043-117895
