PROJECTS

Subcellular localization of cytotoxic drugs: fluorescence microscopy and flow cytometric analyses.
Nitrogen mustards are among the oldest alkylating agents used in the clinic in the treatment of leukemias and solid tumours. Despite their significant contribution to the clinical management of a great number of malignancies over the past 30 years, their precise mechanism of action remains elusive. Previous studies with 3H-labeled agents showed no evidence of specific subcellular localization of nitrogen mustards in viable cells. In order to determine the correlation between their subcellular localization and their antiproliferative properties, our laboratory has designed and synthesized a series of fluorescent-labeled conjugates for fluorescence microscopy and flow cytometric analyses. The results obtained from these studies inspired the design of more potent alkylating agents which are currently being tested against a variety of tumours in our laboratory.

The Combi-Targeting Concept
The “combi-targeting” approach initiated by the Cancer Drug Research Laboratory consists of synthesizing compounds that in addition to being inhibitors of oncoprotein on their own, can be hydrolyzed to generate a “daughter” inhibitor of the same or different oncoprotein (e. g. tyrosine kinase) and a cytotoxic species. These molecules termed “combi-molecules” (CM) are expected to show more sustained antitumour activities than their parent lead drugs alone in refractory tumour cells expressing the targeted oncoproteins.

Breast and Prostate carcinomas
Two major problems persist in the chemotherapy of advanced prostate and breast cancers: resistance to therapy and lack of selectivity of the current drugs. To circumvent these problems, cancer drug research has focused over the past 30 years on the development of multidrug combinations involving many different agents directed at multiple cellular targets. The toxicities associated with the multiple doses of different drugs (mostly non-targeted agents), constitute a major deterrent in their use in the therapy of cancer. We are now exploring a new avenue within the framework of a novel concept termed “Combi-Targeting approach” that seeks to develop single targeted-agents capable of further decomposing into multiple fragments directed at specific tumour markers in breast or prostate carcinomas.

Leukemia Research
The adult leukemias account for about 10% of all cancers and are a heterogenous group of diseases broadly divided into acute and chronic disorders. Acute lymphoblastic leukemia (ALL) and chronic mylogenous leukemia (CML) are clonal diseases affecting lymphoid progenitors in ALL and CLL. In ALL, it affects the pluripotent hematopoietic stem cells. ALL accounts for about 90% of the tumours in children. The therapy of these neoplastic diseases can be achieved by intensive chemotherapy in the acute forms of leukemia. Treatment of the chronic disorders are rarely curative and significant toxicities are often associated with the current therapies. Therefore, novel therapies for chronic leukemias are urgently needed. Our laboratory is developing new models for the selective targeting of leukemias expressing the abl oncogene, a tyrosine kinase directly associated with the etiology of CML.