Camptothecin analogs with enhanced activity against human breast cancer cells. II. Impact of the tumor pH gradient

  title={Camptothecin analogs with enhanced activity against human breast cancer cells. II. Impact of the tumor pH gradient},
  author={David J Adams and Miriam L. Wahl and James L. Flowers and Banalata Sen and Michael O Colvin and Mark W. Dewhirst and Govindarajan Manikumar and Mansukh C. Wani},
  journal={Cancer Chemotherapy and Pharmacology},
Human breast tumors often exist in an acidic and hypoxic microenvironment, which can promote resistance to radiation and chemotherapies. A tumor-selective pH gradient arises in these tumors which favors uptake and retention of drugs like camptothecin that are weak acids. We evaluated the effect of alkyl substitutions at the 7 position in seven CPTs with varying groups at the 10 position on modulation by acidic extracellular pH in three human breast cancer cell lines. Growth inhibition was… 

BACPTDP: a water-soluble camptothecin pro-drug with enhanced activity in hypoxic/acidic tumors

BACPT had superior antiproliferative activity compared to established drugs in monolayer cultures of human neuroblastoma and pancreatic tumor cell lines and in 3-dimensional histocultures of colon and primary ovarian cancer.

Camptothecin resistance in cancer: insights into the molecular mechanisms of a DNA-damaging drug.

The present review focuses on the cellular/ molecular aspects involved in resistance of tumor cells to camptothecins, including the potential role of cancer stem cells and deregulated miRNAs, and on the approaches proposed for overcoming resistance.

Acidic pH of Tumor Microenvironment Enhances Cytotoxicity of the Disulfiram/Cu2+ Complex to Breast and Colon Cancer Cells

Specific pH of tumor microenvironment enhances cytotoxicity of DSF/Cu2+ to breast and colon cancer cells and is associated with changes in cell metabolism, altered Akt kinase and NFκB activity and increased reactive oxygen species production.

Anticancer activities of genistein-topotecan combination in prostate cancer cells

Treatments involving genistein‐topotecan combination may prove to be an attractive alternative phytotherapy or adjuvant therapy for prostate cancer.

TQ-B3203, a potent proliferation inhibitor derived from camptothecin

Topoisomerase I targeted drug candidates with sophisticated liposolubility 7c showed excellent capacity of inhibiting cell proliferation with IC50 value at nanomolar level, and the potency was further confirmed in other human cancer cell lines superior to the positive reference irinotecan.

Tumor physiology and charge dynamics of anticancer drugs: implications for camptothecin-based drug development.

A model is presented to describe the charge dynamics of a new camptothecin analog and the impact on nuclear and mitochondrial mechanism(s) of action and the importance of integrating tumor physiology and charge dynamics into anticancer drug development.

Proton transport inhibitors as potentially selective anticancer drugs.

This reversed proton gradient is driven by a series of proton export mechanisms that underlie the initiation and progression of the neoplastic process and is likely to open new pathways towards the development of more effective and less toxic therapeutic measures for all malignant diseases.

Depletion of carbonic anhydrase IX abrogates hypoxia-induced overexpression of stanniocalcin-1 in triple negative breast cancer cells

Findings show that CAIX inhibitors at least partially act through blocking STC1 induction in BC cells and reveal a subgroup of BC patients, who potentially would benefit most from the treatment with CAix inhibitors.


A review of modern approaches in medicinal chemistry development of CPT, effective anticancer agent that targets topoisomerase I and also with their Clinical studies summarizes the mode of action, the structure-activity relationship (SAR), a list of C PT analogs and their biological action with detail clinical development.



Camptothecin analogues with enhanced antitumor activity at acidic pH

The results suggest that CPT-based drug development and resulting chemotherapy could benefit from evaluation of differential activity at acidic versus physiological pH, and analogues have been identified that could have improved therapeutic indices based on the pH gradient that selectively exists in human tumors.

The activity of camptothecin analogues is enhanced in histocultures of human tumors and human tumor xenografts by modulation of extracellular pH

Evaluation of anticancer drug activity in native-state histoculture supports the concept that pH modulation may be an important approach to improve the selectivity and antitumor effectiveness of camptothecin-based chemotherapy.

DNA topoisomerase I--targeted chemotherapy of human colon cancer in xenografts.

Unlike other anticancer drugs tested, 20(RS)-9-amino-camptothecin (9-AC) induced disease-free remissions and the overall drug toxicity was low and allowed for repeated courses of treatment.

Determinants of drug response in camptothecin-11-resistant glioma cell lines

At least two distinct mechanisms have been selected for the CPT-11-resistant cells, and the resistance of the enzyme itself to the effects of C PT-11 may be responsible for the resistance to the drug.

Enhancement of chemotherapy by manipulation of tumour pH

It is demonstrated that MCF-7 human breast cancer cells in vitro are more susceptible to doxorubicin toxicity at pH 7.4, compared to pH 6.8, the first in vivo demonstration of this important phenomenon.

Modulation of camptothecin analogs in the treatment of cancer: a review

Preclinical and clinical data is presented on CPT analogs that are already being used in clinical practice, or are currently in clinical development, as well as drugs that are still only developed in a preclinical setting.

New highly lipophilic camptothecin BNP1350 is an effective drug in experimental human cancer

BNP1350 shows a broad spectrum of activity in experimental human tumors and is a suitable candidate for oral treatment of cancer.

Mechanism of cross-resistance to a camptothecin analogue (CPT-11) in a human ovarian cancer cell line selected by cisplatin.

Results show that there is no clear relationship between GSH and resistance to CPT-11, and the decreased conversion of C PT-11 to SN-38 is considered to be the main cause of resistance toCPT- 11 in this cell line.

Regulation of intracellular pH in human melanoma: potential therapeutic implications.

Inhibitors of MCTs have great potential to improve the effectiveness of chemotherapeutic drugs that work best at low pHi, such as alkylating agents and platinum-containing compounds, and they should be selective for cells in an acidic tumor bed.