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1. Florida Atlantic University, Department of Chemistry and Biochemistry, Boca Raton, FL 33431
2. University of Texas Arlington, Department of Biology, Arlington, TX 76010
Academic Editor: Tatsuo Kanda
Received: January 31, 2019 | Accepted: May 10, 2019 | Published: May 14, 2019
OBM Hepatology and Gastroenterology 2019, Volume 3, Issue 2, doi:10.21926/obm.hg.1902019
Recommended citation: Carraher Jr. CE, Roner MR, Frank J, Slawek P, Mosca F, Shahi K, Moric-Johnson A, Miller L. Organotin Polymers for the Control of Pancreatic Cancer. OBM Hepatology and Gastroenterology 2019;3(2):10; doi:10.21926/obm.hg.1902019.
© 2019 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
Organotin compounds have been used for a variety of applications . For instance, organotin polyethers made by Carraher and coworkers are employed in the commercial production of poly(vinyl chloride) as thermal stabilizers allowing the construction of tubes and other PVC products [2,3]. More organotin compounds are available commercially than any other metal-containing organometallic . They have been known for over 80 years to inhibit cancer cell growth [4,5,6,7,8,9,10,11] and more organotin compounds have undergone testing as potential anticancer agents than any other single group of compounds .
Cancer is the leading cause of death globally [12,13]. In the USA pancreatic cancer is the fourth leading cause of death with about 32,000 new incidents yearly and about 170,000 globally. The treatment of pancreatic cancer is rarely successful as this disease typically metastasizes throughout the body prior to detection. Current therapies include surgery, radiation and chemotherapy. Standard chemotherapy for patients with locally contained cancer includes gemcitabine. Gemcitabine is employed to improve the quality of life through better pain control, shrinkage of tumor, and prolonged survival. The latest addition is the use of Abraxane, a protein-bound paclitaxel previously used with breast and lung cancer, with Gemcitabine offering a limited additional life expectancy to advanced pancreatic cancer patients [15,16,17,18,19].
The mechanism of action of organotin compounds towards cancer is not well understood but is believed to involve several biological sites including DNA [20,21,22]. This variety of biological activity, while more difficult to understand, may be positive since it allows for potential curtailment of cancer growth at several sites.
For our organotin polymers, activity is believed to occur by the entire chain rather through segments of the chain [20,21,22]. The ability to inhibit pancreatic cancer cell growth by dissolved organotin polymer chains remains for weeks and for some for over a month. The polymers are cytotoxic and cell death is by necrosis .
Synthesis occurs employing the interfacial polycondensation process developed by Morgan and co-workers at DuPont  and later by Carraher and co-workers [24,25,26]. Briefly, reaction occurs at room temperature using rapid stirring, about 18,000 rpm, about double the speed of a model airplane propeller. A commercial Waring blender is used with reaction occurring in a one-quart Kimax emulsifying jar fitted on top of the blender. The Lewis base is dissolved in water and this phase is added to the emulsifying jar. Stirring is begun and the second phase composed of a water-immiscible liquid such as heptane, containing the dissolved Lewis acid is rapidly added. Stirring is continued for 5 to 15 seconds. The polymer precipitates and is recovered, washed with water and the organic solvent to remove unreacted materials and byproducts.
The Lewis acid/base pair react with an activation energy of 10-20 kcal allowing for the rapid reaction. The other feature promoting rapid reaction is the rapid stirring in the emulsifying jar. The emulsifying jar promotes turbine mixing and the rapid stirring encourages interfacial surface formation since formed polymer is readily removed from the interface resulting in new interface formation. Compared with a static or slowly stirred system, for the system employed by us the interfacial surface area is increased about 10,000 times. For our reactions only reactants that are commercially available are employed.
The interfacial polycondensation system is used commercially to produce aramids (aromatic nylons) and polycarbonates. This combination of rapid reactions and using only commercially available reactants allows ready scale-up as well as easy reproducibility.
The overall reaction is referred to as a Lewis acid/base reaction with the Lewis acid being the organotin dichloride and the Lewis base being organic bases as amines, hydroxyls, and neutralized organic acids.
The two basic measures, EMs, typically used to evaluate the effectiveness and ability of drugs to inhibit cell growth inhibition are used in our studies. Briefly, one is simply the amount or effective concentration, EC, of test compound necessary to effect inhibition to some amount, typically 50%, EC50. The lower the EC50 the better, lower concentrations of the drug demonstrating antitumor activity and likely reduced damage to normal tissues versus higher drug concentrations. The second measure is the amount of drug needed to inhibit a standard cell line, generally the human healthy normal embryonic lung fibroblast given the NCI designation WI-38 and strain ATCC CCL-75 compared to the amount of drug needed to inhibit the studied cell line, here a pancreatic cancer cell line. This is simply the ratio of EC50 for the standard cell line divided by the EC50 for the pancreatic cancer test cell line. High CI values are preferred since they indicate a possible difference in toxicity between the healthy test cell line and the target cell line. Typically, CI50 values of 2 and greater are desired. A CI values of two signifies that the drug is twice as likely to kill the tumor cell as it is the normal cell at the indicated concentration. In our cases, while the measured CI values are for 50% inhibition, in fact inhibition occurs to 100% with a steep concentration verses cell death to 100% death occurring.
The two of the most widely used pancreatic cell lines are employed in our studies. These cell lines are AsPC-1 which is an adenocarcinoma pancreatic cell line and PANC-1 which is an epithelioid carcinoma pancreatic cell line [27,28]. About 95% of pancreatic cancers are exocrine pancreatic cancers (ductal adenocarcinoma). The AsPC-1 cell line is the usual cell line employed to mimic test drug behavior for this type of cancer.
The PANC-1 human pancreatic carcinoma is the second cell lines used by us. It is an epithelial-like cell line nuclear lysate employed as an in vitro model of non-endocrine pancreatic cancer for tumorigenicity studies. The PANC-1 cell line is estrogen receptor negative. The PANC-1 cells have a type B phenotype for glucose-6-phosphate dehydrogenase G6PD. It overexpresses the heregulin/human epidermal growth-factor receptor 2 (HER2/neu) oncogene present in 60%-70% of human pancreatic carcinomas.
Following presents selective results of our studies that illustrate important points. We have looked at about 500 organotin compounds for their ability to inhibit pancreatic cancer cell lines. Following briefly describes some generalizations of our results with respect to pancreatic cancer.
Of the various organotin compounds employed, those derived from the dibutyltin dichloride are most effective at inhibiting pancreatic cancer. Butyltin-containing monomers have been commercially used for over eighty years, and while they are quite toxic to bacteria, they are the least toxic organotin moiety to humans . It is widely used as a paint additive and in the treatment of materials subjected to both fresh and salt water . Thus, of the organotin moieties used in cancer studies, it is the best-most is known about it, most available, lowest cost, and lowest toxicity to us.
The following generalizations have been found.
First, the nature of the Lewis base is important in determining the EM. For instance, Table 1 contains results from structually similar bases, in this case the hormones diethylstilbestrol, DES, and dienestrol, DE. While structurally similar, the pancreatic evaluative values are very different.
Figure 1 Polymer repeat unit from DES (left) and dienestrol (right) where R1 represents simple chain extension.
Second, the nature of the Lewis acid is important in determining the evaluative values. Again, using the same Lewis base to illustrate that the nature of the Lewis acid is important, Table 1, the evaluative values are very different for the dibutyltin DES product compared to the dicyclohexyltin DES product.
A third generality is that the structural window for creating compounds with good evaluative values for pancreatic cancer is more limited compared with other cancers we have looked at including colon, breast and prostate cancers.
The fourth generalization is that the evaluative values are generally similar for the AsPC-1 and PAN-1 pancreatic cancer cell lines. This is consistent with the possibility that results from these cell lines will be decent indicators for other pancreatic cancers.
Finally, in general, the products containing the dibutyltin moiety compared to those containing other organotin moieties generally have better evaluative values.
For most of our efforts, we have tried to match the organotin dihalide with a Lewis base that exhibits biological activity itself hoping for a synergetic effect. Thus, we have tried a wide variety of Lewis bases such as known antibiotics as ampicillin  creating polymers that inhibit pancreatic cancer cell lines. Additional biologically active Lewis bases that inhibit pancreatic cancer include thiamine (vitamin B1) , dipicolinic , dicumarol , camphoric acid , 2-ketoglutaric acid , histamine , and salicylic acid . Recently we have included Lewis bases such as gabapentin  that themselves are able to bypass the brain blood barrier in hopes that the resulting organotin polymers can arrest the growth of tumors in the brain. The resulting polymers inhibit the pancreatic cancer test cell lines.
We have studied several polymers from Lewis bases that themselves do not show biological activity. These include a wide variety of diols including ethylene glycol, 1,6-hexanediol and triethylene glycol (Table 2). Many of these showed outstanding evaluative tumor measures. We do not know why they show such good tumor measures and are currently investigating them further. Further, we do not know why some compounds exhibit better activity than others. The variety of potential compounds is almost endless and we are continuing to try to understand more fully structure/property relationships so better potential drugs that exhibit good inhibition pancreatic cancer can be forthcoming.
Included in this group are a series of polymers derived from poly (ethylene glycol) (PEG; also called poly (ethylene oxide)). These formed the foundation for our efforts to create water soluble drugs. Some of these showed good inhibition of the tested pancreatic cancer test cell lines (Table 2). The EMs are similar for the water soluble and non-water soluble tested samples.
PEG, is non-toxic and currently employed in a number of medical-related treatments including as pill coatings and in many laxatives [46,47]. It is attached to materials to create water soluble materials. When attached to certain protein-medications they allow the drug a longer-activity with reduced toxicity 
We also found that organotin polyamines derived from the reaction of organotin dihalides with diamines exhibited good inhibition to the tested pancreatic cancer cell lines .
Figure 2 Synthesis of water-soluble organotin polymers from the reaction of PEG with dibutyltin dichloride.
Organotin polymers act as potentially important agents in the effort to successfully treat pancreatic cancer. A wide variety of organotin polymers show moderate to good inhibition of the tested human pancreatic cancer cell lines. Cell line testing has begun. Further studies continue that will solidify/modify/change many of the preliminary results cited here. Most of all, live animal testing must be carried out to validate the invitro cell line results with inhibiting cancer growth within living subjects. This is being planned.
All of the coauthors contributed to the proofing, literature review of the paper. They also contributed to the original studies.
No funding was provided for this review.
The authors declare no competing interest exists.